B Bai
email: bai@lal.in2p3.fr

A Faus-Golfe

Y Han

I Chaikovska

Z Zhou

Y Chi

K Oide

F Zimmermann

Optimized injector schemes for FCC-ee positron production

Keywords: FCC-ee, injector linac, positron yield, lattice design, beam tracking, optimization

Injectors and in particular the positron production systems are a crucial element in linear and circular colliders. The proposed FCC-ee injector linac accelerates both electrons and positrons up to 6 GeV in order to be injected into the Pre-Booster Ring (PBR) with a high intensity of 3.5 nC per bunch for the Z running mode. The current design baseline of the FCC-ee injector linac is based on the SuperKEKB scheme, in which the electron and the positron beams share the same linacs with a fixed target configuration on-axis hole for electron beam passage.

One of the main drawbacks of this scheme is the positron production efficiency at the exit of the injector linac. In order to achieve a better performance and a higher positron yield, in this paper we study different bypass injection options. Start-to-end design and optimization for beam production, acceleration and transport from the feeding electron source to the positron damping ring are also being presented.

Introduction

With the discovery of Higgs boson at LHC in 2012, there is an increasing interest in precision measurements of electroweak physics including the properties of Higgs boson, which pushes highluminosity and high-precision electron-positron collider studies. So far, CLIC [START_REF] Aicheler | A Multi-TeV Linear Collider Based on CLIC Technology: CLIC Conceptual Design Report[END_REF], ILC [START_REF] Behnke | [END_REF], CEPC [START_REF] Cepc Study Group | CEPC conceptual design report: Volume 1-accelerator[END_REF], and FCC-ee [START_REF]FCC-ee: The lepton collider: Future circular collider conceptual design report volume 2[END_REF] [START_REF]Update of the European Strategy for Particle Physics (Brochure)[END_REF] have been proposed as the possible future machines to explore the High Energy Physics (HEP) frontier.

Large numbers of electrons and positrons are required in such colliders. Electrons can be directly generated by either the photoelectric effect in an RF or a thermionic gun. Conversely, positrons are usually produced by bremsstrahlung in the process of electrons hitting the positron target. The positron yield, which means how many positrons can be generated and captured when one electron impinges on the target, is a crucial metric in this process.

The positron production schemes for electron-positron colliders including SLC, LEP, BEPC/BEPCII, KEKB/SuperKEKB, CEPC and FCC-ee, etc., are all based on the conventional In the case of the Future Circular electron-positron Collider (FCC-ee), 2.13 × 10 (3.5 nC) electrons and positrons per bunch are needed for the most demanding full filling of the Z running mode in the conceptual design report [START_REF]FCC-ee: The lepton collider: Future circular collider conceptual design report volume 2[END_REF]. The baseline selection for FCC-ee is based on the SuperKEKB positron production [START_REF] Akai | SuperKEKB collider[END_REF]. In this scheme, electron and positron bunches are sharing the same transfer lines and linacs with a fixed target configuration on-axis hole for electron beam passage. The main drawback of this scheme is the poor efficiency and flexibility. Recent

The baseline of FCC-ee positron production chain and new bypass options design

FCC-ee positron production chain baseline

The schematic layout of FCC-ee injector complex can be seen in Figure 1 [START_REF]FCC-ee: The lepton collider: Future circular collider conceptual design report volume 2[END_REF], where the injector linac is located at the bottom. The injector complex comprises two electron sources (6.5

nC RF gun and 10 nC thermionic gun), an electron/positron linac (for energies up to 6 GeV), a pre-booster synchrotron ring (PBR) (the existing Super Proton Synchrotron works as the PBR), accelerating from 6 to 20 GeV, and a full energy booster synchrotron ring (BR), integrated in the collider tunnel. We can see the details of the injector linac in Figure 2 (green color for electrons, red color for positrons and blue color for electrons to produce positrons). This 6 GeV linac accelerates both species (electrons and positrons) to obtain an intensity of 2.13 × 10 particles per bunch in the PBR. The positron beam is produced from electrons at the energy of 4.46 GeV. This model follows the SuperKEKB positron production scheme, in which the positron beam is generated by a 3.5 GeV, 10 nC per bunch electron beam. To improve the efficiency of this model where the positron target is fixed in the linac line and a high emittance positron beam shares the same linac with the low emittance electron beam when they come out of the positron target, novel injection designs for FCC-ee positron production chain have been proposed and their schematic layouts are respectively shown in Figures 3,4,5. The main idea of our design is to avoid large losses during transport and to increase the positron yield as much as possible. The only difference among those schemes is the bypass option.

Novel bypass options design

The dogleg scheme design is shown in Figure 3. As in the case of baseline, we use two guns as electron sources. One low emittance electron beam from RF gun will be directly accelerated by section 1, section 2 and section 3 linacs to 6 GeV and then be transferred into the PBR. The other electron beam from the second feeding source (can be an RF gun or a thermionic gun) is used for positron production, which shares section 1 and section 2 linacs with the first electron beam to 4.46 GeV, and then will be bypassed in the dogleg structure to hit the positron target to generate positrons. Afterwards, the produced positrons could be captured in an adiabatic matching device (AMD) with a flux concentrator (FC) and get primary acceleration to about 200 MeV in the capture linac with solenoidal focusing. After the capture system, to get pure positrons, a separator chicane is inserted to separate the mixture of positrons and secondary electrons from the target.

Next, the positron beam will gain 1.54 GeV energy in section 4 linac before being transferred back to the damping ring (DR) via the turnaround loop. Finally, after the beam cooling in the DR, the 1.54 GeV positron beam gains another 4.46 GeV through section 2 and section 3 linacs to 6 GeV before entering the PBR. Actually, this scheme is inspired by the SLC injector [START_REF] Erickson | SLC Design Handbook[END_REF]. The main differences between them are the energy of the electron beam dedicated to positron production and the turnaround loop for transferring positrons back to the DR. In the SLC, the electron beam energy at the positron target is 33 GeV, larger than that of our design (4.46 GeV), and the turnaround loop is just used for the transport of 200 MeV positrons. The optics design and start-toend tracking simulation of the dogleg scheme positron production chain is going to be described in chapter 3.

The chicane scheme design is shown in Figure 4: the electron beam not serving for positron production is bypassed by a chicane structure. The electron beam serving for positron production makes its way in a straight line. No section 3 linac is needed here. There are some similarities between this scheme and the CEPC baseline scheme [START_REF] Cepc Study Group | CEPC conceptual design report: Volume 1-accelerator[END_REF]. They all use a chicane bypass for the transport of the electron beam which is not serving for positron production, and the positron targets are all located in the direct line. An advantage is that an additional positron linac used in CEPC injector could be spared in our chicane scheme.

The arc scheme shown in Figure 5 is quite similar to the dogleg scheme. We use an arc to turn around the 4.46 GeV electron beam for the positron production, which has simpler structures than dogleg scheme. But in this case, the higher energy synchrotron radiation could be a concern.

The descriptions of these two scheme designs are separately presented in chapter 4 and 5.

Dogleg scheme optics design and start-to-end tracking simulation for FCC-ee positron production

The 4.46 GeV electron linac, first part of the whole system, whose parameters taken from FCC-ee CDR [START_REF]FCC-ee: The lepton collider: Future circular collider conceptual design report volume 2[END_REF], has been designed using the simulation tool -SAD [START_REF]Strategic Accelerator Design (SAD)[END_REF]. This is the starting point of the simulation of the whole positron production chain. For the design of the following bypass and after-positron target parts, MADX code [START_REF]Methodical Accelerator Design (MAD-X[END_REF] is used for beam optics design and PLACET code [START_REF] Schulte | PLACET: A program to simulate drive beams[END_REF] for beam tracking study. One hundred thousand macro particles per bunch have been tracked taking into account the impact of the wake fields and the coherent synchrotron radiation (CSR). The short-range wake fields formulas used for simulation here can be seen in reference [START_REF] Yokoya | Short-Range Wake Formulas for Infinite Periodic Pill-Box[END_REF].

The two proposed guns (6.5 nC RF and 10 nC thermionic), whose parameters are taken from FCC-ee CDR [START_REF]FCC-ee: The lepton collider: Future circular collider conceptual design report volume 2[END_REF] and SuperKEKB injector linac [START_REF] Satoh | Commissioning Status of SuperKEKB Injector Linac[END_REF] are listed in Table 2, have been respectively used as feeding electron sources for positron production. Performance comparisons between the two feeding electron sources also have been made and presented in Table 2.

Optics design for the dogleg scheme

The 4.46 GeV electron linac needs to be flexible enough to accelerate both the electron beams with different emittances and different energy spreads. We have recalculated the optics of the 4.46

GeV electron feeding linac (section 1 + section 2) for the two feeding electron sources. The optics studies of their transverse betatron functions are indicated in Figure 6(a), along with their beam envelope evolution. In this linac, electron beam will be accelerated to the energy of about 4.46

GeV in use of 2.856 GHz S-band accelerating structures with length of 3 m, accelerating gradient of 25 MV/m and aperture radius of 10 mm. The length of this linac is around 233 meters. 14.75 m -3 in the case of the 6.5 nC RF gun, while for the 10 nC thermionic gun, sextupoles are not necessary to be used given the beam's high emittance. The optics designs for both feeding electron beams are shown in Figure 6(b). The electron beam sizes , are constrained to be around 1 mm before positron production to avoid much high thermal effect on the positron target. Notice that in the situation of an RF gun, two triplet quadrupoles after the dogleg structure help to increase the beam size. The total length of the dogleg structure is 26 m.

The electron beam coming out of dogleg bypass will hit the positron target for positron production. The generated positrons will be collected in the capture system for later acceleration.

Detailed information can be found in reference [START_REF] Han | FCC-ee positron source[END_REF]. Two feeding electron sources (6.5 nC RF gun and 10 nC thermionic gun) have been simulated in this part and show almost no difference. Two kinds of positron targets have been simulated (Details are presented in Figure 11): conventional target (a thick amorphous tungsten target) and hybrid target (a crystal + an amorphous tungsten target) [START_REF] Artru | Advantages of axially aligned crystals used in positron production at future linear colliders[END_REF]. After the positron generation, an AMD is used to match the positron beam (with very large transverse divergence and energy spread) to the acceptance of the capture linac. In the capture linac, positrons will be accelerated approximately to about 200 MeV. Two operation modes, accelerating mode and decelerating mode in the first RF structure of the capture linac, also have been studied in order to find the best option for a good positron yield potentially. The specific study results of the output positron beam distribution of the capture system for different cases are going to be described in section 3.2, as shown in plot (a) of Figure 11.

In fact, apart from positrons, the beam coming out of the 200 MeV capture linac also contains photons (γ) and secondary electrons generated by the initial positron production process. To get pure positrons after the capture system, a separator chicane is located between the 200 MeV capture linac and the main 1.54 GeV positron linac to separate the mixture of positrons and secondary electrons. The design idea follows the electron/positron separator of SuperKEKB [START_REF] Kamitani | SuperKEKB positron source construction status[END_REF].

In Figure 7, the electron beam and positron beam will be deflected 6° off the longitudinal axis in symmetric directions. In the middle of the chicane, the positron beam passes 30 mm aside from the beam line axis to ensure no interactions with separated electron beam. Its optics can be seen in A turnaround loop has been designed to transfer the 1.54 GeV positron beam back into the damping ring for beam cooling. This is the final step of the whole design of dogleg scheme production chain. The 1.54 GeV positron beam with very high emittance needs to be cooled in the damping ring to meet the requirement of injection into the PBR. Given that the damping ring also can be used for low emittance electron beam cooling besides for positron beam, we locate it near section 1 (1.54 GeV) electron linac. Therefore, a turnaround loop is necessary to turn around the positron beam out of the section 4 linac. In our design, the turnaround arc is composed of two TBA (triple bend achromat) cells, shown in Figure 8 top plot (c), which is inspired by the CLIC Central Arc [START_REF] Aicheler | A Multi-TeV Linear Collider Based on CLIC Technology: CLIC Conceptual Design Report[END_REF]. The reason why we use TBA structure here is that the first-order transfer matrix value R56 (determining the relation between bunch length # and energy spread ΔE/E) can be easily controlled to adjust the longitudinal distribution. The TBA arc has been used to avoid bunch lengthening (R56=0). Quadrupoles are used for betatron manipulation and dispersion correction, and four pairs of sextupoles are used to limit the second-order transfer matrix values T166 and T266 to 0 for the correction of chromaticity with the k2 values of ±10 m -3 . The total length of the arc is 44.25 m.

The start-to-end optics design after positron target from separator chicane to turnaround loop arc is as shown in Figure 8. The total length of this area is 152.8 m.

Start-to-end tracking simulation for the dogleg scheme

The corresponding phase space and beam distributions for the two feeding electron sources (6.5 nC RF gun and 10 nC thermionic gun) at the end of the 4.46 GeV electron linac are shown in Figure 9(a) and 9(b).

Given the condition of the thermionic gun having higher beam intensity, larger beam size, larger energy spread and longer bunch length compared to those of RF gun, the resulting beam size near the low-energy end of the linac will exceed the aperture radius (10 mm) affected by transverse wake field, which causes about 10 % ~ 15 % beam loss in the current design of the 4.46

GeV linac. This can be seen from the vertical phase space y-y' of Figure 9(b). Meanwhile, in such a case, we set the RF phase of all cavities to -4° for an off-crest acceleration to decrease the energy spread between beam head and tail given the effect of longitudinal wake field, but this will of course slightly cut down the energy gain from 4.42 GeV to 4.4 GeV correspondingly. Wake fields have less impact on the electron beam from the RF gun, which can guarantee 100 % transmission without considering misalignments. The geometric transverse emittance of the thermionic electron beam at the end of the linac is , = 14/31 nm, respectively 1.5 times and 3 times larger compared to the theoretical , = 9.2 nm. And for the RF feeding electron beam, the emittance values , = 1.9/2.7 nm, are horizontally 1. As mentioned in the optics design of bypass above, the final beam size , is constrained to be around 1 mm. Although the transverse beam size x-y in Figure 9(d) looks a little weird due to the collective effects of transverse wake fields and small aperture of linac, the largest y is still

Offsets and misalignments Value [μm]

Injection beam offsets (h/v) 100

Cavity misalignments (h/v) 100

Quadrupole misalignments (h/v) 100

BPM misalignments (h/v) with regard to cavities 30 RF cavities and magnets are all misaligned according to a gaussian distribution with standard deviation *+, = 100 μm, as listed in Table 5; the RMS misalignments of BPMs are set to be 30 μm to perform better orbit steering (see reference [START_REF] Ogur | Layout and performance of the FCC-ee pre-injector chain[END_REF] for details); each simulation is a Monte Carlo simulation with 100 different random configurations, which are named machines here. From the left plot of Figure 10 (a), at least 82 % (5.33 nC, 3.33 × 10 ) of the electrons can still survive at the dogleg exit after orbit steering correction within 100 random machines' simulation in the RF gun case. For the simulation with the thermionic gun, about 8.5 nC (5.31 × 10 , 85 % of 10 nC) electrons could survive before hitting the positron target in ideal condition. However, only more than 5.5 nC (3.44 × 10 , 55 % of 10 nC) electrons per bunch can be used for positron production when considering the misalignments of optical elements, which can be seen from the right plot of Figure 10 (a). A more complete and accurate simulation on the imperfection correction remains to be studied further in the future. We also take coherent synchrotron radiation (CSR) into consideration, and the simulation result when the electron beam passes through the dogleg dipoles is shown in Figure 10 (b). The x-coordinate is the electron beam bunch length, and the y-coordinate is the beam energy change (unit: 10 -5 GeV/m) along the bunch length. There is almost no energy change along the bunch length considering the beam energy of 4.36 GeV, which

shows CSR has negligible influence on the electron beam distribution.

A summary of the performances of the two feeding electron beams before the positron target can be seen in Table 6. The final electron beam data of both feeding electron sources is # ≈ 1 mm, = 0.5 ~ 1 mm, = 0.5 ~ 1 mm and 01, 2 , 2 = 5 μrad, 3456 7, 2 , 2 =20 μ rad. The beam distribution before the positron damping ring (DR) can be seen from Figure 12(c), whose normalized emittance !, , is 7.12 mm, geometric transverse emittance , is 2.325 μ m, energy spread ΔE/E is 1 %, and bunch length # is about 2.2 mm. According to the FCC-ee CDR, the transverse emittance acceptance of the damping ring is 22.4 μm, the energy acceptance is ±7.8 % and the longitudinal acceptance is 14.7 mm, which leave a large margin for our tracking simulation.

The final accepted positron bunch intensity is about 7.8 × 10 before the DR without considering positron linac wake fields and misalignments, which meets the demand of 2.13 × 10 positron particles per bunch. The final positron yield before the positron DR is about 7.8 × 10 /(6.25 × 10 ) = 1.2 e + /e -. A realistic bunch intensity will be studied in the future with the experiments of test facilities for positron production.

Chicane scheme optics design and tracking simulation

Optics design for the chicane scheme

In the chicane scheme, the electron beam serving for positron production makes its way in a straight line. It directly impinges on the positron target for positron production when coming out of the 4.46 GeV electron linac (section 1 linac + section 2 linac). The optics design for the two feeding electron sources are similar as shown in Figure 6(a).

In this design, we try to constrain the 4.46 GeV output electron beam to be the same as that in the dogleg scheme. So, the optics design for the part after the positron target remains what it is in the dogleg scheme as presented in Figure 8.

Tracking simulation for the chicane scheme

The tracking simulation before the positron target is similar as Figures 9(a), 9(b). The tracking result after the positron target is almost the same as shown in Figure 12.

For the low emittance electron beam coming out of the chicane structure, its phase space is shown in Figure 14.

Arc scheme optics design and tracking simulation

The part before the positron target in the arc scheme consists of a 4.46 GeV electron linac and a turnaround arc. Its optics can be seen in Figure 15(a). For the arc structure, a double TBA has been used similar to the 1.54 GeV positron turnaround loop in the dogleg scheme and chicane scheme. Each dipole produces a 30° bend with a length of 4 m. The whole system is kept achromatic and isochronous in our initial design. However, considering the transverse emittance increase caused by wake fields, we leave a small non-zero value to R56 for the arc structure working as a bunch compressor to compress the beam length in order to decrease the transverse wake field effect, which can be seen in the longitudinal phase space in Figure 15

Comparisons and Conclusion

A short summary for the new optimized injector schemes for FCC-ee positron production is presented in Table 7.

Schemes

Figure 1 :Figure 2 :

 12 Figure 1: FCC-ee injector complex

Figure 3 :Figure 4 :Figure 5 :

 345 Figure 3: Dogleg scheme

(a) Left: 4 .Figure 6 :

 46 Figure 6: Optics design before the positron target in the dogleg scheme

Figure 8

 8 Figure 8 top plot (a). The total length of the separator chicane is 5.35 m.

Figure 7 :

 7 Figure 7: The schematic layout of the electron/positron separator chicane

Figure 8 :

 8 Figure 8: Optics design after the positron target: Top plot: betatron functions; Bottom plot: beam envelope evolution (This is for the 10 nC thermionic electron gun case, which is similar for the 6.5 nC RF electron gun case)

Figure 9 :

 9 Figure 9: Electron phase space before the positron target (The bunch heads are in opposite directions in longitudinal phase for SAD and PLACET)

  (a) Phase space at the 4.46 GeV electron linac exit using the 6.5 nC RF gun calculated by SAD (b) Phase space at the 4.46 GeV electron linac exit using the 10 nC thermionic gun calculated by SAD (c) Phase space at the dogleg bypass exit using the 6.5 nC RF gun calculated by PLACET (d) Phase space at the dogleg bypass exit using the 10 nC thermionic gun calculated by PLACET smaller than 10 mm, which is the aperture radius of the accelerating structure. Figure 9(c) x-y sizes are smaller than those in Figure 9 (d), but still they are around 1 mm.

( a )Figure 10 :

 a10 Figure 10: Error study of the dogleg scheme before the positron target

  (a) Longitudinal phase space for different cases of positron production in the end of the capture linac (b) Phase space of case 3 at the end of the positron capture linac

Figure 11 :

 11 Figure 11: Positron source: Phase space at the end of the 200MeV positron capture linac using a conventional target with the thermionic gun

Figure 12 (

 12 Figure 12(a), 12(b) and 12(c) separately shows the phase space of the positron beam tracking result at the end of the separator chicane, the 1.54 GeV positron linac and the turnaround loop.

Figure 12 :

 12 Figure 12: Phase space of the positron beam after the positron target

The 3 .

 3 5 nC (2.13 × 10 ) electron beam not serving for positron production will move in the chicane bypass, whose optics design can be seen in Figure 13. The horizontal distance between the middle of the chicane bypass and the straight positron production line is kept at 3 m for positron target shielding. The chicane is a symmetric structure constituted by four 2-meter-long 10° dipoles. Two pairs of sextupoles are used for chromaticity correction. The total length of the chicane is 53.6 m.

Figure 13 :

 13 Figure 13: Optics design of the chicane bypass calculated by MADX

Figure 14 :

 14 Figure 14: Phase space of 4.46 GeV 3.5 nC electron beam at the chicane bypass exit calculated by PLACET

Figure 15 :

 15 Figure 15: Phase space before the positron target in the arc scheme

2 ( 7 :

 27 SchemesBefore e + target After e + target Supplementary linac e + yield @ DR

Figure II: Dogleg scheme alternative 2 Figure III: Dogleg scheme alternative 3 Figure IV :

 23IV Figure II: Dogleg scheme alternative 2

Table 1 :

 1 Positron production in different colliders

	Target	Photons production way for pair creation	bremsstrahlung	bremsstrahlung	bremsstrahlung	oriented crystal (channeling)	bremsstrahlung	bremsstrahlung / oriented crystal (channeling)
	scheme	Target material	W74-Re26	W74-Re26	W	radiator (W) + converter (W74-Re26)	W	W74-Re26 / radiator (W) + converter (W74-Re26)
	Capture system	AMD*	QWT**	AMD	AMD	AMD	AMD
	Capture linac frequency [GHz]	2.856	2.999	2.856	1.999	2.860	1.999/2.856
	DR energy [GeV]	1.15	0.5	1.1	2.86	1.1	1.54
	e + yield @ injector exit	1.1	0.003	0.4	1	> 0.3	> 0.7
		*Adiabatic Matching Device
		**Quarter Wave Transformer
		***CLIC 380 GeV/ CLIC 3 TeV
		****6.5 nC RF Gun (or 10 nC thermionic gun)

Feeding e -source Q/bunch [nC] Injection E [MeV]

				ΔE/E	, [μm]	[mm]
	RF gun	6.5	11	1 %	13	1
	Thermionic gun	10	15	5.25 %	80	1.3

Table 2 :

 2 Feeding electron sources

Table 3 :

 3 Accelerating structures used in the Section 4 positron linac The total length of the linac is 99.9 m.

	Subsection LQ [m]	k [m -2 ]	βmax [m]	Lcell [m] Ncell	Einput [GeV]	Eoutput [GeV]	Linac structure
	1	0.3	±8.20	2	1.2	36	0.214	0.694	12 LAS + 6 Normal S-band
	2	0.4	±4.69	3	1.8	17	0.694	1.254	14 Normal S-band
	3	0.4	±3.22	4	2.4	8	1.254	1.564	8 Normal S-band

FODO lattice has been chosen for the 1.54 GeV linac optics design. Three different FODO subsections have been designed, whose focus-and-defocus-quad distance increases gradually. The detailed parameters are listed in Table

4

. 130 quadrupoles are used in the design, including 8 quadrupoles for matching between different subsections. The lattice design is presented in Figure 10

8 top plot (b).

Table 4 :

 4 Parameters of the three different FODO cells for the 1.54 GeV positron linac (section 4 linac) design

Table 5 :

 5 RMS misalignments for optical elements

Table 6 :

 6 Performances of the two feeding electron beams before the positron target

	Feeding e -source	Parameters	Before the e + target
		E [GeV]	4.39
		ΔE/E	0.5 %
	6.5 nC RF gun	Beam intensity [nC/bunch)] !, , [μm]	5.4 (8 5 9 : 3.38 × 10 ) 15.7/22.7* (ideal value: 13)
		# [mm]	0.94
		Transmission efficiency	> 82 %
		E [GeV]	4.36
		ΔE/E	0.69 %
	10 nC thermionic gun	Beam intensity [nC/bunch)] !, , [μm]	8.44 (8 5 9 : 5.28 × 10 ) 124/250* (ideal value: 80)
		# [mm]	0.97
		Transmission efficiency	> 55 %
	*Collective effects in consideration

Acknowledgement

The author would like to thank the China Scholarship Council (CSC) for the financial support to this work. Thanks to Dr. Robert Chehab for the fruitful discussion on positron targets. Special thanks to Prof. Kazuro Furukawa, Dr. Naoko Iida from KEK for providing SuperKEKB injector information, Dr. Salim Ogur from CERN for providing FCC-ee electron linac information and Dr. Andrea Latina from CERN for providing the CLIC information to us.

The dogleg scheme has the simplest bypass structure among the three cases, but we need an additional 1.54 GeV linac and a turnaround loop for the 1.54 GeV positron beam. The chicane scheme could spare us a 1.54 GeV linac, but a double-chicane structure system more complex than the dogleg is required. The arc scheme remains a simple solution even if the arc is longer than the turnaround loop options and the energy is higher suggesting that synchrotron radiation could be an issue. Meanwhile, an additional 1.54 GeV linac is also required in this scheme. The main objective of this paper is to increase the positron yield and its value before the DR could reach 1.2 e + /e -in the simulation of all three schemes if using a 10 nC thermionic electron gun as the feeding electron source. Furthermore, even in some of the cases (dogleg scheme and arc scheme) we need a supplementary linac, this could give us more possibilities with the design for such a large complex machine. Further studies using multi-bunches in a linac pulse instead of the current 2 bunches per pulse (see Table 1) is being considered. The method using higher energy incident electrons ( 6GeV, even 18.5 GeV, see reference [START_REF] Han | FCC-ee positron source[END_REF]) for positron production is in process too. More potential schemes of the injector linac for FCC-ee are summarized in Appendix A. The optics design of FCC-ee injector linac still remains valid for these cases although and more improvements could be made in the future.

Appendix A

Potential recommended modified schemes:


Mohammed Taouis
email: mohammed.taouis@universite-paris-saclay.fr

Yacir Benomar

Pr Mohammed Taouis

Is resistin the master link between inflammation and inflammation-related chronic diseases?

Resistin has been firstly discovered in mice and was identified as an adipose tissue-secreted hormone or adipokine linking obesity and insulin resistance. In humans, resistin has been characterized as a hormone expressed and secreted by Immune cells especially by macrophages, and was linked to many inflammatory responses including inflammation of adipose tissue due to macrophages' infiltration. Human and mouse resistin display sequence and structural similarities and also dissimilarities that could explain their different expression pattern. In mice, strong pieces of evidence clearly associated high resistin plasma levels to obesity and insulin resistance suggesting that resistin could play an important role in the onset and progression of obesity and insulin resistance via resistin-induced inflammation. In humans, the link between resistin and obesity/insulin resistance is still a matter of debate and needs more epidemiological studies. Also, resistin has been linked to other chronic diseases such as cardiovascular diseases and cancers where resistin has been proposed in many studies as a biological marker.

Introduction

Adipose tissue and especially white adipose tissue (WAT) plays a crucial role in the regulation of whole-body energy homeostasis by buffering circulating glucose as well as free fatty acids. Indeed, in the fasting state adipose tissue provides energy to the whole body whereas in over-nutrition it has an energy storage role due to its plasticity and its ability to store lipids and carbohydrates once transformed into triglycerides. Furthermore, WAT especially visceral adipose tissue presents a high secretory activity as evidenced by the fact that about 30% of WAT genes express secretory proteins named adipokines including hormones and adipocytokines [START_REF] Maeda | Analysis of an Expression Profile of Genes in the Human Adipose Tissue[END_REF] . Thus, WAT fully plays the role of an endocrine tissue that secretes a variety of adipokines acting through endocrine, autocrine, or paracrine mechanisms. The WAT secretome is highly complex and secreted adipokines could be subdivided into four groups: metabolic, pro-inflammatory, extracellular matrix, and promitogenic/pro-angiogenic adipokines [START_REF] Piya | Adipokine Inflammation and Insulin Resistance: The Role of Glucose, Lipids and Endotoxin[END_REF] . The secretion of most of these adipokines is modulated by metabolic environment conditions. Indeed, selected adipokines are secreted in response to acute or chronic over-feeding and others to energy restriction. Consequently, adipokines' secretion is modulated depending upon adipose tissue size either in physiological or pathophysiological states. Besides, increased adipose tissue size as in obesity is known to promote insulin resistance and type 2 diabetes, additionally both obesity and type 2 diabetes are associated to low grade inflammation. Despite numerous epidemiological studies linking obesity to type 2 diabetes, the underlying molecular mechanisms are not fully deciphered. In the present review we will focus on resistin, an adipokine, which has been described as a hormone linking obesity to insulin resistance mainly through inflammatory mechanisms.. Resistin, previously known as FIZZ3 or adipose tissue-specific secretory factor (ADSF), is a cysteine-rich polypeptide encoded by the RETN gene that has been first described by Steppan and collaborators [START_REF] Steppan | The Hormone Resistin Links Obesity to Diabetes[END_REF] through the screen for targets of thiazolidinediones (TZD) (insulin sensitizer drug used to treat type 2 diabetes) in WAT of mice. According to several studies in mice, high resistin plasma levels are linked to many dysfunctions such as the alteration of lipid and carbohydrate metabolisms, inflammation, and insulin resistance. In contrast, in humans the direct relationship between resistin circulating levels and insulin resistance is still a matter of debate. Besides, resistininduced inflammation is also implicated in many other chronic diseases including cardiovascular diseases and cancers. The differences between human and mouse resistin could be attributed to molecular structure, localization, and signaling. Here we will review these issues and highlight resistin implication in chronic diseases: metabolic disorders, cardiovascular diseases, and cancers.

Human and mouse resistin: sequences and distributions

Mouse resistin structure

Three groups have described and functionally characterized mouse resistin. Firstly, resistin has been identified as Found in Inflammatory Zone (FIZZ)3 which was linked to pulmonary inflammation [START_REF] Holcomb | FIZZ1, a Novel Cysteine-Rich Secreted Protein Associated with Pulmonary Inflammation, Defines a New Gene Family[END_REF] . Then a group reported the discovery of a target of the insulin sensitizers' thiazolidinediones (TZDs) that contributes to insulin resistance [START_REF] Steppan | The Hormone Resistin Links Obesity to Diabetes[END_REF] , and concomitantly Kim and collaborators reported the characterization of a serine/cysteine rich secretory protein, which they named Adipose tissue-specific Secretory Factor (ADSF) [START_REF] Steppan | The Hormone Resistin Links Obesity to Diabetes[END_REF][START_REF] Kim | A Cysteine-Rich Adipose Tissue-Specific Secretory Factor Inhibits Adipocyte Differentiation[END_REF] .

Mouse resistin is a 11-kiloDalton protein encoded by a gene named RETN located in chromosome 8A1. The polypeptide is produced as a precursor, which undergoes posttranslational cleavage to form a 94 amino acid mature protein before the elimination of a 20amino-acid signal sequence. Importantly, resistin exhibits five intra-chain disulfide bridges involving several cysteine (Cys) residues at 51-104, 63-103, 72-89, 74-91, and 78-93 positions. Thus, resistin contains 11 cysteine residues structured in a unique motif also found in other secreted growth factors [START_REF] Banerjee | Regulation of Fasted Blood Glucose by Resistin[END_REF] . The presence of these cysteine residues especially at the carboxyterminal of resistin permits the assembly of the globular domain of resistin monomer through the formation of these five disulfide bridges [START_REF] Patel | Disulfide-Dependent Multimeric Assembly of Resistin Family Hormones[END_REF] , the globular domain is thought to be the binding domain of resistin [START_REF] Lee | Adenylyl Cyclase-Associated Protein 1 Is a Receptor for Human Resistin and Mediates Inflammatory Actions of Human Monocytes[END_REF] . The secondary structure of resistin is organized as one α-helix and six β-sheets [START_REF] Patel | Disulfide-Dependent Multimeric Assembly of Resistin Family Hormones[END_REF] . The secondary structure of resistin driven by these cysteine residues appeared to be critical for the biological activity as well as tissue selectivity [START_REF] Codoñer-Franch | Resistin: Insulin Resistance to Malignancy[END_REF] . The structure of resistin allows the formation of oligomers through the disulfide-dependent multimeric assembly. Indeed, trimers and hexamers are the most predominant at the plasma levels, where trimers are thought to be the more biologically active form [START_REF] Patel | Disulfide-Dependent Multimeric Assembly of Resistin Family Hormones[END_REF] . However, the mechanisms involved in the oligomerization of resistin monomers are still unknown. Furthermore, resistin action could be also more complex than thought due to its potential interaction with other members of the resistin-like molecule (RELM) family that includes mouse RELMα and RELMβ as well as other proteins such as heparanase [START_REF] Novick | Heparanase Interacts with Resistin and Augments Its Activity[END_REF] .

Human resistin structure

The human resistin is a 12.5 -kilodalton protein is encoded by the RETN gene located on chromosome 19q13.3 that shares 59% identity with murine resistin [START_REF] Koerner | Adipocytokines: Leptin--the Classical, Resistin--the Controversical, Adiponectin--the Promising, and More to Come[END_REF][START_REF] Ghosh | The Genomic Organization of Mouse Resistin Reveals Major Differences from the Human Resistin: Functional Implications[END_REF] . Human resistin possesses a cysteine signature as its mouse counterpart. These cysteine residues allow as for mouse resistin the formation of oligomers with a molecular mass of 660 kDa and a trimer of 45 kDa that are found in human sera [START_REF] Gerber | Serum Resistin Levels of Obese and Lean Children and Adolescents: Biochemical Analysis and Clinical Relevance[END_REF] . It has been also reported that human resistin tends to form dimers and trimers involving most likely Cys22 [START_REF] Raghu | Dimerization of Human Recombinant Resistin Involves Covalent and Noncovalent Interactions[END_REF] . Similar to mouse resistin, human resistin mainly consists of a α-helical coiled-coil domain and possesses a cysteine residue at position 6, which is crucial for the oligomerization. Furthermore, it has been also reported that human resistin can form oligomers through covalent and non-covalent linkages [START_REF] Raghu | Dimerization of Human Recombinant Resistin Involves Covalent and Noncovalent Interactions[END_REF] . In contrast to mouse resistin, the predicted secondary structures of human resistin lack a βsheet jelly roll folding pattern and instead, it exhibits two β-sheets surrounded by α-helical domains [START_REF] Raghu | Dimerization of Human Recombinant Resistin Involves Covalent and Noncovalent Interactions[END_REF] . In humans, the trimers and the oligomers of resistin exhibit higher proinflammatory effects evidenced by increased secretion of inflammatory cytokines such TNFα, IL-1β IL-6, and IL-8 in human immune cells [START_REF] Filková | The Role of Resistin as a Regulator of Inflammation: Implications for Various Human Pathologies[END_REF] .

Resistin expression locations

The human and mouse resistin gene (RETN) expression patterns show clear distinctions; indeed, mouse RETN is mainly expressed by adipose tissue and exactly by adipocytes as evidenced by Northern blot analysis revealing resistin mRNA in white adipose tissue and adipocytes (Steppan) even though, using PCR, more recent findings reported RETN expression in other locations such as the hypothalamus [START_REF] Kim | Dominant Inhibitory Adipocyte-Specific Secretory Factor (ADSF)/Resistin Enhances Adipogenesis and Improves Insulin Sensitivity[END_REF] (change the reference). In contrast, human RETN is expressed in immune cells: macrophages, monocytes, and neutrophils [START_REF] Jang | Macrophage-Derived Human Resistin Is Induced in Multiple Helminth Infections and Promotes Inflammatory Monocytes and Increased Parasite Burden[END_REF] . Indeed, in human the expression pattern of RETN expression established by Taqman analysis revealed bone marrow and spleen as major site of expression [START_REF] Patel | Disulfide-Dependent Multimeric Assembly of Resistin Family Hormones[END_REF] . In addition during human monocyte-macrophage differentiation RETN expression was increased as evidenced Taqman analysis [START_REF] Patel | Disulfide-Dependent Multimeric Assembly of Resistin Family Hormones[END_REF] . Thus, according to these expression patterns both mouse and human resistins have been associated and linked to specific functions and roles that we will discuss in this review. Several studies reported that mouse resistin is produced during adipocyte differentiation and its circulating levels are high in mouse models of obesity and insulinresistance [START_REF] Steppan | The Current Biology of Resistin[END_REF] , and considered as the potential link between obesity and type 2diabetes [START_REF] Steppan | The Hormone Resistin Links Obesity to Diabetes[END_REF] . Furthermore, mice fed high-fat diet exhibited higher resistin levels, and leptin treatment reduced the resistin expression levels of genetically obese mice (ob/ob) due most likely to the decrease in body weight and the restoration of insulin responsiveness [START_REF] Rajala | Regulation of Resistin Expression and Circulating Levels in Obesity, Diabetes, and Fasting[END_REF] . In humans, resistin has been linked to obesity and type 2 diabetes diseases characterized by chronic low-grade inflammation resulting from macrophage infiltration of adipose tissue [START_REF] Patel | Resistin Is Expressed in Human Macrophages and Directly Regulated by PPAR Gamma Activators[END_REF][START_REF] Lumeng | Inflammatory Links between Obesity and Metabolic Disease[END_REF] .

The difference between human and mouse RETN expression patterns could be attributed to dissimilarities in gene sequences. At the amino acids and mRNA levels, mouse and human resistins respectively exhibit 59% and 64.4% identity [START_REF] Ghosh | The Genomic Organization of Mouse Resistin Reveals Major Differences from the Human Resistin: Functional Implications[END_REF] . At the genomic level, the mouse resistin genomic sequence only shares 46.7% identity with its human counterpart and also shows a longer sequence reaching nearly three times the human resistin genomic sequence.

Most importantly, mouse resistin genomic sequence carries at its 3' UTR region just after the stop codon an extra intron called intron X consisting of 2279 nucleotides in length, which is missing in human [START_REF] Ghosh | The Genomic Organization of Mouse Resistin Reveals Major Differences from the Human Resistin: Functional Implications[END_REF] .. Intron X could be of importance regarding the resistin expression pattern; indeed, this intron carries putative transcription factor binding sites such as PPAR/RXR heterodimer binding sites also called IntX-PPRE that binds PPAR/RXR-like protein factors present in differentiated adipocytes [START_REF] Ghosh | The Genomic Organization of Mouse Resistin Reveals Major Differences from the Human Resistin: Functional Implications[END_REF] , contributing most likely the downregulation of mouse resistin in response to TZDs known as PPARγ agonists [START_REF] Steppan | The Hormone Resistin Links Obesity to Diabetes[END_REF] . The presence of regulatory sequences in introns has been previously reported for various genes such as mouse major histocompatibility gene, human neuropeptide YY1 receptor gene, human S6 ribosomal protein gene, mouse α2u-globulins gene [START_REF] Jansa | A Novel Type of Retinoic Acid Response Element in the Second Intron of the Mouse H2Kb Gene Is Activated by the RAR/RXR Heterodimer[END_REF][START_REF] Marklund | Intron-Mediated Expression of the Human Neuropeptide Y Y1 Receptor[END_REF][START_REF] Antoine | Functional Characterization of Transcriptional Regulatory Elements in the Upstream Region and Intron 1 of the Human S6 Ribosomal Protein Gene[END_REF][START_REF] Wang | The Analysis of Regulatory Sequences Required for High Level Induction of Rat Alpha 2u-Globulin Gene Expression by Dexamethasone[END_REF] .

The human RETN gene contains adipogenic transcription factor C/EBPα binding sites similar to the mouse RETN gene [START_REF] Ghosh | The Genomic Organization of Mouse Resistin Reveals Major Differences from the Human Resistin: Functional Implications[END_REF] . Differences have been reported such as the presence of the Arg-Gly-Asp (RGD) motif in human resistin but not in its mouse counterpart. The RGD motif is known to mediate cell attachment and is found in other proteins as fibronectin [START_REF] Souza | Arginyl-Glycyl-Aspartic Acid (RGD): A Cell Adhesion Motif[END_REF] and integrins [START_REF] Buckley | RGD Peptides Induce Apoptosis by Direct Caspase-3 Activation[END_REF] .

Besides the primary expressing tissues of RETN gene, peripheral blood mononuclear cells, macrophages, and bone marrow in humans; [START_REF] Acquarone | Resistin: A Reappraisal[END_REF] , human RETN gene expression is also expressed to a less extent in the hypothalamus, the pituitary gland, gut epithelial cells, adrenal cells, skeletal muscle, pancreas, spleen, goblet cells, and synovial tissue [START_REF] Acquarone | Resistin: A Reappraisal[END_REF] . Importantly, whether human adipocytes have been described as non-resistin secreting cells, human adipose tissue produces resistin originated from resident non-adipocyte inflammatory cells [START_REF] Savage | Resistin / Fizz3 Expression in Relation to Obesity and Peroxisome Proliferator-Activated Receptor-Gamma Action in Humans[END_REF] .

The disparity between mouse and human resistin is also evidenced by differential regulation in response for example to TNFα where RETN expression is decreased in mouse adipocytes and increased in human monocytes [START_REF] Shojima | Humoral Regulation of Resistin Expression in 3T3-L1 and Mouse Adipose Cells[END_REF][START_REF] Nagaev | Resistin Gene Expression Is Downregulated in CD4(+) T Helper Lymphocytes and CD14(+) Monocytes in Rheumatoid Arthritis Responding to TNF-α Inhibition[END_REF] .

Resistin mechanisms of actions and targeted tissues

Here, we will discuss the signaling pathways activated by resistin with a special focus on the potential binding sites of resistin.

Resistin receptor (s)

The search for resistin receptors was based on the pro-inflammatory action of resistin, and in this context, several groups had described different potential resistin receptors.

Resistin binds to Toll-like receptor 4

Toll-like receptor 4 (TLR-4) belongs to the TLRs family that is activated by recognition of pathogen-associated molecular sequences such as lipopolysaccharides (LPS). Thus, TLRs are implicated in numerous intracellular mechanisms aiming to resist and reduce invading microorganisms in host cells. It is well established that LPS binds to TLR-4 at the cell surface to initiate TLR-4 signaling pathways through the interaction of TLR-4 with myeloid differentiation factor 2 (MD2) and the activation of human myeloid differentiation factor 88 (MyD88). This leads to the cytonuclear translocation of nuclear factor-kB (NF-kB). The activation of the TLR-4 signaling pathway initiates the overexpression and/or secretion of pro-inflammatory cytokines, proteolytic enzymes, and adhesion molecules [START_REF] Akashi-Takamura | Toll-like Receptors (TLRs) and Immune Disorders[END_REF][START_REF] Rallabhandi | Analysis of TLR4 Polymorphic Variants: New Insights into TLR4/MD-2/CD14 Stoichiometry, Structure, and Signaling[END_REF] . Tarkowski and collaborators showed that resistin was able to compete with LPS for TLR-4 and they show that resistin action on human leucocytes and cytokine production was completely abolished in the presence of TLR-4 antibodies [START_REF] Tarkowski | Resistin Competes with Lipopolysaccharide for Binding to Toll-like Receptor 4[END_REF] . The binding of resistin to TLR-4 has been functionally validated in HEK cells expressing TLR-4 where resistin was able to activate TLR-4 signaling pathways promoting NF-kb activation. Furthermore, resistin selectively binds to TLR-4 and, was unable to bind and activate TLR-2 [START_REF] Tarkowski | Resistin Competes with Lipopolysaccharide for Binding to Toll-like Receptor 4[END_REF] . More recently, we reported that resistin when chronically administered intracerebroventricularly (ICV) induces both inflammation and insulin resistance of the hypothalamus and peripheral tissues in a TLR-4 dependent manner, since resistin effects were abrogated in TLR-4 -/-mice [START_REF] Benomar | Central Resistin Overexposure Induces Insulin Resistance through Toll-like Receptor 4[END_REF] . The binding of resistin to TLR-4 has been evidenced by cross-linking experiments in neurons [START_REF] Benomar | Central Resistin Overexposure Induces Insulin Resistance through Toll-like Receptor 4[END_REF] .

Resistin binds to decorin

Decorin is a member of the small leucine-rich proteoglycan gene family that binds to many cellular components including matrix structural molecules and complexes. For example, decorin binds to collagens and growth factors especially those belonging to the transforming factor-β ligand superfamily [START_REF] Neill | Decorin: A Guardian from the Matrix[END_REF] . Furthermore, decorin also induced an anti-tumorigenic signal leading to the repression of tumor cell proliferation, survival, migration, and angiogenesis [START_REF] Neill | Decorin: A Guardian from the Matrix[END_REF] .

Decorin has been also found in adipose stromal cells (ASCs), these cells are considered mesenchymal progenitors in white adipose tissue. Interestingly, cleaved decorin (deltadecorin) has been identified in ASCs and the screen for delta-decorin-binding proteins identifies resistin as a potential ligand [START_REF] Daquinag | An Isoform of Decorin Is a Resistin Receptor on the Surface of Adipose Progenitor Cells[END_REF] . Indeed, the exposure of 3T3-L1 cells expressing delta-decorin to resistin increased cell proliferation and reduced lipid accumulation [START_REF] Daquinag | An Isoform of Decorin Is a Resistin Receptor on the Surface of Adipose Progenitor Cells[END_REF] . Thus, these authors attributed to resistin a role in adipocyte progenitors through the binding to delta-decorin [START_REF] Daquinag | An Isoform of Decorin Is a Resistin Receptor on the Surface of Adipose Progenitor Cells[END_REF] .

Resistin promotes Insulin-like growth factor 1 receptor (IGF-1R) activation.

Rheumatoid arthritis (RA) is characterized by leukocyte infiltration of synovial tissue leading to inflammation that promotes hyperplasia and pannus formation (abnormal layer of fibrovascular tissue). A special focus on different growth factors was assessed to understand the onset of the pathogenesis of RA. In this context, Bostrom and collaborators have described crosstalk between resistin and IGF-1 signaling pathways in RA [START_REF] Boström | Resistin and Insulin/Insulin-like Growth Factor Signaling in Rheumatoid Arthritis[END_REF] . These authors showed that low levels of IGF-1 and increased levels of resistin characterize RA synovia. Furthermore, the stimulation of human synovial fibroblasts with resistin in the absence of exogenous IGF-1 increased the phosphorylation of IGF-1 receptors (IGF1-R) activating then downstream pathways including the phosphorylation of Akt. However, authors did not mention whether human synovial fibroblasts secrete IGF-1 that could contribute to IGF-1R phosphorylation. Authors concluded that resistin uses IGF1-R pathway at least in RA synovia without showing direct binding of resistin to IGF1-R [START_REF] Boström | Resistin and Insulin/Insulin-like Growth Factor Signaling in Rheumatoid Arthritis[END_REF] ROR1 belongs to the tyrosine-kinase family of receptors [START_REF] Sánchez-Solana | Mouse Resistin Modulates Adipogenesis and Glucose Uptake in 3T3-L1 Preadipocytes through the ROR1 Receptor[END_REF] and possesses at the its extracellular domains three well-identified structures: an Ig-like domain located near the Nterminal end, a Frizzled (FZZ)l-like domain (rich in cysteine), and a Kringle (KR) domain (rich in cysteine). The intracellular region of ROR1 contains a conserved tyrosine kinase catalytic domain. ROR1 is implicated in osteogenesis as a co-receptor for WNT proteins [START_REF] Sánchez-Solana | Mouse Resistin Modulates Adipogenesis and Glucose Uptake in 3T3-L1 Preadipocytes through the ROR1 Receptor[END_REF] . Sanchez-Solana and collaborators showed that the effect of resistin on adipose tissue expansion could be mediated by ROR1. They showed that resistin interacts with specific domains of the extracellular region of the ROR1 receptor leading to the inhibition of ROR1 tyrosine phosphorylation modulating then MAP kinase pathway as well as Glut4 and Glut1 expression in 3T3-L1 cells [START_REF] Sánchez-Solana | Mouse Resistin Modulates Adipogenesis and Glucose Uptake in 3T3-L1 Preadipocytes through the ROR1 Receptor[END_REF] .

3.1.5 Resistin binds to adenylyl cyclase-associated protein 1.

ROR1 and decorin have been described as putative receptors for resistin, and no evidence concerning their implication in resistin-induced inflammation in human. More recently, the inflammatory actions of resistin in human monocytes were attributed to the binding of resistin to adenylyl cyclase-associated protein 1 (CAP1) [START_REF] Lee | Adenylyl Cyclase-Associated Protein 1 Is a Receptor for Human Resistin and Mediates Inflammatory Actions of Human Monocytes[END_REF] . CAP-1 has been described to be mainly associated with plasma membrane of human monocytes and involved in many cellular functions such as binding to actin, activation of adenylate cyclase activity, cytoskeleton organization and biogenesis, signal transduction, and the establishment and/or maintenance of cell polarity [START_REF] Wakeel | An Ehrlichia Chaffeensis Tandem Repeat Protein Interacts with Multiple Host Targets Involved in Cell Signaling, Transcriptional Regulation, and Vesicle Trafficking[END_REF] . Lee and collaborators reported that resistin binds to human monocyte CAP-1 initiating signaling cascade involving the up-regulation of cyclic AMP, protein kinase A leading to the activation of the pro-inflammatory NF-kB transcription factor [START_REF] Lee | Adenylyl Cyclase-Associated Protein 1 Is a Receptor for Human Resistin and Mediates Inflammatory Actions of Human Monocytes[END_REF] .

Resistin mechanisms of action

According to the previous reports concerning resistin binding sites, TLR-4 and CAP-1 are the only receptors that have been demonstrated to directly bind resistin to initiate proinflammatory responses both in humans and mouse [START_REF] Tarkowski | Resistin Competes with Lipopolysaccharide for Binding to Toll-like Receptor 4[END_REF][START_REF] Benomar | Central Resistin Overexposure Induces Insulin Resistance through Toll-like Receptor 4[END_REF] . Importantly, resistin interaction with CAP-1 seems to be specific to human monocytes, whereas resistin binding to TLR-4 seems to have a larger specter since this interaction has been reported in both human and mouse tissues (figure 1). Furthermore, most studies brought strong shreds of evidence that link resistin to inflammation both in humans and mice. In human macrophages, resistin induces the expression of pro-inflammatory cytokines as well as intracellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1). Also, human resistin promotes chemotaxis and the recruitment of leukocytes to inflamed tissues through the induction of chemokine (CCL2) and MCP-1 expression [START_REF] Filková | The Role of Resistin as a Regulator of Inflammation: Implications for Various Human Pathologies[END_REF][START_REF] Lehrke | An Inflammatory Cascade Leading to Hyperresistinemia in Humans[END_REF][START_REF] Burnett | Cross-Sectional Associations of Resistin, Coronary Heart Disease, and Insulin Resistance[END_REF] . Thus, the pro-inflammatory action of resistin in humans is mostly attributed to its release by monocytes and macrophages that infiltrated a variety of tissues and organs such as adipose tissue in obese patients. It has been also reported that resistin secretion by immune cells is activated by pro-inflammatory cytokines such as C-Reactive Protein (CRP), IL-6, IL-1, IL-12, and TNFα [START_REF] Filková | The Role of Resistin as a Regulator of Inflammation: Implications for Various Human Pathologies[END_REF][START_REF] Acquarone | Resistin: A Reappraisal[END_REF] . Furthermore, human resistin is predominantly expressed by peripheral blood mononuclear cells (PBMCs) and this expression augments when these cells differentiate to macrophages [START_REF] Park | Resistin in Rodents and Humans[END_REF] . Interestingly, as in mice, human resistin expression in macrophages is diminished in response to thiazolidinedione (TZD) drugs (antidiabetic drug improving insulin sensitivity through most likely the reduction of resistin-induced inflammation) associated to reduce resistin plasma levels [START_REF] Patel | Disulfide-Dependent Multimeric Assembly of Resistin Family Hormones[END_REF][START_REF] Lehrke | An Inflammatory Cascade Leading to Hyperresistinemia in Humans[END_REF] . Resistin has been also suggested to contribute to vascular smooth muscle proliferation in humans and mouse promoting the monocyte adhesion and infiltration into endothelial tissues [START_REF] Calabro | Resistin Promotes Smooth Muscle Cell Proliferation through Activation of Extracellular Signal-Regulated Kinase 1/2 and Phosphatidylinositol 3-Kinase Pathways[END_REF][START_REF] Verma | Resistin Promotes Endothelial Cell Activation: Further Evidence of Adipokine-Endothelial Interaction[END_REF][START_REF] Kougias | Adipocyte-Derived Cytokine Resistin Causes Endothelial Dysfunction of Porcine Coronary Arteries[END_REF][START_REF] Cho | Adipokine Resistin Is a Key Player to Modulate Monocytes, Endothelial Cells, and Smooth Muscle Cells, Leading to Progression of Atherosclerosis in Rabbit Carotid Artery[END_REF][START_REF] Hsu | Resistin Induces Monocyte-Endothelial Cell Adhesion by Increasing ICAM-1 and VCAM-1 Expression in Endothelial Cells via P38MAPK-Dependent Pathway[END_REF] . Besides, its expression by PBMCs in humans, resistin is also found in non-adipocyte stromal vascular fraction of WAT, atherosclerotic lesions, and fibrotic liver, evidencing that the primary sources of human resistin are macrophages that invade these inflamed tissues [START_REF] Fain | Resistin Release by Human Adipose Tissue Explants in Primary Culture[END_REF][START_REF] Bertolani | Resistin as an Intrahepatic Cytokine: Overexpression during Chronic Injury and Induction of Proinflammatory Actions in Hepatic Stellate Cells[END_REF][START_REF] Burnett | The Potential Role of Resistin in Atherogenesis[END_REF] .

In mice, resistin is mainly expressed in white adipose tissue and also in blood cells [START_REF] Steppan | The Hormone Resistin Links Obesity to Diabetes[END_REF] . Furthermore, it has been reported that mouse resistin is produced during adipocyte differentiation and its circulating levels are high in mouse models of obesity and insulinresistance [START_REF] Steppan | The Current Biology of Resistin[END_REF] . Indeed, mouse resistin is considered as the potential link between obesity and type 2diabetes [START_REF] Steppan | The Hormone Resistin Links Obesity to Diabetes[END_REF] .

Resistin initiates pro-inflammatory responses through different signaling pathways depending upon the targeted tissue. Indeed, in vascular smooth muscle cells (VSMCs), resistin induces the expression of cytokines and chemokines via the transcription factor NF-kB leading to the alteration of VSMCs functions [START_REF] Acquarone | Resistin: A Reappraisal[END_REF] . In PBMCs, resistin activates the cytoplasm-nuclear translocation of p65 and p50 NF-kB subunits activating the production of pro-inflammatory cytokines [START_REF] Bokarewa | Resistin, an Adipokine with Potent Proinflammatory Properties[END_REF] . Resistin is also involved in the regulation of bone remodeling through the activation of Nf-kB pathway known as a key regulator of osteoclastogenesis [START_REF] Thommesen | Expression and Regulation of Resistin in Osteoblasts and Osteoclasts Indicate a Role in Bone Metabolism[END_REF] . Resistin also induces inflammation through the activation of several MAP kinase pathways including p38, JNK, and ERK1/2 known to increase the expression of pro-inflammatory cytokines' expression [START_REF] Hsieh | Resistin-Induced Stromal Cell-Derived Factor-1 Expression through Toll-like Receptor 4 and Activation of P38 MAPK/ NFκB Signaling Pathway in Gastric Cancer Cells[END_REF] . Resistin/MAP kinase signaling pathway inhibits eNOS gene expression in VSMCs reducing then NO-dependent vasodilation leading to vascular dysfunctions increasing then the predisposition to thrombosis, angiogenesis, and cell adhesion [START_REF] Chen | Resistin Decreases Expression of Endothelial Nitric Oxide Synthase through Oxidative Stress in Human Coronary Artery Endothelial Cells[END_REF] . Furthermore, resistin/MAP kinase pathways have been associated with the augmentation of VSMCs proliferation in human coronary artery promoting vascular diseases [START_REF] Chen | Resistin Decreases Expression of Endothelial Nitric Oxide Synthase through Oxidative Stress in Human Coronary Artery Endothelial Cells[END_REF] .

Furthermore, the resistin-induced insulin resistance has been largely documented implicating the alteration of insulin signaling pathways, this will be discussed later in the review.

Resistin and chronic diseases 4.1 Resistin in metabolic disorders (obesity and type 2 diabetes):

A class of anti-diabetic drugs called thiazolidinediones (TZDs) known to increase targettissues insulin sensitivity selectively bind to a nuclear receptor, abundant in adipocytes, called peroxisome proliferator activated receptor-γ (PPARγ). Indeed, patients carrying a dominant-negative PPARγ allele have severe insulin resistance. Besides, resistin has been identified as a target gene of TZD-bound PPARγ 3 as evidenced by its down-regulation in human macrophages following TZDs treatment [START_REF] Patel | Resistin Is Expressed in Human Macrophages and Directly Regulated by PPAR Gamma Activators[END_REF] . Furthermore, in mice, resistin plasma levels are positively correlated to obesity and insulin resistance, and resistin-treated mice or transgenic mice overexpressing resistin exhibit glucose intolerance and impaired hepatic insulin responsivenes [START_REF] Steppan | The Hormone Resistin Links Obesity to Diabetes[END_REF][START_REF] Rajala | Regulation of Resistin Expression and Circulating Levels in Obesity, Diabetes, and Fasting[END_REF][START_REF] Muse | Role of Resistin in Diet-Induced Hepatic Insulin Resistance[END_REF] . Resistin-induced insulin resistance has been also evidenced by the almost total recovery of insulin responsiveness of diet-induced obese mice following the treatment with resistin antibodies [START_REF] Steppan | The Hormone Resistin Links Obesity to Diabetes[END_REF] , and the knockdown or deletion of resistin in genetically obese mice ob/ob (lacking leptin gene) restored muscle and WAT insulin sensitivity, and increased hepatic insulin sensitivity of high fat diet mice [START_REF] Steppan | The Hormone Resistin Links Obesity to Diabetes[END_REF][START_REF] Banerjee | Regulation of Fasted Blood Glucose by Resistin[END_REF][START_REF] Qi | Loss of Resistin Improves Glucose Homeostasis in Leptin Deficiency[END_REF] . The implicated signaling pathways have been investigated, indeed, the resistin knock out mice exhibit a higher glucose tolerance with lower fasting glycaemia due in part to the activation of AMP kinase and reduced gluconeogenic enzymes in the liver [START_REF] Banerjee | Regulation of Fasted Blood Glucose by Resistin[END_REF] , associated to lower expression of the proinflammatory cytokine TNFα as well as lower phosphorylation level of JNK (cJun N-terminal kinase, a key MAP kinase involved in inflammatory response) in adipocytes [START_REF] Kim | Inverse Agonist of Nuclear Receptor ERRγ Mediates Antidiabetic Effect through Inhibition of Hepatic Gluconeogenesis[END_REF] . To further decipher implicated signaling pathways different cell models have been used, for instance resistin impaired insulin responsiveness and signaling in murine 3T3-L1 adipocytes, cardiomyocytes, and skeletal muscle cells [START_REF] Park | Resistin in Rodents and Humans[END_REF] ; and abolished insulin-induced IRS1/PI3kinase/Akt signaling pathways through increased phosphorylation of p38 and JNK that phosphorylate IRS1/2 on serine residues altering then insulin signaling [START_REF] Benomar | Central Resistin Overexposure Induces Insulin Resistance through Toll-like Receptor 4[END_REF] .

Besides its peripheral effects, different authors have suggested that resistin could also act directly within the brain, since resistin have been found in human cerebrospinal fluid indicating that it crosses the brain blood barrie [START_REF] Berghoff | Quantification and Regulation of the Adipokines Resistin and Progranulin in Human Cerebrospinal Fluid[END_REF] . In the same line of evidence in mice intracerebroventricular (ICV) infusion of resistin abolished insulin-dependent phosphorylation of insulin receptor, IRS-1/2, and Akt in the hypothalamus and peripheral tissues such as liver, muscle and WAT, concomitantly with the downregulation of adiponectin receptors in these tissues [START_REF] Benomar | Central Resistin Overexposure Induces Insulin Resistance through Toll-like Receptor 4[END_REF][START_REF] Benomar | Central Resistin/TLR4 Impairs Adiponectin Signaling, Contributing to Insulin and FGF21 Resistance[END_REF] . All these resistin effects were abolished in mice lacking TLR-4 [START_REF] Benomar | Central Resistin Overexposure Induces Insulin Resistance through Toll-like Receptor 4[END_REF] revealing that resistin mediates its effects through binding to TLR-4. Furthermore, central resistin impaired adiponectin signaling, an insulin-sensitizing hormone. Indeed, resistin ICV infusion downregulated APPL1, a key protein in adiponectin signaling, in the hypothalamus and liver contributing to insulin resistance [START_REF] Benomar | Central Resistin/TLR4 Impairs Adiponectin Signaling, Contributing to Insulin and FGF21 Resistance[END_REF] . Indeed, APPL1 interacts with Akt and blocks Akt association with its inhibitor TRB3, promoting insulin-dependent Akt activation evidencing the insulin sensitizer role of adiponectin [START_REF] Cheng | Signaling Mechanisms Underlying the Insulin-Sensitizing Effects of Adiponectin[END_REF] . Central resistin also increased plasma FGF-21 levels and down-regulated FGF-1 receptors in the hypothalamus and peripheral tissues leading to FGF-21 resistance amplifying then insulin resistance [START_REF] Benomar | Central Resistin/TLR4 Impairs Adiponectin Signaling, Contributing to Insulin and FGF21 Resistance[END_REF] . FGF-21 has several beneficial effects on insulin sensitivity and glucose and lipid metabolism. Indeed, FGF-21 is mainly produced by liver and promotes the expression of adiponectin by adipose tissue promoting then overall insulin responsiveness [START_REF] Benomar | Central Resistin/TLR4 Impairs Adiponectin Signaling, Contributing to Insulin and FGF21 Resistance[END_REF][START_REF] Woo | Fibroblast Growth Factor 21 as an Emerging Metabolic Regulator: Clinical Perspectives[END_REF] . The effects of resistin on adiponectin and FGF-21 signaling pathways are TLR-4 dependent as evidenced by the abrogation of resistin effects in TLR-4 knock out mice [START_REF] Benomar | Central Resistin/TLR4 Impairs Adiponectin Signaling, Contributing to Insulin and FGF21 Resistance[END_REF] .

In humans, obese patients exhibit a higher infiltration of macrophages into adipose tissue leading to increased resistin expression in adipose tissue associated with higher resistin plasma levels as compared to lean individuals [START_REF] Savage | Resistin / Fizz3 Expression in Relation to Obesity and Peroxisome Proliferator-Activated Receptor-Gamma Action in Humans[END_REF][START_REF] Park | Resistin in Rodents and Humans[END_REF][START_REF] Pagano | Increased Serum Resistin in Adults with Prader-Willi Syndrome Is Related to Obesity and Not to Insulin Resistance[END_REF] . However, in humans, the relationship between resistin plasma levels and insulin resistance is still matter of debate. Indeed, it has been reported that resistin plasma levels were positively correlated with insulin resistance in diabetic women and obese or overweight non-diabetic women [START_REF] Al-Harithy | Serum Resistin, Adiposity and Insulin Resistance in Saudi Women with Type 2 Diabetes Mellitus[END_REF] . Other studies reported higher circulating resistin in diabetic and obese non-diabetic patients 65 . A positive correlation between resistin plasma levels in obese diabetic Egyptian patients has been found but no correlation in obese non-diabetic groups [START_REF] Mabrouk | Serum Visfatin, Resistin and IL-18 in A Group of Egyptian Obese Diabetic and Non Diabetic Individuals. Egypt[END_REF] . Furthermore, other reports positively correlated plasma resistin levels to visceral, intrathoracic, and pericardial fat as reported in a crosssectional study [START_REF] Jain | Cross-Sectional Associations between Abdominal and Thoracic Adipose Tissue Compartments and Adiponectin and Resistin in the Framingham Heart Study[END_REF] . In contrast, other studies revealed no correlation between resistin and insulin resistance in obese individuals [START_REF] Bo | Relationships between Human Serum Resistin, Inflammatory Markers and Insulin Resistance[END_REF][START_REF] Mcternan | Resistin and Type 2 Diabetes: Regulation of Resistin Expression by Insulin and Rosiglitazone and the Effects of Recombinant Resistin on Lipid and Glucose Metabolism in Human Differentiated Adipocytes[END_REF][START_REF] De Luis | Lack of Association of Serum Resistin Levels with Metabolic Syndrome Criteria in Obese Female Patients[END_REF][START_REF] Lee | Circulating Resistin Levels Are Not Associated with Obesity or Insulin Resistance in Humans and Are Not Regulated by Fasting or Leptin Administration: Cross-Sectional and Interventional Studies in Normal, Insulin-Resistant, and Diabetic Subjects[END_REF][START_REF] Reilly | Resistin Is an Inflammatory Marker of Atherosclerosis in Humans[END_REF] , and obese subjects submitted to diet or bariatric surgery exhibited either reduced or not changed resistin plasma levels [START_REF] De Luis | Lack of Association of Serum Resistin Levels with Metabolic Syndrome Criteria in Obese Female Patients[END_REF][START_REF] Azuma | Correlation between Serum Resistin Level and Adiposity in Obese Individuals[END_REF][START_REF] Moschen | Effects of Weight Loss Induced by Bariatric Surgery on Hepatic Adipocytokine Expression[END_REF] . More recently, to address these discrepancies a systematic review and meta-analysis concluded that in type-2 diabetes and obese individuals, the resistin plasma levels were positively correlated with insulin resistance in patients exhibiting hyper-resistinemia, and no correlation was found in patients with normal resistin plasma levels [START_REF] Reilly | Resistin Is an Inflammatory Marker of Atherosclerosis in Humans[END_REF] . Besides, it has been also reported that high resistin plasma levels combined with low adiponectin plasma levels promote T2D in obese individuals [START_REF] Derosa | Adipose Tissue Dysfunction and Metabolic Disorders: Is It Possible to Predict Who Will Develop Type 2 Diabetes Mellitus? Role of MarkErs in the ProgreSsion of DIabeteS in Obese PaTIeNts (The RESISTIN Trial)[END_REF] . Furthermore, in pathologies known to contribute to T2D and to aggravate it such as non-alcoholic fatty liver disease (NAFLD), the liver resistin expression is higher as compared to the control group suggesting its potential Implication in the hepatic insulin resistance of patients with NAFDL [START_REF] Gierej | Expression of Resistin in the Liver of Patients with Non-Alcoholic Fatty Liver Disease[END_REF] .

Besides, epidemiological studies reported that variation of resistin plasma levels could be attributed to genetic factors [START_REF] Menzaghi | Heritability of Serum Resistin and Its Genetic Correlation with Insulin Resistance-Related Features in Nondiabetic Caucasians[END_REF] , a part of this variance is attributed to a single nucleotide polymorphism of the RETN gene -420C>G [START_REF] Menzaghi | Heritability of Serum Resistin and Its Genetic Correlation with Insulin Resistance-Related Features in Nondiabetic Caucasians[END_REF] . Other polymorphisms have been described in the promoter region of the human RETN gene, indeed the -638G>A, -420C>G, and -358G>A polymorphisms were associated with resistin plasma levels in Japanese obese patients [START_REF] Azuma | Correlation between Serum Resistin Level and Adiposity in Obese Individuals[END_REF] .

Interestingly, in the Japanese population, SNP -420 in the RETN gene was correlated to high resistin plasma levels associated with higher monocyte resistin expression and increased predisposition to T2D [START_REF] Osawa | Plasma Resistin, Associated with Single Nucleotide Polymorphism -420, Is Correlated with Insulin Resistance, Lower HDL Cholesterol, and High-Sensitivity C-Reactive Protein in the Japanese General Population[END_REF][START_REF] Osawa | Resistin SNP-420 Determines Its Monocyte MRNA and Serum Levels Inducing Type 2 Diabetes[END_REF] . However, in Caucasian populations such as in an Italian or American Caucasian cohorts -420 C/G SNP in RETN is not associated with changes with resistin plasma levels despite its association with obesity and metabolic disorders [START_REF] Norata | Effect of the -420C/G Variant of the Resistin Gene Promoter on Metabolic Syndrome, Obesity, Myocardial Infarction and Kidney Dysfunction[END_REF][START_REF] Hivert | Association of Variants in RETN with Plasma Resistin Levels and Diabetes-Related Traits in the Framingham Offspring Study[END_REF] .

Besides, in an Egyptian obese cohort, two SNPs of RETN (-420C/G and +299G/A) are significantly associated with high resistin plasma levels [START_REF] El-Shal | Association of Resistin Gene Polymorphisms with Insulin Resistance in Egyptian Obese Patients[END_REF] .

These discrepancies in these data generated from different cohorts might be attributed to ethnic differences and this increases the difficulties to establish a strong link between resistin and obesity/insulin resistance in humans.

Resistin and inflammation

Resistin plasma levels had been associated with many human diseases induced or aggravated by the inflammatory state. Indeed, elevated resistin levels have been associated with a high inflammatory state in patients with sepsis and acute pancreatitis [START_REF] Anderson | Innate Immunity Modulates Adipokines in Humans[END_REF][START_REF] Sundén-Cullberg | Pronounced Elevation of Resistin Correlates with Severity of Disease in Severe Sepsis and Septic Shock[END_REF][START_REF] Koch | Serum Resistin Levels in Critically Ill Patients Are Associated with Inflammation, Organ Dysfunction and Metabolism and May Predict Survival of Non-Septic Patients[END_REF][START_REF] Schäffler | Admission Resistin Levels Predict Peripancreatic Necrosis and Clinical Severity in Acute Pancreatitis[END_REF] . Also, elevated plasma resistin levels have been found in diseases characterized by low-grade inflammation such as T2D, coronary atherosclerosis, chronic kidney diseases, or rheumatologic disorders [START_REF] Lehrke | An Inflammatory Cascade Leading to Hyperresistinemia in Humans[END_REF][START_REF] Mcternan | Resistin and Type 2 Diabetes: Regulation of Resistin Expression by Insulin and Rosiglitazone and the Effects of Recombinant Resistin on Lipid and Glucose Metabolism in Human Differentiated Adipocytes[END_REF][START_REF] Reilly | Resistin Is an Inflammatory Marker of Atherosclerosis in Humans[END_REF][START_REF] Sundén-Cullberg | Pronounced Elevation of Resistin Correlates with Severity of Disease in Severe Sepsis and Septic Shock[END_REF][START_REF] Shetty | Circulating Adiponectin and Resistin Levels in Relation to Metabolic Factors, Inflammatory Markers, and Vascular Reactivity in Diabetic Patients and Subjects at Risk for Diabetes[END_REF] .. Increasing pieces of evidence are linking inflammation to cancer [START_REF] Singh | Inflammation and Cancer[END_REF][START_REF] Su | Resistin Facilitates VEGF-C-Associated Lymphangiogenesis by Inhibiting MiR-186 in Human Chondrosarcoma Cells[END_REF] , in this context many reports indicate that resistin-induced inflammation is a critical hallmark of cancer and its progression [START_REF] Dalamaga | Resistin as a Biomarker Linking Obesity and Inflammation to Cancer: Potential Clinical Perspectives[END_REF][START_REF] Wang | Resistin Facilitates Breast Cancer Progression via TLR4-Mediated Induction of Mesenchymal Phenotypes and Stemness Properties[END_REF][START_REF] Deshmukh | Resistin and Interleukin-6 Exhibit Racially-Disparate Expression in Breast Cancer Patients, Display Molecular Association and Promote Growth and Aggressiveness of Tumor Cells through STAT3 Activation[END_REF] . Importantly, experimental and epidemiological studies revealed the potential association between elevated resistin plasma levels and obesity-associated cancers [START_REF] Dalamaga | Resistin as a Biomarker Linking Obesity and Inflammation to Cancer: Potential Clinical Perspectives[END_REF][START_REF] Wong | Apoptosis in Cancer: From Pathogenesis to Treatment[END_REF] .

Despite the many pieces of evidence linking resistin to inflammation, it is still unclear whether an inflammatory environment is necessary for resistin secretion or whether resistin is necessary for inflammation onset. Thus, hyper-resistinemia could be a consequence of an initial inflammation, which in turn will be amplified by resistin. Further investigations are needed to establish the kinetic of resistin-induced inflammation to understand resistin and pro-inflammatory cytokines cross-talk.

Resistin and cardiovascular diseases (CVD)

Several studies reported that elevated resistin was causally linked to atherosclerosis, heart failure, and cardiac ischemic events [START_REF] Burnett | The Potential Role of Resistin in Atherogenesis[END_REF][START_REF] Reilly | Resistin Is an Inflammatory Marker of Atherosclerosis in Humans[END_REF][START_REF] Langheim | Increased Expression and Secretion of Resistin in Epicardial Adipose Tissue of Patients with Acute Coronary Syndrome[END_REF][START_REF] Pischon | Association of Plasma Resistin Levels with Coronary Heart Disease in Women[END_REF][START_REF] Ohmori | Associations between Serum Resistin Levels and Insulin Resistance, Inflammation, and Coronary Artery Disease[END_REF][START_REF] Tsukahara | Polymorphism in Resistin Promoter Region at -420 Determines the Serum Resistin Levels and May Be a Risk Marker of Stroke in Japanese Type 2 Diabetic Patients[END_REF] . Furthermore, elevated resistin was considered as a predictive marker of coronary atherosclerosis [START_REF] Ohmori | Associations between Serum Resistin Levels and Insulin Resistance, Inflammation, and Coronary Artery Disease[END_REF][100][101][102][103][104] and with myocardial infraction risk as well as cardiovascular diseases and all-cause mortality in T2D patients 105 . High resistin levels were also associated with hypertension in women without T2D 106 , and with the risk of cardiovascular diseases through resistin-induced inflammation 107,108 . Other studies suggested that resistin-induced cardiovascular disease could be independent of inflammation [START_REF] Muse | Role of Resistin in Diet-Induced Hepatic Insulin Resistance[END_REF] . Thus, further clinical investigations are needed to establish the mechanism by which resistin induces directly or indirectly cardiovascular diseases.

Besides, many animal or cell studies aiming to decipher the molecular mechanisms underlying resistin-induced cardiovascular diseases link cardiovascular diseases to elevated resistin. In this line of evidence, resistin overexpression in rat cardiomyocytes reduced cell contractility affecting then contraction/relaxation velocities [START_REF] Burnett | The Potential Role of Resistin in Atherogenesis[END_REF] , which promoted cardiac hypertrophy 109,110 . It has been also reported that human resistin impaired glucose uptake in isolated mouse cardiomyocytes 111 that could increase the severity of heart failure 112 .

Importantly, the deleterious effects of elevated resistin could be also secondary to the alteration of metabolic markers known to promote cardiovascular diseases. Elevated resistin levels have been positively correlated to plasma levels of triglycerides and apolipoprotein B, and negatively correlated to high-density lipoprotein (HDL) 113 , but other studies reported a positive correlation between resistin and HDL cholesterol known to be anti-atherosclerotic 114 .

However, major studies reported negative impact of resistin on cardiovascular functions as also evidenced by resistin-induced atherosclerotic plaques known to damage blood vessels increasing thrombosis risk [START_REF] Filková | The Role of Resistin as a Regulator of Inflammation: Implications for Various Human Pathologies[END_REF]116 .

At the mechanistic levels, resistin promotes the down-regulation of LDL receptors through the activation of PCSK9 (Pro-protein Convertase Subtilisin/Kexin type 9) leading to hypercholesterolemia 117 ; and in the intima of vessels, increases ROS production and LDL accumulation and, also increases monocyte recruitment in the vessels. [START_REF] Codoñer-Franch | Resistin: Insulin Resistance to Malignancy[END_REF]118 . Resistin also augments the lipid accumulation in macrophages leading to foam cells 116,119 . Besides, resistin increases endothelin-1 (ET-1) secretion as well as VCAM1 and MCP-1, and on the other hand reduces the nitric oxide synthase; these events promote endothelial dysfunctions with a defect in vascular vessels contractility 116,118 . Elevated resistin plasma levels aggravated coronary artery diseases [120][121][122] suggesting that resistin plasma levels could be used as a marker of coronary artery disease as well as myocardial ischemia 123 .

Resistin and cancers

It is well established that cancer development and progression are associated with elevated systemic inflammation as well as organ inflammation 124 . It has been reported that in cancer patients, the resistin plasma levels are high 124 . Resistin promotes cancer cells' growth as it promotes prostate cancer cell proliferation via the activation of PI3K/Akt signaling pathway [START_REF] Deshmukh | Resistin and Interleukin-6 Exhibit Racially-Disparate Expression in Breast Cancer Patients, Display Molecular Association and Promote Growth and Aggressiveness of Tumor Cells through STAT3 Activation[END_REF][125][126][127] . Resistin also activates anti-apoptotic signaling pathways promoting tumor cell survival through the activation of Nf-kb and PI3k/Akt signaling pathways [START_REF] Wong | Apoptosis in Cancer: From Pathogenesis to Treatment[END_REF]128 . Other studies reported that resistin exerts its anti-apoptosis effects through the inhibition of caspase-3 and caspase-7 expression 129 . Also, resistin has been described as a promoter of cell invasion and metastasis of lung adenocarcinoma and interestingly this implicated the activation of TLR-4/Src/EGFR/PI3K/Nf-kb signaling pathway 130 . In breast cancer (BC) cells resistin through Src/PP2A/PKCa pathway activates ezrin, radixin, and moesin proteins known to promote migration and invasion 131 . Resistin-induced NF-kb, Akt, and ERK signaling pathways promote metastasis by facilitating the cell adhesion of hepatic carcinoma cells to endothelium and to increase invasion in various liver cancer lines 132,133 . Besides, resistin promotes pancreatic cancer progression through both CAP1 and TLR-4 by activating the STAT-3 signaling pathway 134 . Furthermore, many other studies reported that resistin promotes angiogenesis in various cancer cells through the expression of VGEF, MMP2 implicating different regulatory pathways including miR-186, miR-16-5p/PI3kinase/Akt, Erk1/2 pathways [START_REF] Su | Resistin Facilitates VEGF-C-Associated Lymphangiogenesis by Inhibiting MiR-186 in Human Chondrosarcoma Cells[END_REF]135,136 . Interestingly, resistin induces many factors involved in cancer therapeutic resistance such as KLF4 and Nanog promoting doxorubicin resistance, fatty acid synthase, and caveolin in myeloma promoting resistance to dacarbazine treatment. In the same line, resistin by down-regulating specific microRNAs such as let-7a, miR-200c, and miR-186 conferred resistance towards cisplatin-treatment in ovarian cancer cells 137 .

Taken together these data attribute to resistin an important role in the progression of several cancers through different mechanisms.

Conclusion

Resistin has emerged in recent years as a key inflammatory cytokine involved in many chronic diseases. In mice, resistin was initially identified as a link between obesity and insulin resistance as it is expressed by adipose tissue proportionally to fat size. This has been supported by many reports in mice using diet or genetic models. This role is still a matter of debate in humans. Indeed, several studies reported an association between resistin levels and obesity or insulin resistance and in other studies, no correlation was found. Furthermore, the epidemiological studies were performed in different countries and including different populations (different conditions of inclusion to the studies, lifestyle, ethnic origin, etc…).

Recent systemic review and meta-analysis revealed that in type 2 diabetes and obese individuals, resistin plasma levels were positively correlated to insulin resistance when subjects exhibited high resistin but not in subjects with normal resistinemia. The discrepancies between human and mouse resistin could be attributed to differences in genomic sequences as well as expression sites. Whether mouse resistin is mostly expressed by adipose tissue, human resistin is predominantly expressed in peripheral blood mononuclear cells with higher expression in macrophages. Despite these differences between human and mouse, there is a strong body of evidence demonstrating the potential role of resistin as a mediator between inflammations and many chronic diseases such as metabolic disorders, cardiovascular diseases, and cancers (figure 2). However, further studies are needed to decipher the complex underlying mechanisms by which resistin is implicated in the onset of these chronic diseases with a special focus on resistin signaling. Indeed, whether TLR-4 and CAP-1 receptors appear to be the most plausible initiators of resistin signaling cascade, however, more investigations are needed to understand where, when, and how these two receptors are implicated in resistin actions.

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3. 1 . 4

 14 Resistin binds to mouse receptor tyrosine kinase-like orphan receptor (ROR)1.

Figure 1 : 29 Figure 2 :

 1292 Figure 1: Comparison of resistin signaling pathways involving TLR-4 or CAP1.