BACKGROUND:Efsubaglutide Alfa is a novel long-acting glucagon-like peptide-1 receptor agonist developed to promote weight loss and improve metabolic outcomes. This Phase 2a trial evaluated its efficacy, tolerability, safety, and pharmacokinetics (PK) in overweight and obese individuals unresponsive to lifestyle interventions. METHODS:In this multicenter, randomized, double-blind, placebo-controlled, multiple-ascending dose study, 50 participants were randomized (8:2) across five dose cohorts (5, 7.5, 10, 15, and 20 mg) or placebo. Participants received once-weekly subcutaneous injections of Efsubaglutide Alfa or placebo, with individualized dose escalation every 2 weeks, followed by 4 weeks at target doses. Primary endpoints were percentage change in body weight from baseline and the proportion achieving ≥5% weight loss. Secondary endpoints included changes in body composition and a metabolic composite index (BMI, waist circumference, blood pressure, lipid profiles). Tolerability, safety, immunogenicity, and PK were assessed. FINDINGS:Between 25 April 2024 and 18 November 2024, 50 individuals were randomly assigned. Mean baseline characteristics included age 36.3 years, bodyweight 92.9 kg, and BMI 33.0 kg/m2. Efsubaglutide Alfa produced a mean weight reduction of 7.16% (95% CI: -8.08 to -6.24) versus 0.86% with placebo. Overall, 82.5% of Efsubaglutide-treated participants achieved ≥5% weight loss (vs. 0% placebo). Fat mass decreased by 4.47 kg, and lean mass also declined by 2.00 kg from baseline; however, the lean-to-fat mass ratio improved by 19.73 percentage points. BMI, waist circumference, and systolic blood pressure significantly decreased. Gastrointestinal adverse events were the most common, mostly mild to moderate, occurring primarily during dose escalation. No treatment-related serious adverse events occurred. Efsubaglutide Alfa showed dose-proportional PK. INTERPRETATION:Efsubaglutide Alfa demonstrated significant weight-loss efficacy, metabolic improvements, and a preferable tolerability and safety profile, supporting further clinical development for obesity and related metabolic disorders.

Background Promoting the thermogenic remodeling of white adipose tissue (WAT) is a promising strategy to combat obesity. Lipophagy degrades lipid droplets to supply free fatty acids that fuel thermogenesis in beige adipocytes. GDP dissociation inhibitor 2 (GDI2) is a negative regulator of Rab GTPases implicated in adipocyte lipid storage, but its role in lipophagy-mediated WAT browning has not been explored. This study aimed to characterize GDI2 as a novel regulator of lipophagy and beige fat thermogenesis. Methods The metabolic relevance of GDI2 was profiled in differentiated adipocytes, obese mouse models, thermogenic mouse models, and human subjects. Subcellular localization was determined by confocal microscopy and immunogold electron microscopy. Adipocyte-specific Gdi2 knockout mice were generated and subjected to cold exposure or β3-adrenergic stimulation, and assess thermogenic capacity. Stimulated lipolysis was evaluated in primary adipocytes, Gdi2 -knockout C3H10T1/2 cells, and ex vivo WAT explants. The lipophagy stage at which GDI2 acts was defined by immunoblotting, confocal imaging of lipid droplets with LC3B, autophagic inhibitor treatments, mCherry-EGFP-LC3B reporter, and transmission electron microscopy. RNA-seq was employed to profile downstream transcriptional adaptations. High-fat diet feeding was used to determine whether Gdi2 deficiency confers resistance to obesity and associated metabolic disorders. Results GDI2 expression is positively correlated with BMI in humans and is upregulated in the adipose tissue of obese mice, while it is suppressed by cold exposure. Adipocyte-specific deletion of Gdi2 in mice promotes cold-induced WAT browning and energy expenditure, and confers resistance to diet-induced obesity, insulin resistance, and hepatic steatosis. Mechanistically, GDI2 acts as a molecular brake on lipophagy by inhibiting the late-stage fusion of autophagosomes with lysosomes independently of the canonical neutral lipolysis pathway. Gdi2 deficiency releases this brake, accelerating the lipophagic degradation of lipid droplets and generating a robust supply of free fatty acids. These fatty acids serve as signaling ligands to activate a PPARα/PGC1α-dependent transcriptional program, driving thermogenic and mitochondrial oxidative phosphorylation gene expression to channel lipid flux into energy dissipation. Conclusions GDI2 functions as a key inhibitor of adipocyte lipophagy that restrains beige fat thermogenesis, positioning it as a potential therapeutic target to combat obesity and related metabolic disorders.

Introduction and Objective: RDSY1801 is a novel GLP-1 peptide composed of a single mutation in Thr7→Pro and activates GLP-1R. This is the first-in human study of oral RDSY1801 capsules, designed to investigate its pharmacokinetics and safety in healthy adults. Methods: Total 54 healthy volunteers participated in the single escalation dose study. Participants were randomized into six groups to receive a single oral dose of RDSY1801 of 4, 10, 40, 80, 120 and 200 mg, respectively. Each dose group contained either 6 or 8 participants, with total 12 participants receiving placebo. Pharmacokinetic parameters were assessed within the dosage groups of 4, 40, 120 and 200mg. Results: Following oral administration of 4, 40, 120 and 200 mg doses of RDSY1801, pharmacokinetic studies showed that Tmax appeared consistently at approximately 3 hours for all dose groups, with Cmax of 2.56±0.29, 34.60±6.94, 137.25±18.78, and 242.00±25.52 ng/ml, respectively. Within the dose range of 4 to 200 mg, AUC increased in a dose-dependent manner, and T1/2 was about 0.5 hour. No deaths or SAEs occurred in this study. TEAEs were mild to moderate and transient. Specifically, regarding gastrointestinal adverse events, only one case of diarrhea (1/8) occurred in the dose group of 120 mg, and another case of nausea (1/8) occurred in the dose group of 200 mg. Unlike other GLP-1RAs, no increase in heart rates was observed in all participants treated with RDSY1801. Conclusion: RDSY1801 achieves effective plasma concentrations when administered orally. It was well tolerated in healthy volunteers, and no serious adverse events have been reported. Its clinical efficacies will be further studied. Disclosure W. Jia: None. F. Gao: None. J. Zhou: None. J. Liu: Advisory Panel; Current; Landing Laboratories.

Introduction and Objective: Efsubaglutide alfa (Suba) is a novel GLP-1RA. ENLIGHT is a seamless Phase 2b/3 program; the Phase 2b stage evaluated Suba regimens to inform dose selection for the subsequent Phase 3 study. Methods: This double-blind, placebo (PBO)-controlled trial (NCT06921486) randomized participants to Suba 5, 10, or 20 mg once weekly (QW), 20 mg once every 2 weeks (Q2W), or PBO. Treatment started at 1 mg with individualized dose escalation every 2 weeks to reach target doses and continued for a total of 18 weeks. The primary endpoint was percent change in body weight (BW) at end of treatment. Secondary endpoints included BW change (kg), the proportion achieving ≥5% weight loss, and waist circumference (WC). Safety endpoints included TEAEs, vital signs, 12-lead ECG, and laboratory tests. Results: BW change (%) was −3.61 with PBO and −7.95, −9.99, −10.58, and −9.70 with Suba 5, 10, and 20 mg QW, and 20 mg Q2W; BW change (kg) was −2.88 vs −6.73, −8.59, −9.22, and −8.48. The proportions achieving ≥5% weight loss were 26.8% with PBO and 75.6%, 78.0%, 81.6%, and 73.7% with Suba regimens. WC decreased by −4.35 cm with PBO vs −6.88 to −8.94 cm with Suba. Efficacy was generally dose dependent (20mg Q2W comparable with 10mg QW) (Fig. 1). TEAEs were mostly mild-to-moderate gastrointestinal, with no premature discontinuations or drug-related SAEs. Conclusion: ENLIGHT regimens (QW and Q2W) produced clinically meaningful weight loss with a favorable safety profile, supporting progression to the Phase 3 stage. Disclosure Y. Bao: None. F. Gao: None. Z. Li: None. Y. Yang: None. Y. Wang: None. Z. Cheng: None. L. Chen: Research Support; Current; AstraZeneca, Lilly, Gan & Lee Pharmaceuticals, Novo Nordisk, Sanofi. J. Xiao: None. Y. Wang: None. B. Liu: None. L. Yan: None. Y. Lu: None. C. Yang: None. H. Chen: None. J. Zhou: None. W. Jia: None. Q. Wang: Board Member; Current; Innogen Pharmaceuticals Technology Co., Ltd. Funding Innogen Pharmaceutical Co. Ltd.

Malignant gliomas are lethal brain tumors characterized by profound local immunosuppression and a radically remodeled myeloid landscape. Although these tumors mobilize resident microglia and infiltrating monocyte-derived macrophages, the mechanisms governing their phenotypic convergence and diversification remain elusive. Here, we integrated single-cell profiling and spatial transcriptomics of glioma-associated microglia in the GL261 model. We identified distinct microglial states that aligned with tumor architecture, most notably Cst7-expressing disease-associated microglia (DAMs) that aggregated at the tumor invasive margin and exhibited a conserved transcriptional signature shared across various central nervous system pathologies. Interferon-γ and toll-like receptor signaling sequentially tuned stage-specific DAM features, including transient MHC-II expression and sustained PD-L1 upregulation, thereby recalibrating the local immune equilibrium by reshaping bidirectional DAM-T cell interactions during glioma progression. Our findings highlight microglial state transitions as a stage-specific layer of immune regulation in glioma that shapes T cell fate and support targeting microglial plasticity to rebalance anti-tumor immunity.

IntroductionThis study investigated the clinical efficacy and safety of CalliSpheres® drug-eluting bead transarterial chemoembolization (DEB-TACE) combined with programmed death protein (PD)-1 inhibitors for treatment of unresectable head and neck squamous cell carcinoma (HNSCC).MethodsClinical data of 31 patients with unresectable HNSCC were retrospectively analyzed. All patients received local treatment with DEB-TACE combined with systemic PD-1 inhibitor. Modified Response Evaluation Criteria in Solid Tumors (mRECIST) criteria were used to evaluate the tumor response at 1, 3 and 6 months after the first treatment. Progression-free survival and overall survival were recorded. The changes in quality of life before and after treatment and adverse reactions during treatment were recorded.ResultsPatients were treated with DEB-TACE 51 (average 1.65 ± 0.51) times. At 1, 3 and 6 months after the first treatment, objective response rate was 96.77%, 87.09% and 74.19%, and disease control rate was 100%, 96.77% and 83.87%, respectively. As of October 31, 2024, the mean follow-up was 21.71 ± 9.56 months, median survival time was 9.0 months, and the median progression-free survival was 19.0 months. The adverse reactions related to DEB-TACE were mainly fever, pain, nausea and vomiting; all of which were mild and relieved after symptomatic treatment. Three patients had mild skin ulceration in the embolic area, which healed after symptomatic treatment, and no serious complications such as ectopic embolism occurred. The adverse reactions associated with PD-1 inhibitor treatment were mainly fatigue, hypothyroidism and rash. Most of these were grade 1/2, three patients had grade 3 adverse reactions, but no grade 4 adverse reactions occurred. One month after the first treatment, the scores of physical function, emotional function and general health status increased, and the scores of pain, insomnia and anorexia decreased, and quality of life was significantly improved.DiscussionCombination of DEB-TACE with PD-1 inhibitors is safe and effective for treatment of unresectable HNSCC, significantly improves quality of life, and warrants clinical promotion and application.

Deubiquitinating enzymes play crucial roles in various cellular activities, yet their involvement in central nervous system (CNS) vascularization and barrier function remains elusive. Canonical Wnt signaling is essential for proper CNS vascularization and barrier maintenance. Using a loss-of-function screening for Wnt-signaling activity, we identified ubiquitin-specific peptidase 9 X-linked (USP9X) as a key regulator in brain endothelial cells (BECs). Endothelium-specific Usp9x knockout mice exhibit reduced Wnt-signaling activity, compromising CNS vascularization and barrier function during development. Activation of Wnt signaling rescues these defects. Mechanistically, we identified β-catenin as a direct substrate of USP9X, with USP9X catalyzing K48 polyubiquitin chains to stabilize β-catenin. In pathological mouse models of impaired CNS vascular barrier function, including intracerebral hemorrhage and an oxygen-induced retinopathy, loss of Usp9x intensifies barrier disruption, accentuating defects. This finding implicates USP9X as a critical regulator of CNS vascularization and barrier function through Wnt signaling, offering insights into CNS disease implications.

Bacterial infections and the resultant pyroptosis-exacerbated inflammatory crises lead to a range of local or systemic diseases. Current therapeutic strategies are still constrained by host cellular barriers and biofilm, significantly impeding spatiotemporal precision, and functional robustness. Notably, residual pathogen- and damage-associated molecular patterns can manipulate host cell biology even after antibacterial monotherapy. In this study, a modular self-assembly strategy for the nano-antibiotic system (EM NPs) is developed through stepwise construction design, leveraging non-covalent interactions between polyphenol frameworks and antibiotic molecules. The assembled modules exhibit intrinsic protonation capability and strong intermolecular affinity, facilitating the dynamic modulation of molecular interactions and surface charge reversal of the EM NPs under acidic conditions. This enables intracellular delivery through adaptive drug release behavior, lysosomal escape, and efficient cytoplasmic distribution. In vitro, EM NPs leverage polyphenol-mediated cellular barrier penetration and biofilm-targeted accumulation, achieving superior intracellular bacterial eradication and biofilm clearance compared to free antibiotics. Furthermore, the data validates that EM NPs modulate the mitochondria-inflammasome axis to effectively suppress pyroptosis and subsequent inflammatory responses. In mouse models of periodontitis and sepsis, EM NPs significantly alleviate inflammation and tissue damage. Overall, this work provides a promising therapeutic strategy for comprehensively managing bacterial infection-induced inflammation.

Introduction and Objective: Efsubaglutide Alfa (Suba) is a novel long-acting GLP-1RA. This trial aimed to evaluate its efficacy and safety in overweight/obese participants (pts) with inadequate body weight (BW) control despite lifestyle interventions. Methods: This double-blind, placebo (PBO)-controlled trial (NCT06732960) randomized pts into Suba or PBO groups in 8:2 across five dose groups (5, 7.5, 10, 15, and 20 mg). Pts underwent biweekly dose escalation to achieve target doses, and maintained for 4 weeks for efficacy and safety evaluation. The primary endpoints were the BW change (%) from baseline and the proportion of pts achieving ≥5% weight loss after 4 weeks at target doses. Results: 50 pts were enrolled (mean age: 36.3 years; mean BMI: 33.0 kg/m²). The mean BW reduction by Suba was -7.2% (-6.5 kg) vs. PBO -0.9% (-0.5 kg). 84.6% of pts in Suba groups achieved ≥5% weight loss (PBO: 0%). Mean fat mass decreased by 4.5 kg (13.1%) (PBO: -0.2 kg, -1.2%), and the ratio of muscle-to-fat mass increased significantly by 19.7% (PBO: 0.6%). Treatment-related adverse events were mostly mild to moderate gastrointestinal, with no premature discontinuations, SAEs, or hyperglycemia. Conclusion: Suba showed a favorable safety profile and significant weight loss in overweight/obese pts. Most pts achieved clinically meaningful weight loss target, indicating Suba's potential as an effective weight management option. Y. Bao: None. J. Zhou: None. F. Gao: None. A. Shao: Employee; Innogen Pharmaceutical Co., Ltd. Y. Xu: Employee; Innogen Pharmaceutical Co., Ltd. Q. Wang: Employee; Innogen PharmaceuticalCo., Ltd. W. Jia: None. This study was sponsored by Innogen Pharmaceutical Co. Ltd.

Pancreatic cancer (PC) is a highly malignant and lethal tumor in gastrointestinal tract. Lactate accumulation is a classical feature of metabolic reprogramming in cancers. Lactate-derived lysine lactylation (Kla) is identified as a new type of post-translational modifications (PTMs), which is confirmed to be involved in multiple biological processes. However, the cancer-specific regulation of protein Kla in PC requires further elucidation. Here, we report a range of dysregulated Kla sites specifically related to RNA splicing in human pancreatic cancer, leading to the observation that the Kla at lysine 176 of heterogeneous nuclear ribonucleoprotein C (HNRNPC K176la) is significantly elevated in PC. Blocking HNRNPC K176la dramatically inhibits pancreatic cancer growth and metastasis. Mechanistically, K176la strengthened the binding of HNRNPC with poly-U motifs in p21-activated kinase 6 (PAK6) pre-mRNA, facilitating the expression of the oncogenic isoform PAK6S. Therefore, our study identifies a number of cancer-specific Kla sites spanned on alternative splicing (AS)-related proteins and unravels the significance of HNRNPC K176la in RNA splicing and PC development.

During deep-water drilling operations, due to the conditions with low temperature and high pressure in the wellbore, methane hydrate can be easily formed in the presence of methane and plug the wellbore. In addition, the deep-water sediments are dominated by clay-silty with weak cementation, so well instability may be occurred due to clay hydration. In order to inhibit hydrate formation and clay hydration in deepwater drilling, a zwitterionic polymer AADV was synthesized through quaternary copolymerization of AM/AMPS/DMDAAV/VAC. The hydrate inhibition performance of AADV was evaluated in a high-pressure reactor chamber, and the results showed that AADV can delay the hydrate formation time from 330 min in pure water to 2204 min, indicating an excellent inhibition effect of hydrate formation. Meanwhile, 1 % AADV can significantly reduce the linear swelling rate of the calcium-based bentonite to 3.69 % for 10 h and increase the rolling recovery rate to 94.7 %, suggesting an excellent inhibition effect on clay hydration. The mechanism of dual-functional inhibition of AADV was further analyzed. The zwitterionic group in AADV and the hydrophilic amide group can strongly adsorb the water molecules through a strong hydration effect and the hydrogen bonding effect, respectively, which contributes to destroy the water molecules cage structure, and thus to suppress the hydrate formation. Besides, AADV can effectively obstruct mass transfer of methane molecules by increasing the viscosity of the aqueous phase and absorbing on the hydrate surface, leading to hydrate formation inhibition. For the inhibition of clay hydration, the SEM and XRD results proved that AADC inhibits the clay hydration through the film-forming effect. In addition, the contact angle of Na-Bent/AADC composite reached to 55.68° when the polymer concentration increased to 2 %, suggesting that the hydrophobicity of Na-Bent surface can be enhanced after AADC treatment. AADV can wrap around clay particles and form hydrophobic film through adsorption and intercalation, preventing the intrusion of external fluids and inhibiting clay hydration.

INTRODUCTION:We found the G132R heterozygous mutation of thyroid stimulating hormone receptor (TSHR) gene in a patient with recurrent hypokalemia. Because the patient had a medical history of hyperthyroidism, the mutation was suspected to be related to hyperthyroidism at first. Subsequently, the expression and function studies in vitro were conducted. METHODS:Wide-type TSHR and mutant TSHR (mutTSHR) were constructed in the phage vector and pEGFP-C1 vector. After transfection, the samples were collected for detection of mRNA level, protein expression, cell activity and cAMP content. RESULTS:Compared with the wild-type TSHR, the mRNA level of the mutTSHR was not significantly different. But the protein expression, cell activity and cAMP content of the mutTSHR were significantly lower. So this indicated that the G132R mutation is a loss-of-function mutation. CONCLUSION:We identified the G132R monoallelic heterozygous mutation of TSHR gene in a patient with hyperthyroidism. Based on disease history of the patient, we speculated that the heterozygous mutation did not cause thyroid dysplasia or hypothyroidism for her. Our study enriched experiment content in vitro studies and clinical phenotype about the G132R mutation in TSHR gene.

Chiglitazar (carfloglitazar) is a peroxisome proliferator-activated receptor pan-agonist presenting non-inferior glucose-lowering efficacy with sitagliptin in patients with type 2 diabetes. To delineate the subgroup of patients with greater benefit from chiglitazar, we conducted a machine learning-based post-hoc analysis in two randomized controlled trials. We established a character phenomap based on 13 variables and estimated HbA1c decline to the effects of chiglitazar in reference to sitagliptin. Out of 1,069 patients, 63.3% were found to have greater reduction in HbA1c levels with chiglitazar, while 36.7% showed greater reduction with sitagliptin. This distinction in treatment response was statistically significant between groups (pinteraction<0.001). To identify patients who would gain the most glycemic control benefit from chiglitazar, we developed a machine learning model, ML-PANPPAR, which demonstrated robust performance using sex, BMI, HbA1c, HDL, and fasting insulin. The phenomapping-derived tool successfully identified chiglitazar responders and enabled personalized drug allocation in patients with drug-naïve diabetes.

Background: Molecular genetic testing is the most sensitive and specific method to confirm acute intermittent porphyria (AIP), a rare autosomal dominant disease, caused by Hydroxymethylbilane synthase (HMBS) gene mutation. According to the Human Gene Mutation Database (HGMD), approximately 20% of the reported HMBS gene variants affect pre-RNA splicing. Thus, the ensuing challenge is how to decipher the pathogenicity of these splicing variants.Methods: Using next-generation sequencing, we identified a novel heterozygous variant in the HMBS gene (c.160 + 5G>C) from a Chinese family with AIP. And, previously, seven HMBS variants (c.33 + 5G>A, c.88-16_88-4del, c.88-2A>G, c.161-1G>C, c.652-1G>A, c.772-2A>G and c.772-1G>C) have been reported to be linked with AIP. Herein, we performed a valid and novel in vitro minigene assay to analyze the pathogenicity of these eight splicing variants.Results: By minigene assay in 293 T cell experiments, we demonstrated that all eight variants caused splicing defects in the pre-mRNA of the HMBS gene: c.160 + 5G>C (intron3p_141bp retention), c.33 + 5G>C(intron1p_91bp retention), c.88-16_88-4del and c.88-2A>G (Exon3p_15bp deletion), c.161-1G>C (Exon4p_18bp deletion), c.652-1G>A (Exon11p_1bp deletion), c.772-2A>G and c.772-1G>C (intron11q_104bp retention or Exon12p_4bp deletion).Encouragingly, the c.160 + 5G>C RNA sequencing from peripheral blood lymphocytes was consistent with the minigene assay result.Conclusion: We have made a pioneering attempt to apply minigene in vitro validation to the HMBS gene to evaluate the splicing effect of eight variants, including a novel splice variant (c.160 + 5G>C). This study provides a molecular basis for future research on the pathogenesis and gene therapy of AIP.

BACKGROUND The association between prolactin and mortality has been less studied, and findings were inconsistent among different populations. We aimed to investigate the association between serum prolactin (PRL) and mortality among patients with type 2 diabetes. METHODS We performed a retrospective cohort study of 10,907 patients with at least two prolactin measurements within two years since their first inpatient diagnosis of type 2 diabetes. Baseline and mean values of serum PRL were used as exposures. A multivariable-adjusted Cox proportional hazards model was used to estimate the association between PRL and mortality. RESULTS During a mean follow-up of 5.34 years, 863 patients died, of whom 274 were due to cardiovascular events. Multivariable-adjusted hazard ratios (aHRs) based on different levels of baseline PRL (<100, 100-199, 200-299, and ≥300 mIU/L) were 1.00, 1.10 (95% confidence interval (CI), 0.90-1.36), 1.35 (95% CI 1.11-1.67), and 1.49 (95% CI 1.18-1.84) for all-cause mortality, and 1.00, 1.24 (95% CI 0.86-1.81), 1.71 (95% CI 1.14-2.62), and 2.42 (95% CI 1.55-3.78) for cardiovascular mortality, respectively. Positive associations were also found when we used the mean values of PRL as the exposure. These associations were consistent among patients of different baseline characteristics. Further sensitivity analyses excluding patients with subclinical or clinical hypothyroidism at baseline and who died within the first six months since baseline demonstrated similar results. CONCLUSIONS A positive association between baseline PRL and mortality was observed among patients with type 2 diabetes. PRL may be considered a potential biomarker of mortality among patients with type 2 diabetes.

Optically controlled neuromodulation is a promising approach for basic research of neural circuits and the clinical treatment of neurological diseases. However, developing a non‐invasive and well‐controllable system to deliver accurate and effective neural stimulation is challenging. Micro/nanorobots have shown great potential in various biomedical applications because of their precise controllability. Here, a magnetically‐manipulated optoelectronic hybrid microrobot (MOHR) is presented for optically targeted non‐genetic neuromodulation. By integrating the magnetic component into the metal–insulator–semiconductor junction design, the MOHR has excellent magnetic controllability and optoelectronic properties. The MOHR displays a variety of magnetic manipulation modes that enables precise and efficient navigation in different biofluids. Furthermore, the MOHR could achieve precision neuromodulation at the single‐cell level because of its accurate targeting ability. This neuromodulation is achieved by the MOHR's photoelectric response to visible light irradiation, which enhances the excitability of the targeted cells. Finally, it is shown that the well‐controllable MOHRs effectively restore neuronal activity in neurons damaged by β‐amyloid, a pathogenic agent of Alzheimer's disease. By coupling precise controllability with efficient optoelectronic properties, the hybrid microrobot system is a promising strategy for targeted on‐demand optical neuromodulation.

Previous studies have demonstrated that both CS and LiCl possess anti-Alzheimer's disease (AD) activities. We prepared chondroitin sulfate-Li (CS-Li) and investigated its effect on AD and explored the possible mechanisms both in vitro and in vivo. We found that CS-Li could inhibit amyloid β (Aβ) aggregation and protect SH-SY5Y cells from Aβ1-42-induced cytotoxicity in vitro. In D-gal and AlCl3-induced AD mouse model, CS-Li improves the spatial learning and memory abilities of AD mice, reverses the nuclear pyknosis and cell edema, and increases the survival rate of neurons in hippocampus of mice. Moreover, CS-Li significantly increased the levels of GSH-Px, Na+/K+-ATPase, and ChAT and decreased the levels of MDA and AchE in AD mice. Western blot results demonstrated that CS-Li could decrease the hyperphosphorylation of tau (Ser396/Ser404) by regulating the expression of p-GSK-3β (Ser9) and PP2A and inhibit the expression of proinflammatory factors through inhibiting NF-κB nuclear translocation by activating the MAPK signaling pathways. In a word, CS-Li can delay AD development through multitarget processes, including Aβ aggregation inhibition, oxidative stress damage, tau hyperphosphorylation, and inflammatory response, thereby improves learning and memory abilities.

Growth differentiation factor 15 (GDF15) was newly discovered to be a promising target of metformin. The study was aimed to investigate the relationship between GDF15 and glycemic control after metformin treatment in patients with type 2 diabetes mellitus. The study was a post-hoc analysis of AIM (the effect of Acarbose on glycemic variability in patients with type 2 diabetes mellitus using premixed Insulin compared to Metformin) study. The participants were randomly assigned to 12 weeks of metformin (MET) or acarbose (ACA) treatment combined with insulin. Serum GDF15 levels of 51 subjects from MET group and 53 subjects from ACA group were measured at baseline and after a 12-week treatment. Fasting plasma glucose (FPG), 2-h postprandial plasma glucose (2-h PG) and glycated hemoglobin A1c (HbA1c) were measured at baseline and endpoint. After a 12-week treatment, serum GDF15 levels significantly increased in MET group [baseline vs. endpoint, 936.70 (741.00, 1205.40) pg/mL vs. 1265.20 (1027.90, 1634.00) pg/mL, P < 0.001], but not in ACA group [baseline vs. endpoint, 920.60 (701.45, 1332.55) pg/mL vs. 893.80 (663.25, 1284.05) pg/mL, P = 0.944]. However, there were no significant differences of glycemic control parameters (ΔFPG, Δ2-h PG and ΔHbA1c) between subgroups of MET group divided by median of ΔGDF15 (all P > 0.05). Spearman correlation coefficient and analysis of covariance after adjustment for baseline HbA1c levels showed that ΔGDF15 was not correlated with ΔFPG, Δ2-h PG and ΔHbA1c (all P > 0.05). Serum GDF15 levels were significantly elevated after metformin treatment in patients with type 2 diabetes mellitus. However, the increase was not an indicator of the glucose-lowering effect of metformin. Clinicaltrials.gov, NCT02438397 . Registered 8 May 2015.

The reduced expression of angiotensin-converting enzyme (ACE) 2 in the kidneys of animal models and patients with diabetes suggests ACE2 involvement in diabetic nephrology. To explore the renoprotective effects of ACE2 overexpression, ACE inhibition (ACEI) or both on diabetic nephropathy and the potential mechanisms involved, 50 Wistar rats were randomly divided into a normal group that received an injection of sodium citrate buffer and a diabetic model group that received an injection of 60 mg/kg streptozotocin. Eight wks after streptozotocin injection, the diabetic rats were divided into no treatment group, adenoviral (Ad)-ACE2 group, Ad-green flurescent protein (GFP) group, ACEI group receiving benazepril and Ad-ACE2 + ACEI group. Four wks after treatment, physical, biochemical, and renal functional and morphological parameters were measured. An experiment in cultured glomerular mesangial cells was performed to examine the effects of ACE2 on cellular proliferation, oxidative stress and collagen IV synthesis. In comparison with the Ad-GFP group, the Ad-ACE2 group exhibited reduced systolic blood pressure, urinary albumin excretion, creatinine clearance, glomeruli sclerosis index and renal malondialdehyde level; downregulated transforming growth factor (TGF)-β1, vascular endothelial growth factor (VEGF) and collagen IV protein expression; and increased renal superoxide dismutase activity. Ad-ACE2 and ACEI had similar effects, whereas combined use of Ad-ACE2 and ACEI offered no additional benefits. ACE2 transfection attenuated angiotensin (Ang) II-induced glomerular mesangial cell proliferation, oxidative stress and collagen IV protein synthesis. In conclusion, ACE2 exerts a renoprotective effect similar to that of ACEI treatment. Decreased renal Ang II, increased renal Ang-(1–7) levels, and inhibited oxidative stress were the possible mechanisms involved.