Melatonin improves influenza virus infection-induced acute exacerbation of COPD by suppressing macrophage M1 polarization and apoptosis.

BACKGROUND: Influenza A viruses (IAV) are extremely common respiratory viruses for the acute exacerbation of chronic obstructive pulmonary disease (AECOPD), in which IAV infection may further evoke abnormal macrophage polarization, amplify cytokine storms. Melatonin exerts potential effects of anti-inflammation and anti-IAV infection, while its effects on IAV infection-induced AECOPD are poorly understood. METHODS: COPD mice models were established through cigarette smoke exposure for consecutive 24 weeks, evaluated by the detection of lung function. AECOPD mice models were established through the intratracheal atomization of influenza A/H3N2 stocks in COPD mice, and were injected intraperitoneally with melatonin (Mel). Then, The polarization of alveolar macrophages (AMs) was assayed by flow cytometry of bronchoalveolar lavage (BAL) cells. In vitro, the effects of melatonin on macrophage polarization were analyzed in IAV-infected Cigarette smoking extract (CSE)-stimulated Raw264.7 macrophages. Moreover, the roles of the melatonin receptors (MTs) in regulating macrophage polarization and apoptosis were determined using MTs antagonist luzindole. RESULTS: The present results demonstrated that IAV/H3N2 infection deteriorated lung function (reduced FEV20,50/FVC), exacerbated lung damages in COPD mice with higher dual polarization of AMs. Melatonin therapy improved airflow limitation and lung damages of AECOPD mice by decreasing IAV nucleoprotein (IAV-NP) protein levels and the M1 polarization of pulmonary macrophages. Furthermore, in CSE-stimulated Raw264.7 cells, IAV infection further promoted the dual polarization of macrophages accompanied with decreased MT1 expression. Melatonin decreased STAT1 phosphorylation, the levels of M1 markers and IAV-NP via MTs reflected by the addition of luzindole. Recombinant IL-1ß attenuated the inhibitory effects of melatonin on IAV infection and STAT1-driven M1 polarization, while its converting enzyme inhibitor VX765 potentiated the inhibitory effects of melatonin on them. Moreover, melatonin inhibited IAV infection-induced apoptosis by suppressing IL-1ß/STAT1 signaling via MTs. CONCLUSIONS: These findings suggested that melatonin inhibited IAV infection, improved lung function and lung damages of AECOPD via suppressing IL-1ß/STAT1-driven macrophage M1 polarization and apoptosis in a MTs-dependent manner. Melatonin may be considered as a potential therapeutic agent for influenza virus infection-induced AECOPD.

Predictors of Acute Cerebellar Bulge Prior to Posterior Fossa Lesion Resection.

OBJECTIVE: A cerebellar bulge prior to posterior fossa resection is an emergency condition during surgery. Intraoperative cerebellar bulging not only increases the difficulty of lesion resection but also brings additional postoperative complications. Currently, there are few systematic reports on this topic. The predictors of cerebellar bulge and how to effectively prevent intraoperative cerebellar bulge are discussed in this article. METHODS: The clinical and imaging data of 527 patients with posterior fossa lesions who underwent resection at our hospital were retrospectively collected and analyzed. Perioperative clinical and imaging data were assessed. Variables were analyzed using univariate and multivariate regression analyses. RESULTS: Overall, 10.4% (55/527) of patients had intraoperative acute bulges. Multivariate analysis revealed that age <60 years, body mass index ≥24, lesion size ≥30 (mm), cerebellar tonsillar herniation and/or hydrocephalus, and perilesional edema (moderate-severe) were predictors of cerebellar bulging. Relief of the cerebellar bulge can be accomplished by excising the lesion, releasing cerebrospinal fluid, and removing the cerebellum (the outer one-third). Obvious cerebellar-related complications occurred in 4 patients postoperatively, and the symptoms disappeared after 6 months of follow-up. CONCLUSIONS: Cerebellar bulging during intraoperative posterior fossa resection deserves attention. Through the analysis of multiple factors related to cerebellar bulge, comprehensive evaluation and early intervention during the perioperative period are necessary. The incidence of cerebellar bulges can be reduced, and surgical complications related to cerebellar bulges can be avoided.

Effects of hysteroscopic septum incision versus expectant management on IVF outcomes in women with complete septate uterus: a retrospective study.

OBJECTIVE: This retrospective study aimed to assess the impact of hysteroscopic septum incision on in vitro fertilization (IVF) outcomes among infertile women diagnosed with a complete septate uterus and no history of recurrent pregnancy loss. METHODS: The study was conducted at a tertiary reproductive center affiliated with a university hospital and involved 78 women with a complete septate uterus. Among them, 34 women underwent hysteroscopic septum incision, while 44 women opted for expectant management. The primary outcome measure was the live birth rate, while secondary outcomes included clinical pregnancy rate, preterm birth rate, miscarriage rate, and ongoing pregnancy rate. RESULTS: Women who underwent hysteroscopic septum incision demonstrated a comparable likelihood of achieving a live birth compared to those managed expectantly (25% vs. 25%, Relative Risk (RR): 1.000, 95% Confidence Interval (CI): 0.822 to 1.216). No preterm births occurred in either group. The clinical pregnancy rate, ongoing pregnancy rate, and miscarriage rate showed no significant differences between the surgical group and the expectant management group. Subgroup analyses based on the type of embryo transferred also revealed no significant differences in outcomes. CONCLUSIONS: Hysteroscopic septum incision does not appear to yield improved IVF outcomes compared to expectant management in infertile women with a complete septate uterus and no history of recurrent pregnancy loss.

Full-thickness nasolabial facial artery flap: A modified surgical approach for reconstruction of lower lip defects.

OBJECTIVES: Reconstruction of large lower lip defects remains challenging in terms of aesthetics, function and safety. The aim of this study is to explore a modified nasolabial flap to repair large lower lip defects. METHODS: The full-thickness nasolabial facial artery flap was used for reconstruction of defects in lip squamous cell carcinoma (LSCC) patients after tumor ablation. The postoperative recovery of patients was obtained through clinical review and follow-up in the first and sixth month. RESULTS: There were four LSCC patients who received tumor ablation at the Beijing Stomatological Hospital of Capital Medical University from November 2022 to March 2023, were included in our study. All patients did not suffer from postoperative infection, orocutaneous fistula, flap necrosis, and flap loss. One patient had the trapdoor deformity. These patients achieved better lip closure function. One patient developed cervical lymph node metastasis 2 months after surgery. CONCLUSIONS: The modified nasolabial flap could achieve good outcomes in terms of aesthetics, function, and safety. It provided a supplementary strategy for the using of nasolabial flap in larger defects of lower lip.

Development of an immunoassay based on a specific antibody for the detection of diphenyl ether herbicide fomesafen.

Fomesafen belongs to the diphenyl ether herbicide, and is widely used in the control of broadleaf weeds in crop fields due to its high efficiency and good selectivity. The residual of fomesafen in soil has a toxic effect on subsequent sensitive crops and the microbial community structure because of its long residual period. Therefore, an efficient method for detecting fomesafen is critical to guide the correct and reasonable use of this herbicide. Rapid and sensitive immunoassay methods for fomesafen is unavailable due to the lack of specific antibody. In this study, a specific antibody for fomesafen was generated based on rational design of haptens and a sensitive immunoassay method was established. The half maximal inhibitory concentration (IC50) of the immunoassay was 39 ng/mL with a linear range (IC10-90) of 1.92-779.8 ng/mL. In addition, the developed assay had a good correlation with the standard UPLC-MS/MS both in the spike-recovery studies and in the detection of real soil samples. Overall, the developed indirect competitive enzyme immunoassay reported here is important for detecting and quantifying fomesafen contamination in soil and other environmental samples with good sensitivity and high reproducibility.

[Mechanism of Proliferation and Apoptosis of Acute Promyelocytic Leukemia Cell Line NB4 Induced by TPA].

OBJECTIVE: To investigate the effect of phorbol-12-myristate-13-ace-tate (TPA) on the proliferation and apoptosis of acute promyelocytic leukemia cell line NB4 and its molecular mechanism. METHODS: The effect of different concentrations of TPA on the proliferation of NB4 cells at different time points was detected by CCK-8 assay. The morphological changes of NB4 cells were observed by Wright-Giemsa staining. The cell cycle and apoptosis of NB4 cells after TPA treatment were detected by flow cytometry. The mRNA expressions of NB4 cells after TPA treatment were analyzed by high-throughput microarray analysis and real-time quantitative PCR. Western blot was used to detect the protein expression of CDKN1A, CDKN1B, CCND1, MYC, Bax, Bcl-2, c-Caspase 3, c-Caspase 9, PIK3R6, AKT and p-AKT. RESULTS: Compared with the control group, TPA could inhibit the proliferation of NB4 cells, induce the cells to become mature granulocyte-monocyte differentiation, and also induce cell G1 phase arrest and apoptosis. Differentially expressed mRNAs were significantly enriched in PI3K/AKT pathway. TPA treatment could increase the mRNA levels of CCND1, CCNA1, and CDKN1A, while decrease the mRNA level of MYC. It could also up-regulate the protein levels of CDKN1A, CDKN1B, CCND1, Bax, c-Caspase 3, c-Caspase 9, and PIK3R6, while down-regulate MYC, Bcl-2, and p-AKT in NB4 cells. CONCLUSION: TPA induces NB4 cell cycle arrest in G1 phase and promotes its apoptosis by regulating PIK3/AKT signaling pathway.

Ultrasound-assisted extraction and characterization of Penthorum chinense polysaccharide with anti-inflammatory effects.

Penthorum chinense has been used in both food and medication for many years, and polysaccharide of which was considered as one of the bioactive compounds. However, the extraction process of polysaccharide from P. chinense (PCP) was not well optimized. Ultrasound-assisted extractionhas been widely employed in the extraction of natural products for its compliance with the concept of green and economic chemistry. To better investigate the structure and biology activity of PCP, response surface methodology was employed to optimize the ultrasound-assisted extraction conditions of PCP. The optimum extraction for the ultrasound-assisted extraction of PCP were obtained as ratio of solvent to material 40 mL/g, ultrasonic power 380 W, and extraction time of 50 min. The yield of PCP reached 8.71% under these optimized conditions. PCP was further purified by using anion exchange chromatography and gel filtration, an acidic fraction PCP-AP-1 was hereby obtained. The results of structural elucidation indicated that PCP-AP-1 was a typical pectic polysaccharide with a molecular weight of 66360 Da, mainly composed of galacturonic acid (68.5 mol%), followed by arabinose (9.8 mol%), rhamnose (9.4 mol%), glucose (7.7 mol%), with homogalacturonan region and rhamnogalacturonan I regions. In vitro study showed that PCP-AP-1 could improve the inflammation induced by lipopolysaccharide in intestinal epithelial cells, which was probably performed through the inhibition of multiple signaling pathways including the inhibition of TLR4, NOD1/2 and NF-κB pathway, as well as the reduction of NLRP3 inflammasome. This study defined the type of polysaccharide present in P. chinense and revealed a potential of application this plant in the prevention of intestinal inflammatory diseases.

KIF23, under regulation by androgen receptor, contributes to nasopharyngeal carcinoma deterioration by activating the Wnt/ß-catenin signaling pathway.

Our study aimed to explore the potential mechanisms of KIF23 regulating function in the progression of nasopharyngeal carcinoma and pinpoint novel therapeutic targets for the clinical treatment of nasopharyngeal carcinoma patients. Firstly, the mRNA and protein level of KIF23 in nasopharyngeal carcinoma was measured using quantitative real-time PCR and western blot. Then, the influence of KIF23 on tumor metastasis and growth in nasopharyngeal carcinoma was determined through the in vivo and in vitro experiments. Lastly, the regulatory mechanisms of KIF23 in nasopharyngeal carcinoma were illustrated in the chromatin immunoprecipitation assay. KIF23 was first found to be overexpressed in nasopharyngeal carcinoma samples, and its expression was associated with poor prognosis. Then, the nasopharyngeal carcinoma cell's proliferation, migration, and invasion potential could be improved by inducing KIF23 expression both in vivo and in vitro. Furthermore, androgen receptor (AR) was found to bind to the KIF23 promoter region directly and enhance KIF23 transcription. At last, KIF23 could accelerate nasopharyngeal carcinoma deterioration via activating the Wnt/ß-catenin signaling pathway. AR/KIF23/Wnt/ß-catenin pathway promotes nasopharyngeal carcinoma deterioration. Our findings could serve as a new therapeutic strategy for nasopharyngeal carcinoma in the clinical practice.

Alfuzosin ameliorates diabetes by boosting PGK1 activity in diabetic mice.

AIMS: Diabetes mellitus (DM) has become a global problem, causing a huge economic burden. The purpose of this study is to find a new potential method and mechanism for the treatment of DM. MAIN METHODS: The oxidation, glycation and insulin resistance cell models were built to screen the potential anti-diabetic chemicals. Then the DM mice were induced by the combination of high-fat diet (HFD) and intraperitoneal injection of streptozotocin (50 mg/kg) for five days. The alfuzosin (1.2 mg/kg) was administered by intraperitoneal injection once daily for sequential 12 weeks. Fasting blood glucose, blood lipid, oxidative stress and key markers of glucose metabolism were detected. PGK1/AKT/GLUT4 pathway related proteins were analyzed by Western blot. KEY FINDINGS: Alfuzosin ameliorated oxidative stress, glycative stress and insulin resistance in HepG2 cells. Further, in a high-fat diet/streptozotocin (HFD/STZ)-induced diabetic mouse model, alfuzosin reduced fasting blood glucose, improved insulin sensitivity. Mechanically, alfuzosin activated PGK1 directly to stimulate the protein kinase B (AKT) signaling pathway, thus facilitating glucose uptake as well as improving insulin resistance. SIGNIFICANCE: The present finding has shed a new light on the treatment of DM and provides validation for PGK1 as a therapeutic target for DM.

Quinacrine attenuates diet-induced obesity by inhibiting adipogenesis via activation of AMPK signaling.

Obesity, a global epidemic chronic metabolic disease, urgently demands novel therapies. As an antimalarial drug, quinacrine has not been reported for its anti-obesity effect to our knowledge. This study aimed to explore the ability of quinacrine to attenuate obesity. In an in vitro adipogenic model, quinacrine exhibited an outstanding suppression on adipogenesis of 3T3-L1 cells, mainly by activating the AMPK (Adenosine 5'-monophosphate (AMP)-activated protein kinase) signaling pathway to regulate preadipocytes differentiation and lipid accumulation. In addition, C57BL/6N female mice were fed with high-fat diet and high-fructose water for 14 weeks to establish an obesity model, followed by oral administration of quinacrine or orlistat. After 9 weeks of treatment, quinacrine significantly reduced the body weight and energy intake, ameliorated the impaired glucose tolerance and restored the homeostasis of serum lipids. Also, quinacrine improved lipid profile and optimized the expression of AMPK signaling pathway related proteins in livers and adipose tissues of obese mice. Quinacrine reverses obesity through activating AMPK phosphorylation to down-regulate adipogenesis, along with lowering the risk of type 2 diabetes and atherosclerosis. It should be a novel application for the treatment of obesity and its associated diseases.

Tumour-stroma ratio is a valuable prognostic factor for oral tongue squamous cell carcinoma.

OBJECTIVE: The objectives of this study were to estimate the prognostic value of the tumour-stroma ratio (TSR) and tumour budding (TB) in oral tongue squamous cell carcinoma (OTSCC) and to establish a reliable model to predict the outcome of OTSCC patients. METHODS: A total of 103 patients surgically treated at our hospital were enrolled in this study. Chi-square tests, Kaplan-Meier analyses and Cox proportional hazards regression models were performed for statistical analysis. RESULTS: Fifty-six patients were categorized as stroma-rich, and 47 patients were categorized as stroma-poor. Only pathological grade was associated with the TSR (p = 0.017). Kaplan-Meier analysis showed that stroma-rich, high-intensity budding and high risk groups were associated with worse prognosis. The Cox regression model showed that the TSR was an independent risk factor for OTSCC patients prognosis, and the high risk group was also related to poor prognosis (p < 0.05). TB was significantly associated with poor prognosis but was not an independent risk factor. CONCLUSIONS: We found that patients in the stroma-rich group had a worse long-term prognosis. The TSR is an independent risk factor for OTSCC patients' outcome. In addition, a risk model that combined the TSR and TB proved to be valuable for predicting OTSCC patients' outcome.

Causal effect of polyunsaturated fatty acids on bone mineral density and fracture.

Background: Polyunsaturated fatty acids (PUFAs) are closely related to osteoporosis. To test their causal relationship, we conducted a Mendelian randomization (MR) analysis. Methods: We analyzed the causal relationship between four PUFAs measures, n-3 PUFAs (n-3), n-6 PUFAs (n-6), the ratio of n-3 PUFAs to total fatty acids (n-3 pct), and the ratio of n-6 PUFAs to n-3 PUFAs (n-6 to n-3), and five measures of osteoporosis, including estimated bone mineral density (eBMD), forearm (FA) BMD, femoral neck (FN) BMD, lumbar spine (LS) BMD, and fracture, using two-sample MR analysis. In order to verify the direct effect between PUFAs and BMD, we chose interleukin-6 (IL-6), tumor necrosis factor-ß (TNF-ß), and bone morphogenetic proteins 7 (BMP-7), three markers or cytokines strongly related to BMD, as possible confounding factors, and analyzed the possible causal relationships between them and PUFAs or BMD by MR. Inverse variance weighting (IVW), MR-Egger, weighted and weighted median were conducted. MR Pleiotropy RESidual Sum and Outlier (MR-PRESSO) and MR-Egger regression methods were used to evaluate the potential pleiotropy of instrumental variables (IVs) and outliers were identified by MR-PRESSO. Cochran's Q statistic was used to detect the heterogeneity among IVs. Leave-one-out sensitivity analysis was used to find SNPs that have a significant impact on the results. All results were corrected by the Bonferroni correction. Results: The IVW results showed that n-3 PUFAs (OR = 1.030, 95% CI: 1.013, 1.047, P = 0.001) and n-6 PUFAs (OR = 1.053, 95% CI: 1.034, 1.072, P < 0.001) were positively correlated with eBMD, while n-6 to n-3 (OR = 0.947, 95% CI: 0.924, 0.970, P < 0.001) were negatively correlated with eBMD. These casual relationships still existed after Bonferroni correction. There were positive effects of n-3 PUFAs on FA BMD (OR = 1.090, 95% CI: 1.011, 1.176, P = 0.025) and LS BMD (OR = 1.056, 95% CI: 1.011, 1.104, P = 0.014), n-3 pct on eBMD (OR = 1.028, 95% CI: 1.002, 1.055, P = 0.035) and FA BMD (OR = 1.090, 95% CI: 1.011, 1.174, P = 0.025), n-6 to n-3 on LS BMD (OR = 1.071, 95% CI: 1.021, 1.124, P = 0.005); negative effects of n-3 pct on fracture (OR = 0.953, 95% CI: 0.918, 0.988, P = 0.009) and n-6 to n-3 on FA BMD (OR = 0.910, 95% CI: 0.837, 0.988, P = 0.025). However, these causal effects all disappeared after Bonferroni correction (all P > 0.0025). None of IL-6, TNF-ß, and BMP-7 had a causal effect on PUFA and BMD simultaneously (all P > 0.05). Conclusion: Evidence from this MR study supports the genetically predicted causal effects of n-3, n-6, n-3 pct, and n-6 to n-3 on eBMD. In addition, n-3 not only associate with FA BMD and LS BMD through its own level and n-6 to n-3, but also link to fracture through n-3 pct.

Melatonin Suppresses Macrophage M1 Polarization and ROS-Mediated Pyroptosis via Activating ApoE/LDLR Pathway in Influenza A-Induced Acute Lung Injury.

Influenza virus infection is one of the strongest pathogenic factors for the development of acute lung injury (ALI)/ acute respiratory distress syndrome (ARDS). However, the underlying cellular and molecular mechanisms have not been clarified. In this study, we aim to investigate whether melatonin modulates macrophage polarization, oxidative stress, and pyroptosis via activating Apolipoprotein E/low-density lipoprotein receptor (ApoE/LDLR) pathway in influenza A-induced ALI. Here, wild-type (WT) and ApoE-/- mice were instilled intratracheally with influenza A (H3N2) and injected intraperitoneally with melatonin for 7 consecutive days. In vitro, WT and ApoE-/- murine bone marrow-derived macrophages (BMDMs) were pretreated with melatonin before H3N2 stimulation. The results showed that melatonin administration significantly attenuated H3N2-induced pulmonary damage, leukocyte infiltration, and edema; decreased the expression of proinflammatory M1 markers; enhanced anti-inflammatory M2 markers; and switched the polarization of alveolar macrophages (AMs) from M1 to M2 phenotype. Additionally, melatonin inhibited reactive oxygen species- (ROS-) mediated pyroptosis shown by downregulation of malonaldehyde (MDA) and ROS levels as well as inhibition of the NLRP3/GSDMD pathway and lactate dehydrogenase (LDH) release. Strikingly, the ApoE/LDLR pathway was activated when melatonin was applied in H3N2-infected macrophages and mice. ApoE knockout mostly abrogated the protective impacts of melatonin on H3N2-induced ALI and its regulatory ability on macrophage polarization, oxidative stress, and pyroptosis. Furthermore, recombinant ApoE3 (re-ApoE3) inhibited H3N2-induced M1 polarization of BMDMs with upregulation of MT1 and MT2 expression, but re-ApoE2 and re-ApoE4 failed to do this. Melatonin combined with re-ApoE3 played more beneficial protective effects on modulating macrophage polarization, oxidative stress, and pyroptosis in H3N2-infected ApoE-/- BMDMs. Our study indicated that melatonin attenuated influenza A- (H3N2-) induced ALI by inhibiting the M1 polarization of pulmonary macrophages and ROS-mediated pyroptosis via activating the ApoE/LDLR pathway. This study suggested that melatonin-ApoE/LDLR axis may serve as a novel therapeutic strategy for influenza virus-induced ALI.

Downregulation of MCF2L Promoted the Ferroptosis of Hepatocellular Carcinoma Cells through PI3K/mTOR Pathway in a RhoA/Rac1 Dependent Manner.

Methods and Results: The levels of MCF2L were detected by PCR and western blotting assay. The effect of MCF2L on ferroptosis was confirmed by MTT, colony formation assay, Brdu, in vivo animal experiment, and the content of Iron, GSH, ROS, and MDA. The underlying mechanisms were explored by PCR, western blotting, and affinity precipitation assay. Our findings demonstrated that MCF2L is remarkedly upregulated in HCC tissues, and sorafenib can induce the levels of MCF2L, suggesting that MCF2L might function in sorafenib resistance of HCC. Further analysis showed that downregulation of MCF2L enhances HCC cell death induced by sorafenib, and ferroptosis inhibitor can reverse this process. Subsequent experiments showed that downregulation of MCF2L elevates the content of Iron, ROS, and MDA, which are all indicators of ferroptosis. Finally, mechanism analysis showed that MCF2L regulates the PI3K/AKT pathway in a RhoA/Rac1 dependent manner. Conclusions: Our study showed that targeting MCF2L may be a hopeful method to overcome sorafenib-resistance through inducing ferroptosis in HCC.

Dual Inhibition of EGFR and IGF-1R Signaling Leads to Enhanced Antitumor Efficacy against Esophageal Squamous Cancer.

Both the epidermal growth factor receptor (EGFR) and insulin-like growth factor 1 receptor (IGF-1R) have been implicated in the development of cancers, and the increased expression of both receptors has been observed in esophageal cancer. However, the tyrosine kinase inhibitors of both receptors have thus far failed to provide clinical benefits for esophageal cancer patients. Studies have confirmed the complicated crosstalks that exist between the EGFR and IGF-1R pathways. The EGFR and IGF-1R signals act as mutual compensation pathways, thereby conveying resistance to EGFR or IGF-1R inhibitors when used alone. This study evaluated the antitumor efficacy of the EGFR/HER2 inhibitors, gefitinib and lapatinib, in combination with the IGF-1R inhibitor, linsitinib, on the esophageal squamous cell carcinoma (ESCC). Gefitinib or lapatinib, in combination with linsitinib, synergistically inhibited the proliferation, migration, and invasion of ESCC cells, caused significant cell cycle arrest, and induced marked cell apoptosis. Their combination demonstrated stronger inhibition on the activation of EGFR, HER2, and IGF-1R as well as the downstream signaling molecules. In vivo, the addition of linsitinib to gefitinib or lapatinib also potentiated the inhibition effects on the growth of xenografts. Our results suggest the next clinical exploration of the combination of gefitinib or lapatinib with linsitinib in the treatment of ESCC patients.

Acyclovir alleviates insulin resistance via activating PKM1 in diabetic mice.

AIMS: Diabetes mellitus (DM) is a major global health threat characterized by insulin resistance. A new tactic to ameliorate insulin resistance, thereby reversing the exacerbation of DM, is urgently needed. The work is aiming to provide a new strategy for DM treatment as well as to identify new targets. MAIN METHODS: C57BL/6 N mice were raised with high-fat diet (HFD) and infused with streptozotocin (STZ) to induce diabetes. The blood glucose, serum insulin, blood lipid and oxidative stress were detected. In vitro insulin resistance model experiment has been made to examine the molecular mechanisms underlying anti-diabetic effect of potential active chemicals in human hepatocellular carcinoma cells (HepG2). KEY FINDINGS: Acyclovir, an antiviral nucleotide analog, alleviates insulin resistance by reducing blood lipids as well as oxidative stress and elevating insulin sensitivity on diabetic mice, which is in accord with results in the insulin resistance model of HepG2 cells. Mechanically, acyclovir stimulates pyruvate kinase M1 (PKM1) directly to activate adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK)/Sirtuin1 (SIRT1) signaling pathway, thus improving insulin resistance. SIGNIFICANCE: The present study supports that acyclovir should be translated to remedy DM, and PKM1 might be a valuable target to develop new medicines.

Does smoking protect against developing osteoarthritis? Evidence from a genetically informed perspective.

OBJECTIVE: Cumulative evidence from observational studies showed an inverse association between smoking and osteoarthritis (OA), but this association could be confounded by obesity. This study aimed to decipher the causal effect of smoking on osteoarthritis risk from a genetically informed perspective. METHODS: We performed a two-sample univariable and multivariable MR to evaluate the independent effect of smoking on OA risk. Summary-level data were obtained from the largest available genome-wide association studies (GWASs) of smoking initiation, body mass index (BMI) and OA. Genetic variants predicted the exposure were selected as instruments from the respective GWAS. RESULTS: Genetically liability for smoking initiation had an effect estimate consistent with increased risk for overall OA (odds ratio (OR)=1.61, 95% confidence interval (CI)=1.43-1.81, P=7.50 × 10-15), hip OA (OR=1.62, 95%CI=1.29-2.02, P=2.93 × 10-5), knee OA (OR=1.54, 95%CI=1.29-1.84, P =1.80 × 10-6) and hip and/or knee OA (OR=1.56, 95%CI=1.34-1.80, P=3.63 × 10-9), respectively. We also found that genetic liability of BMI was significantly associated with OA risk and the OR per genetically predicted 1 kg/m2 increase of BMI ranged from 2.19 to 2.64. Additionally, multivariate MR analysis revealed a strong evidence for an effect of smoking initiation on the risk of overall OA (OR=1.45, 95%CI=1.31-1.61, P=3.69 × 10-12) and its subtypes after controlling for BMI. CONCLUSION: Our findings support an independent deleterious causal effect for smoking upon OA risk, which further strengthen the importance of smoking cessation interventions and obesity management in the general population, in order to lessen the huge burden of OA in the global aging era.

Synthesis of 8-Fluoroneocryptolepine and Evaluation for Cytotoxic Activity against AGS Cancer Cells.

Neocryptolepine derivatives have attracted great interest because of their unique cytotoxic activity. 8-Fluoroneocryptolepine (8FNC) was synthesized, and its cytotoxicity was evaluated by MTT assay in AGS gastric cancer cells and gastric mucosa GES-1 cells. 8-Fluoroneocryptolepine showed greater selectivity and cytotoxicity to AGS cells than the cisplatin (CIS) and fluorouracil (5-Fu) commonly used in clinical treatment of gastric cancer. Most importantly, we significantly improved the cytotoxic effect of 8FNC against AGS cells by structural modification and reduced the cytotoxicity against GES-1 cells compared with neocryptolepine. We further evaluated the activity of 8FNC against AGS cells in vitro. Our results indicate that 8FNC arrests the AGS cell cycle in the G2/M phase, reduces the mitochondrial membrane potential of AGS cells, and drives the initiation of apoptotic body formation in 8FNC-induced apoptosis. Moreover, 8FNC exhibits strong inhibitory effects on AGS cell migration. Studies on the molecular mechanisms of the cytotoxic activities of 8FNC revealed that it may play a significant role in the inhibitory effect on AGS human gastric cancer cells through the PI3K/AKT signaling pathway. In conclusion, 8FNC may become a promising lead compound in the development of potential clinical drug candidates for the treatment of gastric cancer.

A bispecific decoy receptor VEGFR-EGFR/Fc binding EGF-like ligands and VEGF shows potent antitumor efficacy.

Epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor (VEGFR) represent two clinically validated targets for a variety of human cancers, and dual inhibition of EGFR and VEGF(R) has demonstrated superior activity to single EGFR inhibitors. This study was to construct a novel bispecific decoy receptor VEGFR-EGFR/Fc that contains Fc portion of human IgG1 acted as molecular scaffold, and the immunoglobulin-like domain 1-3 of VEGFR1 and extracellular domain of EGFR fused to the N-terminal and C-terminal of Fc, respectively, aiming at capturing the EGF-like ligands and VEGF. ELISA showed that VEGFR-EGFR/Fc bound to EGF, TGF-α and VEGF with high affinity. It displayed potent proliferation inhibitory effects on human non-small-cell lung cancer A549 cells and human umbilical vein endothelial cells revealed by MTT assays. VEGFR-EGFR/Fc significantly inhibited cell invasion and migration demonstrated by wound healing assay and transwell assay. In vivo, VEGFR-EGFR/Fc showed remarkable growth inhibition on A549 xenografts. Cell apoptosis and inhibition of angiogenesis were also observed in xenograft tumour tissues. Mechanistically, VEGFR-EGFR/Fc pre-treatment blocked the phosphorylation of EGFR and VEGFR2 and resulted in a decrease in the downstream signalling molecules, AKT, p44/42MAPK and p38MAPK. These data suggest VEGFR-EGFR/Fc would be a promising candidate for cancer targeted therapy.

A randomized controlled study of vaginal fractional CO2 laser therapy for female sexual dysfunction.

The purpose of this study is to evaluate the efficacy and safety of vaginal fractional CO2 laser therapy for female sexual dysfunction (FSD). A total of 84 women at high risk of sexual dysfunction were randomly divided into two groups. Women in the laser group received vaginal fractional CO2 laser therapy. Others in the Kegel group were advised to participate in Kegel exercise training. Sexual distress and sexual function were evaluated by using the Female Sexual Distress Scale-Revised (FSDS-R) and the Chinese version Female Sexual Function Index (CVFSFI), respectively. Adverse events were recorded during the 12-month follow-up. At the end of the 6th and 12th months, the lubrication scores of the CVFSFI in the laser group (4.55±0.05, 4.58±0.09) were significantly higher than those in the Kegel group (4.19±0.15, 4.20±0.14) (P<0.05). The satisfaction scores in the laser group (4.43±0.08) were higher than those in the Kegel group (4.20±0.16) at the end of the 6th month (P<0.05). The self-contrast test in the laser group showed significant improvement in lubrication, pain, satisfaction and total scores after CO2 laser therapy (p<0.05). These improvements were maintained for 1 year. The improvement of FSDS-R in the laser group (10.0±0.2) was more evident than in the Kegel group (11.1±0.4) at the end of the 12th month. There were no major adverse events reported during laser therapy. Vaginal fractional CO2 laser therapy can effectively improve sexual function without any serious adverse events. It might be an effective and relatively safe treatment option for improving vaginal mucosa status in sexually active women with sexual dysfunction.