The application of nanodiscs in membrane protein drug discovery & development and drug delivery.

The phospholipid bilayer nanodiscs (LNDs), as a rapidly-developing tool in recent years, provide a natural bio-memebrane environment to maintain the native conformation and functions of membrane proteins as well as a versatile delivery vehicle for a variety of hydrophobic and hydrophilic drugs. We have seen unprecedented advantages of phospholipid bilayer nanodiscs in membrane protein structure characterization, biochemical and physiological studies of membrane proteins, membrane environment studies, drug discovery & development, and drug delivery. Many previous reviews have been mainly focused on the advantages of nanodiscs in membrane protein researches, but few have touched upon the importance and potential application of nanodiscs in pharmaceutical industries. This review will provide general description of the structural characteristics, advantages, classification, and applications of phospholipid nanodiscs, with particular focus on nanodisc-enabled membrane protein drug discovery & development as well as drug delivery.

Activation of the γ-secretase/NICD-PXR/Notch pathway induces Taxol resistance in triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is currently the only subtype lacking efficient targeted therapies. Taxol is the primary chemotherapeutic agent for TNBC. However, Taxol resistance often develops in the treatment of TNBC patients, which importantly contributes to high mortality and poor prognosis in TNBC patients. Recent preclinical studies have shown that the inhibition of Notch pathway by γ-secretase inhibitors can slow down the progression of TNBC. Our studies in bioinformatic analysis of breast cancer patients and TNBC/Taxol cells in vitro showed that there was high correlation between the activation of Notch pathway and Taxol resistance in TNBC. Increased γ-secretase activity (by the overexpression of catalytic core PSEN-1) significantly reduced Taxol sensitivity of TNBC cells, and enhanced biological characteristics of malignancy in vitro, and tumour growth in vivo. Mechanistically, increased γ-secretase activity led to the accumulation of NICD in the nucleus, promoting the interaction between NICD and PXR to activate PXR, which triggered the transcription of PXR downstream associated drug resistance genes. Furthermore, we showed that pharmacological inhibition of γ-secretase with γ-secretase inhibitors (Nirogacestat and DAPT) can reverse Taxol resistance in vivo and in vitro. Our results for the first time demonstrate that the activation of γ -secretase/NCD-PXR/Notch pathway is one of important mechanisms to cause Taxol resistance in TNBC, and the blockades of this pathway may represent a new therapeutic strategy for overcoming Taxol resistance in TNBC.

The epidemiological and infectious characteristics of novel types of Coxiella burnetii co-infected with Coxiella-like microorganisms from Xuyi County, Jiangsu province, China.

Coxiella burnetii (C. burnetii) is the causative agent of Q fever, a type of zoonoses withwidespread distribution. In 2019, a case of Q fever was diagnosed by metagenomic next-generation sequencing (mNGS) method in Xuyi County (Jiangsu province, China). The seroprevalence of previous fever patients and the molecular epidemiology of Coxiella in wild hedgehogs and harbouring ticks around the confirmed patient were detected to reveal the genetic characteristics and pathogenicity of the Coxiella strains. Four of the 90 serum samples (4.44%) were positive for specific C. burnetii IgM antibody, suggesting that local humans are at risk of Q fever. The positive rates of C. burnetii in hedgehogs and ticks were 21.9% (7/32) and 70.5% (122/173), respectively. At least 3 strains of Coxiella were found prevalent in the investigated area, including one new genotype of pathogenic C. burnetii (XYHT29) and two non-pathogenic Coxiella-like organisms (XYHT19 and XYHT3). XYHT29 carried by ticks and wild hedgehogs successfully infected mice, imposing a potential threat to local humans. XYHT19, a novel Coxiella-like microorganism, was first discovered in the world to co-infect with C. burnetii in Haemaphysalis flava. The study provided significant epidemic information that could be used for prevention and control strategies against Q fever for local public health departments and medical institutions.

An ultrastable 1397-nm laser stabilized by a crystalline-coated room-temperature cavity.

State-of-the-art optical cavities are pivotal in pushing the envelope of laser frequency stability below 10-16. This is often achieved by extending the cavity length or cooling the system to cryogenic temperatures to reduce the thermal noise floor. In our study, we present a 30-cm-long cavity that operates at room temperature and is outfitted with crystalline coatings. The system has a predicted ultralow thermal noise floor of 4.4 × 10-17, comparable to what is observed in cryogenic silicon cavities. A 1397-nm laser is stabilized in this advanced cavity, and the stable frequency is then transferred to the clock transition in strontium optical lattice clocks via a frequency-doubling process. We have meticulously minimized and assessed the technical noise contributions through comparisons with an ultrastable reference laser that is locked to a commercially available 30-cm cavity. The frequency instability of the system is rigorously evaluated using a three-cornered-hat method. The results demonstrate that the laser frequency instability remains below 2 × 10-16 for averaging times ranging from 1 to 50 s. These findings underscore the significant potential of room-temperature cavities with crystalline coatings in high-precision metrology and pave the way for further improvements in optical lattice clocks.

Real-time coloration control of gallium-based strips through cold rolling.

Cold rolling has been used as a real-time surface oxidation control method to create colored strips on flexible substrates. By controlling the extrusion rate in real time, a variety of colored strips have been fabricated on Ga-based liquid metal (LM) strips. X-ray photoelectron spectroscopy (XPS) analysis shows that the surfaces of the colored strips, which were obtained through extrusion rate control of LM-Al, consist primarily of metal oxide composites, including Ga2O3, Ga2O, Al2O3, SnO2, and In2O3. The colors of the strip surfaces are directly correlated with the oxide film thickness. Additionally, these cold-rolled colored thin strips demonstrate high conductivity and have significant potential for use as conductive flexible components with indicator functions in the flexible electronics realm.

Homochiral Tetraphenylethene-Based Metal-Organic Frameworks with Circularly Polarized Luminescence for Enantioselective Recognition.

A pair of water-stable and highly porous homochiral fluorescent silver-organic framework enantiomers, namely, R-Ag-BPA-TPyPE (R-1) and S-Ag-BPA-TPyPE (S-1), had been prepared as enantioselective fluorescence sensors. Combining homochiral 1,1'-binaphthyl-2,2'-diyl hydrogen phosphate (BPA) with an AIE-based ligand tetrakis[4-(pyridin-4-yl)phenyl]ethene (TPyPE) in complexes R-1 and S-1 made them possess favorable circularly polarized luminescence (CPL) properties, and their CPL spectra were almost mirror images of each other. The luminescence dissymmetry factors (glum) are ±2.2 × 10-3 for R-1 and S-1, and the absolute fluorescence quantum yields (ΦFs) are 32.0% for R-1 and S-1, respectively. Complex R-1 could enantioselectively recognize two enantiomers of amino acids in water or DMF with high Stern-Volmer constants of 236-573 M-1 and enantioselectivity ratios of 1.40-1.78.

SHU9119 and MBP10 are biased ligands at the human melanocortin-4 receptor.

The melanocortin-4 receptor (MC4R), a G protein-coupled receptor, is critically involved in regulating energy homeostasis as well as modulation of reproduction and sexual function. Two peptide antagonists (SHU9119 and MBP10) were derived from the endogenous agonist α-melanocyte stimulating hormone. But their pharmacology at human MC4R is not fully understood. Herein, we performed detailed pharmacological studies of SHU9119 and MBP10 on wild-type (WT) and six naturally occurring constitutively active MC4Rs. Both ligands had no or negligible agonist activity in Gαs-cAMP signaling on WT MC4R, but stimulated extracellular signal-regulated kinases 1 and 2 (ERK1/2) activation on WT and mutant MC4Rs. Mechanistic studies revealed that SHU9119 and MBP10 stimulated ERK1/2 signaling of MC4R by different mechanisms, with SHU9119-stimulated ERK1/2 signaling mediated by phosphatidylinositol 3-kinase (PI3K) and MBP10-initiated ERK1/2 activation through PI3K and ß-arrestin. In summary, our studies demonstrated that SHU9119 and MBP10 were biased ligands for MC4R, preferentially activating ERK1/2 signaling through different mechanisms. SHU9119 acted as a biased ligand and MBP10 behaved as a biased allosteric modulator.

A new preparation method of covalent annular nanodiscs based on MTGase.

The preservation of the native conformation and functionality of membrane proteins has posed considerable challenges. While detergents and liposome reconstitution have been traditional approaches, nanodiscs (NDs) offer a promising solution by embedding membrane proteins in phospholipids encircled by an amphipathic helical protein MSP belt. Nevertheless, a drawback of commonly used NDs is their limited homogeneity and stability. In this study, we present a novel approach to construct covalent annular nanodiscs (cNDs) by leveraging microbial transglutaminase (MTGase) to catalyze isopeptide bond formation between the side chains of terminal amino acids, specifically Lysine (K) and Glutamine (Q). This methodology significantly enhances the homogeneity and stability of NDs. Characterization of cNDs and the assembly of membrane proteins within them validate the successful reconstitution of membrane proteins with improved homogeneity and stability. Our findings suggest that cNDs represent a more suitable tool for investigating interactions between membrane proteins and lipids, as well as for analyzing membrane protein structures.

Ultrahigh-reflective optical thin films prepared by reactive magnetron sputtering with RF-induced substrate bias.

Optical thin films with high-reflectivity (HR) are essential for applications in quantum precision measurements. In this work, we propose a coating technique based on reactive magnetron sputtering with RF-induced substrate bias to fabricate HR-optical thin films. First, atomically flat SiO2 and Ta2O5 layers have been demonstrated due to the assistance of radio-frequency plasma during the coating process. Second, a distributed Bragg reflector (DBR) mirror with an HR of ∼99.999 328% centered at 1397 nm has been realized. The DBR structure is air-H{LH}19-substrate, in which the L and H denote a single layer of SiO2 with a thickness of 237.8 nm and a single layer of Ta2O5 with a thickness of 171.6 nm, respectively. This novel coating method would facilitate the development of HR reflectors and promote their wide applications in precision measurements.

The CK1ε/SIAH1 axis regulates AXIN1 stability in colorectal cancer cells.

Casein kinase 1ε (CK1ε) and axis inhibitor 1 (AXIN1) are crucial components of the ß-catenin destruction complex in canonical Wnt signaling. CK1ε has been shown to interact with AXIN1, but its physiological function and role in tumorigenesis remain unknown. In this study, we found that CK1δ/ε inhibitors significantly enhanced AXIN1 protein level in colorectal cancer (CRC) cells through targeting CK1ε. Mechanistically, CK1ε promoted AXIN1 degradation by the ubiquitin-proteasome pathway by promoting the interaction of E3 ubiquitin-protein ligase SIAH1 with AXIN1. Genetic or pharmacological inhibition of CK1ε and knockdown of SIAH1 downregulated the expression of Wnt/ß-catenin-dependent genes, suppressed the viability of CRC cells, and restrained tumorigenesis and progression of CRC in vitro and in vivo. In summary, our results demonstrate that CK1ε exerted its oncogenic role in CRC occurrence and progression by regulating the stability of AXIN1. These findings reveal a novel mechanism by which CK1ε regulates the Wnt/ß-catenin signaling pathway and highlight the therapeutic potential of targeting the CK1ε/SIAH1 axis in CRC.

Transition from Flat-Band Localization to Anderson Localization in a One-Dimensional Tasaki Lattice.

We report an extensive experimental investigation on the transition from flat-band localization (FBL) to Anderson localization (AL) in a one-dimensional synthetic lattice in the momentum dimension. By driving multiple Bragg processes between designated momentum states, an effective one-dimensional Tasaki lattice is implemented with highly tunable parameters, including nearest-neighbor and next-nearest-neighbor coupling coefficients and onsite energy potentials. With that, a flat-band localization phase is realized and demonstrated via the evolution dynamics of the particle population over different momentum states. The localization effect is undermined when a moderate disorder is introduced to the onsite potential and restored under a strong disorder. We find clear signatures of the FBL-AL transition in the density profile evolution, the inverse participation ratio, and the von Neumann entropy, where good agreement is obtained with theoretical predictions.

Flexible Self-Supporting MOF-Based Bean Pod Cube Hollow Nanofibers for Ultralong Cycling and High Rate Na Storage.

Sodium-ion batteries (SIBs) have garnered significant attention due to their potential as an emerging energy storage solution. Tin sulfide (SnS) has emerged as a promising anode material for SIBs due to its impressive theoretical specific capacity of 1022 mA h g-1 and excellent electrical conductivity. However, its practical application has been hindered by issues such as large volume expansion, which adversely affects cycling stability and rate performance during the charge/discharge processes. In this study, a novel approach to address these issues by synthesizing the bean pod cube hollow metal-organic framework (MOF)-SnSx/NC@N-doped carbon nanofibers through a process involving electrospinning, PDA coating, and calcination. The Sn-MOF serves as a self-sacrificing template, facilitating the simultaneous dissociation of MOF and polymerization of dopamine, leading to the creation of hollow intermediates that retain tin components. Subsequent sulfidation results in the integration of the hollow MOF-SnSx/NC nanoparticles within 3D nitrogen-doped carbon nanofibers, forming the distinctive bean pod cube composite structure. This unique configuration effectively shortens the diffusion path and mitigates volume expansion for sodium ions, ultimately yielding an exceptional high rate performance of 130 mA h g-1 (10 A g-1) and an ultralong cycling performance of 328 mA h g-1 even after 3500 cycles (2 A g-1) as the anode for SIBs.

ISX9 loaded thermoresponsive nanoparticles for hair follicle regrowth.

There is a high demand for an optimal drug delivery system to treat androgenetic alopecia. Topical application of ISX9, which is a neurogenesis inducer, has been found to stimulate hair follicle (HF) regrowth by upregulating the Wnt/ß-catenin signaling pathway, an essential pathway involved in initiating HF growth and development. In the present study, a temperature-sensitive, biopolymer-based, biocompatible, and eco-friendly drug-delivery system was synthesized. This system comprised chitosan-grafted poly(glycidyl methacrylate-co-N-isopropyl acrylamide) (Poly(GMA-co-NIPAAm)@CS-PGNCS) as the shell component and PF127 as the core polymer. The hydrophobic nature of the PF127 block copolymer efficiently dissolved the partially water-soluble drug, ISX9, and the thermos-responsive shell polymer effectively released the drug at a definite skin temperature. The optimized spherical nanoparticles demonstrated the lowest critical solution temperature (LCST) at 32 ± 2 °C with a diameter of 100-250 nm, which delivered encapsulated ISX9 with greater precision than topical ISX9. In a series of in vivo experiments, we demonstrated that ISX9-coated TBNPs upregulated the expression of ß-catenin, active ß-catenin, Wnt target genes, stemness marker genes, proliferating cell nuclear antigen, HF stem cell markers, and HF markers including VEGF, TGF, and IGF-1 more effectively than topical ISX9. These results suggest that TBNPs could be employed as a platform for effective transdermal delivery of various hydrophobic drugs.

Black chokeberry (Aronia melanocarpa L.) polyphenols attenuate obesity-induced colonic inflammation by regulating gut microbiota and the TLR4/NF-κB signaling pathway in high fat diet-fed rats.

This study investigated the potential benefits of black chokeberry polyphenol (BCP) supplementation on lipopolysaccharide (LPS)-stimulated inflammatory response in RAW264.7 cells and obesity-induced colonic inflammation in a high fat diet (HFD)-fed rat model. Our findings demonstrated that BCP treatment effectively reduced the production of nitric oxide (NO) and pro-inflammatory cytokines (TNF-α, IL-1ß, IL-6, and MCP-1) in LPS-induced RAW264.7 cells and concurrently mitigated oxidative stress by modulating the levels of malondialdehyde (MDA), catalase (CAT), and glutathione peroxidase (GSH-Px) in a dose-dependent manner. Furthermore, BCP supplementation significantly ameliorated HFD-induced obesity, improved glucose tolerance, and reduced systemic inflammation in HFD-fed rats. Notably, BCP treatment suppressed the mRNA expression of pro-inflammatory cytokines and alleviated intestinal barrier dysfunction by regulating the mRNA and protein expression of key tight junction proteins (ZO-1, occludin, and claudin-1), thereby inhibiting colonic inflammation caused by the TLR4/NF-κB signaling pathway. Additionally, BCP treatment altered the composition and function of the gut microbiota, leading to an increase in the total content of short-chain fatty acids (SCFAs), particularly acetic acid, propionic acid, isobutyric acid, and butyric acid. Collectively, our results highlighted the potential of BCP supplementation as a promising prebiotic strategy for treating obesity-induced colonic inflammation.

Tracing COVID-19 drugs in the environment: Are we focusing on the right environmental compartment?

The Coronavirus Disease 2019 (COVID-19) pandemic led to over 770 million confirmed cases, straining public healthcare systems and necessitating extensive and prolonged use of synthetic chemical drugs around the globe for medical treatment and symptom relief. Concerns have arisen regarding the massive release of active pharmaceutical ingredients (APIs) and their metabolites into the environment, particularly through domestic sewage. While discussions surrounding this issue have primarily centered on their discharge into aquatic environments, particularly through treated effluent from municipal wastewater treatment plants (WWTPs), one often overlooked aspect is the terrestrial environment as a significant receptor of pharmaceutical-laden waste. This occurs through the disposal of sewage sludge, for instance, by applying biosolids to land or non-compliant disposal of sewage sludge, in addition to the routine disposal of expired and unused medications in municipal solid wastes. In this article, we surveyed sixteen approved pharmaceuticals for treating COVID-19 and bacterial co-infections, along with their primary metabolites. For this, we delved into their physiochemical properties, ecological toxicities, environmental persistence, and fate within municipal WWTPs. Emphasis was given on lipophilic substances with log Kow >3.0, which are more likely to be found in sewage sludge at significant factions (25.2%-75.0%) of their inputs in raw sewage and subsequently enter the terrestrial environment through land application of biosolids, e.g., 43% in the United States and as high as 96% in Ireland or non-compliant practices of sewage sludge disposal in developing communities, such as open dumping and land application without prior anaerobic digestion. The available evidence underscores the importance of adequately treating and disposing of sewage sludge before its final disposal or land application in an epidemic or pandemic scenario, as mismanaged sewage sludge could be a significant vector for releasing pharmaceutical compounds and their metabolites into the terrestrial environment.

G-Quadruplex/Hemin-Mediated Polarity-Switchable and Photocurrent-Amplified System for Escherichia coli O157:H7 Detection.

The contamination of food by pathogens is a serious problem in global food safety, and current methods of detection are costly, time-consuming, and cumbersome. Therefore, it is necessary to develop rapid, portable, and sensitive assays for foodborne pathogens. In addition, assays for foodborne pathogens must be resistant to interference resulting from the complex food matrix to prevent false positives and negatives. In this study, hemin and reduced graphene oxide-MoS2 sheets (GMS) were used to design a near-infrared (NIR)-responsive photoelectrochemical (PEC) aptasensor with target-induced photocurrent polarity switching based on a hairpin aptamer (Hp) with a G-quadruplex motif. A ready-to-use analytical device was developed by immobilizing GMS on the surface of a commercial screen-printed electrode, followed by the attachment of the aptamer. In the presence of Escherichia coli O157:H7, the binding sites of Hp with the G-quadruplex motif were opened and exposed to hemin, leading to the formation of a G-quadruplex/hemin DNAzyme. Crucially, after binding to hemin, the charge transfer pathway of GMS changes, resulting in a switch of the photocurrent polarity. Further, G-quadruplex/hemin DNAzyme enhanced the cathodic photocurrent, and the proposed sensor exhibited a wide linear range ((25.0-1.0) × 107 CFU/mL), a low limit of detection (2.0 CFU/mL), and good anti-interference performance. These findings expand the applications of NIR-responsive PEC materials and provide versatile PEC methods for detecting biological analytes, especially for food safety testing.

An integrated high-flux cold atomic beam source for strontium.

We present the design, construction, and characterization of an integrated cold atomic beam source for strontium (Sr), which is based on a compact Zeeman slower for slowing the thermal atomic beam and an atomic deflector for selecting the cold flux. By adopting arrays of permanent magnets to produce the magnetic fields of the slower and the deflector, we effectively reduce the system size and power compared to traditional systems with magnetic coils. After the slower cooling, one can employ additional transverse cooling in the radial direction and improve the atom collimation. The atomic deflectors employ two stages of two-dimensional magnetic-optical trapping (MOT) to deflect the cold flux, whose atomic speed is lower than 50 m/s, by 20° from the thermal atomic beam. We characterize the cold atomic beam flux of the source by measuring the loading rate of a three-dimensional MOT. The loading rates reach up to 109 atoms/s. The setup is compact, highly tunable, lightweight, and requires low electrical power, which addresses the challenge of reducing the complexity of building optical atomic clocks and quantum simulation devices based on Sr.

Scalable Multipartite Entanglement Created by Spin Exchange in an Optical Lattice.

Ultracold atoms in optical lattices form a competitive candidate for quantum computation owing to the excellent coherence properties, the highly parallel operations over spins, and the ultralow entropy achieved in qubit arrays. For this, a massive number of parallel entangled atom pairs have been realized in superlattices. However, the more formidable challenge is to scale up and detect multipartite entanglement, the basic resource for quantum computation, due to the lack of manipulations over local atomic spins in retroreflected bichromatic superlattices. In this Letter, we realize the functional building blocks in quantum-gate-based architecture by developing a cross-angle spin-dependent optical superlattice for implementing layers of quantum gates over moderately separated atoms incorporated with a quantum gas microscope for single-atom manipulation and detection. Bell states with a fidelity of 95.6(5)% and a lifetime of 2.20±0.13 s are prepared in parallel, and then connected to multipartite entangled states of one-dimensional ten-atom chains and two-dimensional plaquettes of 2×4 atoms. The multipartite entanglement is further verified with full bipartite nonseparability criteria. This offers a new platform toward scalable quantum computation and simulation.

Multi-Pleated Alkalized Ti3 C2 Tx MXene-Based Sandwich-Like Structure Composite Nanofibers for High-Performance Sodium/Lithium Storage.

The volume expansion of CoFe2 O4 anode poses a significant challenge in the commercial application of lithium/sodium-ion batteries (LIBs/SIBs). However, metal-organic-frameworks (MOF) offer superior construction of heterostructures with refined interfacial interactions and lower ion diffusion barriers in Li/Na storage. In this study, the CoFe2 O4 @carbon nanofibers derived from MOF are produced through electrospinning, in situ growth followed by calcination, which are then confined within an MXene-confined MOF-derived porous CoFe2 O4 @carbon composite architecture under alkali treatment. The CoFe2 O4 nanofibers anchor on the alkalized MXene that is decorated with the NaOH solution to form a multi-pleated structure. The sandwich-like structure of the composite effectively alleviates the volume expansion and shortens the Li/Na-ion diffusion path, which displays high capacity and outstanding rate performance as anode materials for LIBs/SIBs. As a consequence, the obtained CoFe2 O4 @carbon@alkalized MXene composite anode shows satisfied rate performance at current density of 10 A g-1 for LIBs (318 mAh·g-1 ) and 5 A g-1 for SIBs (149 mAh g-1 ). The excellent cycling performance is further demonstrated at a high current density, where it maintains a discharge capacity of 807 mAh g-1 at 2 A g-1 after 400 cycles for LIBs and 130 mAh g-1 at 1 A g-1 even after 1000 cycles for SIBs.

Hedgehog interacting protein as a circulating biomarker in women with obesity: a cross-sectional study and intervention studies.

BACKGROUND: Although a study found a significant increase in serum hedgehog interacting protein (HHIP) concentrations in impaired fasting blood glucose, impaired glucose tolerance and newly diagnosed T2DM patients, the variation in circulating HHIP levels in obese individuals remains unknown. PATIENTS AND METHODS: Gene Set Enrichment Analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis were used for differentially expressed genes and signal pathways. The study is comprised of a total of 452 young women, including 248 obese individuals and 204 controls. Circulating HHIP and Adipoq levels were determined with ELISA kits. Euglycemic-hyperinsulinemic clamps (EHC) and oral glucose tolerance test (OGTT) were conducted in every subject. 32 women were given metformin and 49 were given liraglutide treatment for 6 weeks. The study was registered with www.chictr.org.cn (ChiCTR2000032878 and ChiCTR1800019776). RESULTS: Obesity was significantly associated with the cAMP signal pathway, and HHIP was a secreted protein related to cAMP signalling, as determined by KEGG analysis. In this population-based cohort study, we found that the level of circulating HHIP was significantly elevated in obese women, and positively correlated with body mass index and blood glucose, blood lipid, insulin, homeostasis model assessment of insulin resistance, dehydroepiandrostenedione sulphate, and luteinizing hormone, while negatively correlated with M-value and Adipoq. Insulin resistance (IR) and ove™rweight/obesity were associated with the higher HHIP concentration. OGTT and EHC tests revealed that the levels of circulating HHIP were regulated by blood glucose but to a less extent by insulin. After therapy with metformin and liraglutide, circulating HHIP levels were decreased, whereas Adipoq levels increased significantly. CONCLUSIONS: Our findings support HHIP as a potential biomarker for predicting obesity and IR. In addition, drugs targeting HHIP may be a new strategy to treat obesity.