GDF15 is a major determinant of ketogenic diet-induced weight loss.

A ketogenic diet (KD) has been promoted as an obesity management diet, yet its underlying mechanism remains elusive. Here we show that KD reduces energy intake and body weight in humans, pigs, and mice, accompanied by elevated circulating growth differentiation factor 15 (GDF15). In GDF15- or its receptor GFRAL-deficient mice, these effects of KD disappeared, demonstrating an essential role of GDF15-GFRAL signaling in KD-mediated weight loss. Gdf15 mRNA level increases in hepatocytes upon KD feeding, and knockdown of Gdf15 by AAV8 abrogated the obesity management effect of KD in mice, corroborating a hepatic origin of GDF15 production. We show that KD activates hepatic PPARγ, which directly binds to the regulatory region of Gdf15, increasing its transcription and production. Hepatic Pparγ-knockout mice show low levels of plasma GDF15 and significantly diminished obesity management effects of KD, which could be restored by either hepatic Gdf15 overexpression or recombinant GDF15 administration. Collectively, our study reveals a previously unexplored GDF15-dependent mechanism underlying KD-mediated obesity management.

Hyperlactatemia in patients undergoing pulmonary endarterectomy with deep hypothermic circulatory arrest: Risk factors and its effects on the outcome.

INTRODUCTION: To determine the risk factors of hyperlactatemia in pulmonary endarterectomy (PEA) surgery and assess whether elevated blood lactate levels are associated with adverse outcomes. METHODS: In this retrospective observational study, a total of 111 consecutive patients who underwent PEA for chronic thromboembolic pulmonary hypertension at the XXX Hospital between December 2016 and January 2022 were included. We retrospectively evaluated arterial blood samples analyzed intraoperatively. The pre- and intraoperative risk factors for hyperlactatemia and the postoperative outcomes were recorded. RESULTS: Lactate levels gradually increased during surgery. The optimal cut-off lactate level for major postoperative complications, calculated using receiver operating characteristic analysis, was 7.0 mmol/L. Deep hypothermic circulatory arrest (DHCA) duration, nadir hematocrit, and preoperative pulmonary vascular resistance were risk factors for lactate levels >7 mmol/L. Moreover, the intraoperative peak lactate level during PEA under DHCA was found to be a statistically significant predictor of major complications being associated with longer mechanical ventilation time (r = 0.294; p = .003) and intensive care unit length of stay (r = 0.327; p = .001). CONCLUSIONS: Deep hypothermic circulatory arrest duration, nadir hematocrit, and preoperative pulmonary vascular resistance were associated with hyperlactatemia. Increased lactate levels were independent predictors of longer mechanical ventilation time, intensive care unit length of stay, and major complications.

Asymmetric [3 + 2] Photocycloaddition of ß-Keto Esters and Vinyl Azides by Dual Photoredox/Nickel Catalysis.

Photocatalytic [3 + 2] cycloadditions and control of stereochemistry have remained a substantial challenge, particularly in the context of heterocycle synthesis; sporadic successful examples have involved enantioselective [3 + 2] photocycloaddition between redox-active direct group-containing cyclopropanes and alkenes for creation of cyclopentanes. Herein, we report a cooperative catalytic system comprising a chiral nickel Lewis acid catalyst and an organic photocatalyst fueled by visible-light irradiation that allows for the hitherto elusive asymmetric [3 + 2] photocycloaddition of ß-keto esters with vinyl azides under redox-neutral conditions. This protocol enables highly enantioselective construction of polycyclic densely substituted 3,4-dihydro-2H-pyrrole heterocycles featuring two contiguous tetrasubstituted carbon stereocenters, including a useful chiral N,O-ketal motif that is not easily accessible with other catalytic methods. Mechanistic studies revealed that the overall reactivity relies on the seamless integration of dual roles of nickel catalysts by the catalytic formation of the substrate/Ni complex, assisting both photoredox event and enantioselective radical addition.

Open-channel microfluidic chip based on shape memory polymer for controllable liquid transport.

Open microfluidics has attracted increasing attention over the last decade because of its flexibility and simplicity with respect to cell culture and clinical diagnosis. However, traditional valves and pumps are difficult to integrate on open-channel microfluidic chips, in which a liquid is usually driven by capillary forces. Poor fluid control performance is a common drawback of open microfluidics. Herein, we proposed a method for controlling the liquid flow in open channels by controlling the continuous Laplace pressure induced by the deformation of the shape memory microstructures. The uniformly arranged cuboidal microcolumns in the open channels have magnetic/light dual responses, and the bending angle of the microcolumns can be controlled by adjusting Laplace pressure using near-infrared laser irradiation in a magnetic field. Laplace pressure and capillary force drove the liquid flow together, and the controllable fluid transport was realized by adjusting the hydrophilicity of the channel surface and the bending angle of the microcolumns. We demonstrated the controllability of the flow rate and the directional transport of water along a preset path. In addition, the start and stop of water transport were realized via local hydrophobic modification. The proposed strategy improves poor fluid control in traditional open systems and makes fluid flow highly controllable. We tried to extract and detect rhodamine B in tiny droplets on the open microfluidic chip, demonstrating the advantages of the proposed strategy in the separation and analysis of tiny samples.

Photothermal visual sensing of alkaline phosphatase based on the etching of Au@MnO2 core-shell nanoparticles.

Alkaline phosphatase (ALP), as a crucial enzyme involved in many physiological activities, is always used as one of the significant biomarkers in clinical diagnosis. Herein, a novel, simple, and effective photothermal quantitative method based on the etching of MnO2-coated gold nanoparticles (Au@MnO2 NPs) was established for ALP activity assay with a household thermometer-based visual readout. The photothermal effect of Au@MnO2 NPs is much higher than that of MnO2 NPs or Au NPs. The MnO2 shell of Au@MnO2 NPs can be etched by ascorbic acid, a product of ALP-catalyzed hydrolysis of 2-phospho-l-ascorbic acid. With the etching of Au@MnO2 NPs, the photothermal conversion efficiency decreased gradually, causing the decrease of the temperature increment of the solutions by degrees. A household thermometer, instead of large-scale and professional instruments, was used as a signal reader to realize the visual quantitative detection. The photothermal platform was used successfully for the determination of ALP with a wide linear range from 2.0 to 50 U/L and a detection limit as low as 0.75 U/L. Moreover, the inhibition efficiency of sodium vanadate for ALP activity was investigated, proving the photothermal quantitative method will be a potential platform for screening enzyme inhibitors. Such a sensitive, facile, and low-cost sensing assay provides a new prospect to develop platforms for point-of-care testing.

Taming Chiral Quaternary Stereocenters via Remote H-Bonding Stereoinduction in Palladium-Catalyzed (3+2) Cycloadditions.

Ring-opening transformations of donor-acceptor (D-A) cyclopropanes enable the rapid assembly of complex molecules. However, the enantioselective formation of chiral quaternary stereocenters using substrates bearing two different acceptors remains a challenge. Herein, we describe the first palladium-catalyzed highly diastereo- and enantioselective (3+2) cycloaddition of vinyl cyclopropanes bearing two different electron-withdrawing groups, a subset of D-A cyclopropanes. The key to the success of this reaction is the remote stereoinduction through hydrogen bond from chiral ligands, which thereby addressed the aforementioned challenge. A variety of chiral five-membered heterocycles were produced in good yields and with high stereoselectivity (up to 99 % yields, 99 : 1 er and >19 : 1 dr). In-depth mechanistic investigations, including control experiments and theoretical calculations, revealed the origin of the stereoselectivity and the importance of H-bonding in stereocontrol.

In-situ and amplification-free imaging of hERG ion channels at single-cell level using a unique core-molecule-shell-secondary antibody SERS nanoprobe.

Research on ion channels and their monoclonal antibodies plays a critical role in drug development and disease diagnosis. The current ion channel researches are often not conducted in the microenvironment for cells survival, which restricts the mechanism study of the links between the cell structure and the ion channel function. In this work, we synthesized gold core-4-mercaptobenzonitrile-sliver shell-goat anti-rabbit immunoglobulin G (Au@4-MBN@Ag@IgG) nanoparticles as surface-enhanced Raman scattering (SERS) nanoprobes for investigating the human ether-a-go-go related gene (hERG) potassium ion channel in cell membranes. This is the first attempt to study ion channels using SERS. Due to the unique core-molecule-shell structure and the silver shell of nanoprobes, strong and stable SERS signal was obtained. With the help of antibodies, the Au@4-MBN@Ag@IgG nanoprobes were captured by hERG antibodies and then bonded with hERG ion channels based on the sandwich immune response. The reporter molecule, 4-MBN, displayed a strong and sharp characteristic peak at 2233 cm-1 in the Raman silent region. The intensity of this peak denoted the concentration of antibodies and the expression of ion channel proteins. We successfully applied this amplification-free method for in-situ imaging the distribution of the hERG ion channel on the transfected HEK293 cell surface at the single-cell level. This hERG ion channel profiling strategy promises a maneuverable tool for ion channel research.

The association between heart failure and risk of fractures: Pool analysis comprising 260,410 participants.

Background: HF and osteoporosis shared many common etiological risk factors. However, studies exploring whether patients with HF were associated with a higher risk of osteoporotic fracture resulted in inconsistent findings. This meta-analysis aimed to summarize the association between HF and the risk of incident fracture. Methods: Following the Meta-analysis of Observational Studies in Epidemiology group recommendations, we searched multiple electronic databases (PubMed, Cochran Library, and EMBASE) for related studies from inception to April 30, 2021. Studies evaluating the risk of incident fracture in patients with HF compared with those without HF were included for analysis. The random-effects models were used to combine the estimated hazard ratios (HRs) of incident fracture associated with HF. Results: We included 8 observational studies for meta-analysis. The sample size ranged from 5,613 to 87,748 participants, with a total of 260,410 participants included. The median follow-up duration was 5.0 years. Random-effects model analyses showed that compared with control groups, patients with HF were associated with a higher risk of all incident fractures (HR = 1.67, 95% CI = 1.30-2.16, P < 0.001) and hip fracture (HR = 2.20, 95% CI = 1.28-3.77, P < 0.001). The risk of all incident fractures was increased in all subgroup analyses according to age, sample size, sex, and follow-up duration. Conclusions: Patients with HF were associated with a higher risk of incident fracture, as well as hip fracture.

Analysis of two naval pilots' ejection injuries: Two case reports.

BACKGROUND: Recently, two naval pilots in a two-seat trainer jet were forced to eject urgently due to sudden mechanical failure during night-time training. They were both successfully rescued and sent to the hospital for emergency treatment. In this study, we investigate their ejection injuries and recovery process. CASE SUMMARY: We analyzed the clinical data of the traumatic condition and recovery process from ejection injuries of two pilots who ejected from a failed trainer jet and survived. After being successfully rescued and sent to the hospital, they were diagnosed with multiple ejection injuries, including eye trauma, limb bone and joint injury, rib and spine injury, and so on. Both cases underwent fluid replacement, acid suppression, nutritional support, hemostasis, bone metabolism improvement, phlegm elimination, psychological measurement, blood circulation promotion and detumescence, physical therapy, and external fixation with braces for 1 mo before being discharged from hospital. They then recuperated in a sanatorium for 2 mo, and the related laboratory tests and supplementary examinations show that they recovered from all the above injuries. After successfully passing the psychological test and physical examination, they returned to flight duty 3 mo after ejection. CONCLUSION: The causes and conditions of ejection injury in the pilots were very complex. Although they finally recovered quickly and were released, it also serves as a reminder that attention should be paid to pilots' ejection and parachute training in order to significantly reduce ejection injury and improve the ejection success rate. In addition, air defense support personnel should strengthen search and rescue and on-site emergency measures, and locate and rescue pilots in distress as early as possible to reduce subsequent injuries.

A nanohybrid of Prussian blue supported by boracic acid-modified g-C3N4 for Raman recognition of cell surface sialic acid and photothermal/photodynamic therapy.

Theranostic nanoplatforms with accurate diagnosis and effective therapy show a bright prospect for tumor treatments. Herein, a novel boracic acid-modified graphite carbon nitride and Prussian blue nanohybrid (PB@B-g-C3N4) was developed, which provides sialic acid-targeted Raman recognition and synergistic photothermal/photodynamic therapy in the near-infrared region. Owing to the specific interaction between boracic acid and sialic acid and Raman response at 2157 cm-1 of PB, the nanohybrids exhibit high specificity and Raman sensitivity for detection of the overexpressed sialic acid on tumor cells. Moreover, the photothermal conversion efficiency of PB@B-g-C3N4 is as high as 47.0% with 808 nm laser irradiation due to the enhanced absorbance of PB@B-g-C3N4. PB@B-g-C3N4 also possesses excellent photodynamic activity, which is attributed to the energy transfer of PB (type I) and electron transfer between PB and B-g-C3N4 (type II). This nanotheranostic agent for Raman recognition of cancer markers and synergistic photothermal/photodynamic therapy holds great potential for the development of efficient theranostic nanoplatforms.

Structural Characterization and Anticoagulant Activity of a 3-O-Methylated Heteroglycan From Fruiting Bodies of Pleurotus placentodes.

Pleurotus placentodes, a fungus, belongs to the Pleurotaceae family. The aim of the present study was to characterize the structure of a novel polysaccharide from fruiting bodies of P. placentodes (PPp-W) and evaluate its anticoagulant activity in vitro. The high-performance liquid chromatography and GC-MS analysis indicated that PPp-W with a molecular weight of 27.4 kDa was mainly composed of mannose (17.56%), glucose (6.37%), galactose (44.89%), and fucose (1.22%) with a certain amount of 3-O-methyled galactose. SEM, XRD, and AFM combined with Congo red test revealed that PPp-W was an irregular curly sheet with triple-helix conformation. The FT-IR, methylation, and nuclear magnetic resonance analysis indicated that PPp-W contained→6)-α-D-Galp-(1→, →6)-3-O-Me-α-D-Galp-(1→and →2, 6)-α-D-Galp-(1→ as main chain, partially substituted at O-2 and O-6 by non-reducing ends of ß-D-Manp-(1→ and ß-L-Fucp-(1→ with a small amount of α-1,3-linked-Glcp in backbone. PPp-W could significantly prolong APTT (12.9 ± 0.42 s, p < 0.001) and thrombin time (39.9 ± 0.28 s, p < 0.01) compared with the control group (11.45 ± 0.071 s and 38.05 ± 0.21 s), which showed that PPp-W had anticoagulant activity. These studies suggested that PPp-W was a 3-O-methylated heteroglycan and might be suitable for functional foods and natural drugs as an anticoagulant ingredient, which provided a basis for the application of polysaccharides from P. placentodes.

Meniscus repair with simultaneous anterior cruciate ligament reconstruction: Clinical outcomes, failure rates and subsequent processing.

PURPOSE: To retrospectively analyze the clinical outcomes of meniscus repair with simultaneous anterior cruciate ligament (ACL) reconstruction and explore the causes of failure of meniscus repair. METHODS: From May 2013 to July 2018, the clinical data of 165 patients who were treated with meniscus surgery and simultaneous ACL reconstruction, including 69 cases of meniscus repair (repair group) and 96 cases of partial meniscectomy (partial meniscectomy group) were retrospectively analyzed. The exclusion criteria were as follows: (1) ACL rupture associated with fracture, collateral ligament injury, or complex ligament injury; (2) a history of knee surgery; or (3) a significant degree of osteoarthritis. The 69 patients in the repair group were divided into the non-failure group (62 cases) and the failure group (7 cases) depending on the repair effect. Postoperative outcomes of the repair group and the partial meniscectomy group were compared. General conditions and postoperative outcomes of the failure group and the non-failure group were compared. During the median follow-up period of 28 months (range, 4 - 65 months) after the second arthroscopy, postoperative outcomes of seven patients in the failure group were summarized. SPSS 25.0 statistical software was used for statistical analysis. A p value less than 0.05 was considered statistically significant. RESULTS: Seven patients in the failure group who underwent the second arthroscopy were followed up for (30 ± 17.4) months and their postoperative outcomes were summarized. Compared with the partial meniscectomy group, the International Knee Documentation Committee scores of patients in the repair group improved significantly (p = 0.031). Compared with the non-failure group, more patients in the failure group were younger than 24 years (p = 0.030). The median follow-up period was 39.5 months. All patients recovered well after subsequent partial meniscectomy and relieved clinical symptoms. Visual analog scale scores decreased significantly (p = 0.026), and the International Knee Documentation Committee and Lysholm scores improved significantly (p = 0.046 for both). CONCLUSION: The failure rate of meniscus repair in this study was 10.1% (7/69), all of which were medial meniscus tears. However, the surgical outcomes of ACL reconstruction were not affected, and there might be a role for graft protection. Therefore, meniscus retears can be successful treated by performing subsequent partial meniscectomy in patients with repair failure.

68Ga-PSMA ligand PET/CT integrating indocyanine green-guided salvage lymph node dissection for lymph node metastasis after radical prostatectomy.

To efficiently remove all recurrent lymph nodes (rLNs) and minimize complications, we developed a combination approach that consisted of 68Gallium prostate-specific membrane antigen (PSMA) ligand positron emission tomography (PET)/computed tomography (CT) and integrated indocyanine green (ICG)-guided salvage lymph node dissection (sLND) for rLNs after radical prostatectomy (RP). Nineteen patients were enrolled to receive such treatment. 68Ga-PSMA ligand PET/CT was used to identify rLNs, and 5 mg of ICG was injected into the space between the rectum and bladder before surgery. Fluorescent laparoscopy was used to perform sLND. While extensive LN dissection was performed at level I, another 5 mg of ICG was injected via the intravenous route to intensify the fluorescent signal, and laparoscopy was introduced to intensively target stained LNs along levels I and II, specifically around suspicious LNs, with 68Ga-PSMA ligand PET/CT. Next, both lateral peritonea were exposed longitudinally to facilitate the removal of fluorescently stained LNs at levels III and IV. In total, pathological analysis confirmed that 42 nodes were rLNs. Among 145 positive LNs stained with ICG, 24 suspicious LNs identified with 68Ga-PSMA ligand PET/CT were included. The sensitivity and specificity of 68Ga-PSMA ligand PET/CT for detecting rLNs were 42.9% and 96.6%, respectively. For ICG, the sensitivity was 92.8% and the specificity was 39.1%. At a median follow-up of 15 (interquartile range [IQR]: 6-31) months, 15 patients experienced complete biochemical remission (BR, prostate-specific antigen [PSA] <0.2 ng ml-1), and 4 patients had a decline in the PSA level, but it remained >0.2 ng ml-1. Therefore, 68Ga-PSMA ligand PET/CT integrating ICG-guided sLND provides efficient sLND with few complications for patients with rLNs after RP.

In situ monitoring PUVA therapy by using a cell-array chip-based SERS platform.

Psoralen ultraviolet A (PUVA) therapy has thrived as a promising treatment for psoriasis. However, overdose of PUVA treatment will cause side-effects, such as melanoma formation. And these side-effects are often ignored during PUVA therapy. Hence, in situ monitoring therapeutic response of PUVA therapy is important to minimize side-effects. Aberrant expression of tyrosinase (TYR) has been proved to be associated with melanoma, indicating that TYR is a potential target for evaluation of PUVA therapy. Herein, we reported a strategy for in situ monitoring TYR activity during PUVA therapy by using a cell-array chip-based SERS platform. The cell-array chip was used to simulate cell survival environment for cell culture. Capture of single cells and living cell analysis were realized in the isolated microchambers. An enzyme-induced core-shell self-assembly substrate was used to evaluate TYR activity in living cells during PUVA therapy. The gold nanoparticle modified with a SERS reporter, 4-mercaptobenzonitrile (4-MBN), was used as the core. In the presence of oxygen and TYR, hydroxylation of l-tyrosine occurred, leading to the reduction of silver ion on the surface of gold cores. The growth of silver shells was accompanied by the increased SERS intensity of the reporter, which is related directly to TYR activity. The detection limit for TYR activity is 0.45 U/mL. Upregulation of TYR activity was successfully monitored after PUVA therapy. Notably, real-time and in situ information of therapeutic response can be obtained through monitoring PUVA therapy by using a cell-array chip-based SERS platform, which has great potential to guide the clinical application of PUVA therapy.

Aerobic Cross-Dehydrogenative Coupling Reactions for Selective Mono- and Dithiolation of Phenols.

A highly efficient strategy for the direct thiolation of phenols under transition metal-free and solvent-free conditions has been developed. These reactions are operationally simple with employing air (molecular oxygen) as an ideal oxidant and can selectively provide mono- and dithiolation products in good to excellent yields under basic conditions. The reaction tolerates a broad range of aryl thiols and arenes and is especially applicable for large-scale synthesis.

Endoscopic Surgery for Delayed Wound Healing After Achilles Tendon Suture Repair: A Report of Three Cases.

BACKGROUND: Delayed wound healing is a potention complication after Achilles tendon suture repair and occurs for various reasons. The conventional treatment for delayed wound healing is open surgery, but patients face long recovery times and postoperative care is difficult. CASE PRESENTATION: This report presents three patients who were seen at our institute from April 2008 to October 2017 due to long-term non-healing wounds after surgery. All three patients had undergone surgery at least 2 months previously. We performed endoscopic surgery on these patients. After the operation, patients received less antibiotics and simpler care than would be required for conventional open surgery. There is no need to keep the wound open after the operation or perform wound cleaning for multiple times at the same time, which can reduce healing time. At the last follow up, all postoperative scores among the patients were significantly improved compared to before surgery. The Achilles tendon total rupture scores were excellent and the American Orthopedic Foot and Ankle Society scores were satisfactory, indicating improvements in Achilles tendon function and movement in patients after surgery. CONCLUSION: Our case reports demonstrate that arthroscopic treatment for delayed wound healing after Achilles tendon suture repair is satisfactory and reliable; frequent opening of the wound for cleaning is not required after the operation, thus reducing the healing time.

Evaluation of the efficiency of peptide receptor radionuclide therapy in patients with metastatic prostate carcinoma: A protocol for systematic review and meta-analysis.

BACKGROUND: Metastatic prostate carcinoma has poor prognoses with a median survival period ranging from 2 to 5 years with existing therapeutic challenges. Currently, peptide receptor radionuclide therapy is permitted as a treatment method for metastatic prostate carcinoma patients. Therefore, it is crucial to comprehend the efficiency and safety of peptide receptor radionuclide therapy among this patient population. This study aims to analyse the efficacy of peptide receptor radionuclide therapy when used to treat metastatic prostate carcinoma patients. METHODS: This research will perform a methodological search in the following electronic databases to find related randomized controlled trials: Cochrane Library, EMBASE, PubMed, Web of Science, Scopus, China National Knowledge Infrastructure (CNKI), WanFang database, and Chinese BioMedical Literature. All the databases are searched from their inauguration till November 2020. Two independent authors will screen and select literature for review. The two authors will independently utilize the Cochrane Risk of Bias tool to assess the bias risk in studies. This study also plans to conduct subgroup and sensitivity analyses to evaluate the robustness in the results. Statistical analyses will be conducted with the RevMan 5.3 software. RESULTS: A high-quality synthesis of existing evidence related to peptide receptor radionuclide therapy in the treatment of metastatic prostate carcinoma will be presented in this study. CONCLUSION: Our findings will provide evidence to judge whether peptide receptor radionuclide treatment is efficient for metastatic prostate carcinoma patients. ETHICS AND DISSEMINATION: An ethics approval is not required because the data of the present study are primarily obtained from published studies.OSF registration number: December 1, 2020.osf.io/3psx7. (https://osf.io/3psx7/).

Synthesis and Evaluation of Liposomal Anti-GM3 Cancer Vaccine Candidates Covalently and Noncovalently Adjuvanted by αGalCer.

GM3, a typical tumor-associated carbohydrate antigen, is considered as an important target for cancer vaccine development, but its low immunogenicity limits its application. αGalCer, an iNKT cell agonist, has been employed as an adjuvant via a unique immune mode. Herein, we prepared and investigated two types of antitumor vaccine candidates: (a) self-adjuvanting vaccine GM3-αGalCer by conjugating GM3 with αGalCer and (b) noncovalent vaccine GM3-lipid/αGalCer, in which GM3 is linked with lipid anchor and coassembled with αGalCer. This demonstrated that ßGalCer is an exceptionally optimized lipid anchor, which enables the noncovalent vaccine candidate GM3-ßGalCer/αGalCer to evoke a comparable antibody level to GM3-αGalCer. However, the antibodies induced by GM3-αGalCer are better at recognition B16F10 cancer cells and more effectively activate the complement system. Our study highlights the importance of vaccine constructs utilizing covalent or noncovalent assembly between αGalCer with carbohydrate antigens and choosing an appropriate lipid anchor for use in noncovalent vaccine formulation.

SIS3, a good candidate for the reverse of type 2 diabetes mellitus in mice.

TGF-ß signaling plays an extremely important role in the occurrence and development of type 2 diabetes mellitus (T2DM), and the blockade of TGF-ß/Smad3 pathway protests against the high-fat diet-induced obesity and diabetes. As a specific small molecule inhibitor of Smad3 protein, the biological activities of compound SIS3 were evaluated by high-fat diet-induced T2DM model mice. In vivo results indicated that SIS3 can not only significantly reduce the body weight, fat mass, and fasting blood glucose in high-fat diet-induced T2DM model mice, but also improve insulin sensitivity and oral glucose tolerance of high-fat diet-induced T2DM model mice after the injection of SIS3 with 5 mg/kg for 45 days.