EMC10 modulates hepatic ER stress and steatosis in an isoform-specific manner.

BACKGROUND & AIMS: Endoplasmic reticulum (ER) membrane protein complex subunit 10 (EMC10) has been implicated in obesity. Here we investigated the roles of the two isoforms of EMC10, including a secreted isoform (scEMC10) and an ER membrane-bound isoform (mEMC10), in metabolic dysfunction-associated steatotic liver disease (MASLD). METHODS: Manifold steatotic mouse models and HepG2 cells were employed to investigate the role of EMC10 in the regulation of hepatic PERK-eIF2α-ATF4 signaling and hepatosteatosis. The therapeutic effect of scEMC10-neutralizing antibody on mouse hepatosteatosis was explored. Associations of MASLD with serum scEMC10 and hepatic mEMC10 were determined in two cohorts of participants with MASLD. RESULTS: scEMC10 promoted, while mEMC10 suppressed, the activation of hepatic PERK-eIF2α-ATF4 signaling. Emc10 gene knockout exacerbated, while hepatic overexpression of mEMC10 ameliorated, hepatic ER stress and steatosis in mice challenged with either a methionine- and choline-deficient diet or tunicamycin, highlighting a direct, suppressive role of mEMC10 in MASLD via modulation of hepatic ER stress. Overexpression of scEMC10 promoted, whereas neutralization of circulating scEMC10 prevented, hepatosteatosis in mice with fatty liver, suggesting a role of scEMC10 in MASLD development. Clinically, serum scEMC10 was increased, while hepatic mEMC10 was decreased, in participants with MASLD. Correlative analysis indicated that serum scEMC10 positively, whereas hepatic mEMC10 negatively, correlated with liver fat content and serum ALT, AST, and GGT. CONCLUSIONS: These findings demonstrate a novel isoform-specific role for EMC10 in the pathogenesis of MASLD and identify the secreted isoform as a tractable therapeutic target for MASLD via antibody-based neutralization. IMPACT AND IMPLICATIONS: We have shown the role of EMC10 in the regulation of energy homeostasis and obesity. In this study, we determine the distinct roles of the two isoforms of EMC10 in the regulation of hepatic endoplasmic reticulum stress and steatosis in mice, and report on the associations of the different EMC10 isoforms with metabolic dysfunction-associated steatotic liver disease in humans. Our findings delineate a novel regulatory axis for hepatosteatosis and identify EMC10 as a modulator of the PERK-eIF2α-ATF4 signaling cascade that may be of broad physiological significance. Moreover, our pre-clinical and clinical studies provide evidence of the therapeutic potential of targeting scEMC10 in MASLD.

A novel N-heterocycles substituted oseltamivir derivatives as potent inhibitors of influenza virus neuraminidase: discovery, synthesis and biological evaluation.

Our previous studies have shown that the introduction of structurally diverse benzyl side chains at the C5-NH2 position of oseltamivir to occupy 150-cavity contributes to the binding affinity with neuraminidase and anti-influenza activity. To obtain broad-spectrum neuraminidase inhibitors, we designed and synthesised a series of novel oseltamivir derivatives bearing different N-heterocycles substituents that have been proved to induce opening of the 150-loop of group-2 neuraminidases. Among them, compound 6k bearing 4-((r)-2-methylpyrrolidin-1-yl) benzyl group exhibited antiviral activities similar to or weaker than those of oseltamivir carboxylate against H1N1, H3N2, H5N1, H5N6 and H5N1-H274Y mutant neuraminidases. More encouragingly, 6k displayed nearly 3-fold activity enhancement against H3N2 virus over oseltamivir carboxylate and 2-fold activity enhancement over zanamivir. Molecular docking studies provided insights into the explanation of its broad-spectrum potency against wild-type neuraminidases. Overall, as a promising lead compound, 6k deserves further optimisation by fully considering the ligand induced flexibility of the 150-loop.

C-peptide, glycaemic control, and diabetic complications in type 2 diabetes mellitus: A real-world study.

OBJECTIVE: To explore the relationship between C-peptide and glycaemic control rate and diabetic complications (microvascular complication and cerebral infarction) and provide evidence for stratified treatment of type 2 diabetes mellitus (T2DM)-based C-peptide. METHOD: This is a cross-sectional real-world observational study. According to the inclusion and exclusion criteria, we studied 1377 patients with T2DM, grouped by fasting C-peptide and HOMA-IR. Blood samples were collected after fasting overnight. Logistic regression was used to analyse the relationship among fasting C-peptide, HOMA-IR, C2/C0 ratio (the ratio of 2 h postprandial C-peptide to fasting C-peptide), glycaemic control rate, and occurrence of diabetic complications. Restricted cubic spline (RCS) curves based on logistic regression were used to evaluate the relationship between C-peptide, glycaemic control rate, and diabetic kidney disease (DKD). RESULTS: Patients were subdivided according to their fasting C-peptide in 4 groups (Q1,Q2,Q3,Q4). Patients of group Q3 (1.71 ≤ C-peptide < 2.51 ng/ml) showed the lowest incidence of DKD, diabetic retinopathy (DR), and rate of insulin absorption as welll as higher glycaemic control rate. Logistic regression shows that the probability of reaching glycemic control increased with higher levels of C-peptide, compared with group Q1, after adjusting for age, gender, duration of diabetes, body mass index, systolic blood pressure, diastolic blood pressure, creatinine, low-density lipoprotein, triglyceride, total cholesterol, and high-density lipoprotein. RCS curve shows that, when C-peptide is ≤2.68 ng/ml, the incidence of not reaching glycaemic control decreases with increasing C-peptide. The possibility of not reaching glycaemic control decreased with increasing C2/C0, when C-peptide is ≥1.71 ng/ml. RCS curve shows that the relationship between C-peptide and DKD follows a U-style curve. When C-peptide is <2.84 ng/ml, the incidence of DKD decreased with increasing C-peptide. With the increase in the C2/C0 ratio, the incidence of DKD, DR, and fatty liver did not decrease. CONCLUSION: When C-peptide is ≥ 1.71 and < 2.51 ng/ml, patients with T2DM had a higher glycemic control rate. Excessive C-peptide plays different roles in DKD and DR; C-peptide may promote the incidence of DKD but protects patients from DR. Higher C2/C0 ratio is important for reaching glycaemic control but cannot reduce the risk of DKD, DR, and fatty liver.

Design and Synthesis of Novel Oleanolic Acid-Linked Disulfide, Thioether, or Selenium Ether Moieties as Potent Cytotoxic Agents.

A series of novel oleanolic acid (OA)-linked disulfide, thioether, or selenium ether derivatives was synthesized, and their antiproliferative activity was evaluated against human liver cancer (BEL-7402 and HepG-2), colon cancer (HCT116), and normal liver (L02) cell lines using methyl thiazolyl tetrazolium assay (MTT). Preliminary bioassay results revealed that OA derivatives modified at the C3-OH position, i. e., compound a4 containing sulfide ether, exhibited the best antiproliferative activity against BEL-7402 cells, with an IC50 value of 5.70±0.82 µM. Further flow cytometry assays revealed that compound a4 exerted its antiproliferative effects by inducing cell cycle arrest in the G2/M phase leading to apoptosis. Moreover, compared with the lead compound OA and the positive control drug 5-fluorouracil (5-FU), the OA derivatives demonstrated potent antiproliferative activities against the cancer cell lines.

Discovery of Novel Boron-Containing N-Substituted Oseltamivir Derivatives as Anti-Influenza A Virus Agents for Overcoming N1-H274Y Oseltamivir-Resistant.

To address drug resistance to influenza virus neuraminidase inhibitors (NAIs), a series of novel boron-containing N-substituted oseltamivir derivatives were designed and synthesized to target the 150-cavity of neuraminidase (NA). In NA inhibitory assays, it was found that most of the new compounds exhibited moderate inhibitory potency against the wild-type NAs. Among them, compound 2c bearing 4-(3-boronic acid benzyloxy)benzyl group displayed weaker or slightly improved activities against group-1 NAs (H1N1, H5N1, H5N8 and H5N1-H274Y) compared to that of oseltamivir carboxylate (OSC). Encouragingly, 2c showed 4.6 times greater activity than OSC toward H5N1-H274Y NA. Moreover, 2c exerted equivalent or more potent antiviral activities than OSC against H1N1, H5N1 and H5N8. Additionally, 2c demonstrated low cytotoxicity in vitro and no acute toxicity at the dose of 1000 mg/kg in mice. Molecular docking of 2c was employed to provide a possible explanation for the improved anti-H274Y NA activity, which may be due to the formation of key additional hydrogen bonds with surrounding amino acid residues, such as Arg152, Gln136 and Val149. Taken together, 2c appeared to be a promising lead compound for further optimization.

Design, Synthesis and Structure-Activity Relationships of Phenylalanine-Containing Peptidomimetics as Novel HIV-1 Capsid Binders Based on Ugi Four-Component Reaction.

As a key structural protein, HIV capsid (CA) protein plays multiple roles in the HIV life cycle, and is considered a promising target for anti-HIV treatment. Based on the structural information of CA modulator PF-74 bound to HIV-1 CA hexamer, 18 novel phenylalanine derivatives were synthesized via the Ugi four-component reaction. In vitro anti-HIV activity assays showed that most compounds exhibited low-micromolar-inhibitory potency against HIV. Among them, compound I-19 exhibited the best anti-HIV-1 activity (EC50 = 2.53 ± 0.84 µM, CC50 = 107.61 ± 27.43 µM). In addition, I-14 displayed excellent HIV-2 inhibitory activity (EC50 = 2.30 ± 0.11 µM, CC50 > 189.32 µM) with relatively low cytotoxicity, being more potent than that of the approved drug nevirapine (EC50 > 15.02 µM, CC50 > 15.2 µM). Additionally, surface plasmon resonance (SPR) binding assays demonstrated direct binding to the HIV CA protein. Moreover, molecular docking and molecular dynamics simulations provided additional information on the binding mode of I-19 to HIV-1 CA. In summary, we further explored the structure­activity relationships (SARs) and selectivity of anti-HIV-1/HIV-2 of PF-74 derivatives, which is conducive to discovering efficient anti-HIV drugs.

One-step synthesis of methylene-bridged bis-carbazole and evaluation of its antitumor activity and G-quadruplex DNA binding property.

Most reported carbazolyl G-quadruplex DNA (G4-DNA) ligands possess a rigid structure rather than a flexible one. The conformationally flexible ligands are paid much less attention. In this study, we report a novel class of non-rigid methylene-bridged biscarbazolyl ligand and their G4-DNA binding properties. Moreover, the antitumor activities of all these oligomers have been evaluated. The results show that this family of oligomers could be facilely synthesized via solely one step. Among them, compound 2, the bis-carbazole derivative, displays the best antitumor activity and IC50 values against HT-29, HepG2, A375 and MCF-7 cells are 0.69, 5.09, 3.15 and 3.8 µ mol/L, respectively. Although conformationally flexible, 2 is still capable of binding to as well as stabilizing G4-DNA via π-π stacking interaction. Moreover, 2 selectively binds to G4-DNA over duplex DNA. The current study enriches the category of carbazolyl G4-DNA ligands and paves the way for the search of more efficient G4-DNA ligands and antitumor leads.

Design and synthesis of novel oridonin analogues as potent anticancer agents.

To identify anticancer agents with higher potency and lower toxicity, a series of oridonin derivatives with substituted benzene moieties at the C17 position were designed, synthesised, and evaluated for their antiproliferative properties. Most of the derivatives exhibited antiproliferative effects against AGS, MGC803, Bel7402, HCT116, A549, and HeLa cells. Compound 2p (IC50 = 1.05 µM) exhibited the most potent antiproliferative activity against HCT116 cells; it was more potent than oridonin (IC50 = 6.84 µM) and 5-fluorouracil (5-FU) (IC50 = 24.80 µM). The IC50 value of 2p in L02 cells was 6.5-fold higher than that in HCT116 cells. Overall, it exhibited better selective antiproliferative activity and specificity than oridonin and 5-FU. Furthermore, compound 2p arrested HCT116 cells at the G2 phase of the cell cycle and increased the percentage of apoptotic cells to a greater extent than oridonin.

Design and synthesis of new triazoles linked to xanthotoxin for potent and highly selective anti-gastric cancer agents.

Two series of xanthotoxin-triazole derivatives were designed, synthesized, and studied for their antiproliferative properties. The in vitro cytotoxicity of the compounds in the AGS cancer cell line and the L02 normal cell line was evaluated via MTT assay. Among the synthesized compounds, 9-((1-(4-(trifluoromethyl)phenyl)-1H-1,2,3-triazol-4-yl)methoxy)-7H-furo[3,2-g]chromen-7-one (6p) was found to have the greatest antiproliferative activity against AGS cells (IC50=7.5µM) and showed better activity than the lead compound (xanthotoxin, IC50>100µM) and the reference drug (5-fluorouracil, IC50=29.6µM) did. The IC50 value of 6p in L02 cells was 13.3 times higher than that in the AGS cells. Therefore, the compound exhibited better therapeutic activity and specificity compared with the positive control 5-fluorouracil. Cell cycle analysis revealed that compound 6p inhibited cell growth via the induction of S/G2 phase arrest in AGS cells. Compound 6p was identified as a promising lead compound for the further development and identification of 1,2,3-triazole-based anticancer agents.

Synthesis and biological evaluation of novel 7-hydroxy-4-phenylchromen-2-one-linked to triazole moieties as potent cytotoxic agents.

A new series of novel 7-hydroxy-4-phenylchromen-2-one (1a)-linked 1,2,4-triazoles were synthesised using a click chemistry approach. All derivatives were subjected to 3-(4,5-dimethylthiazol-yl)-diphenyl tetrazolium bromide (MTT) cytotoxicity screening against a panel of six different human cancer cell lines (AGS, MGC-803, HCT-116, A-549, HepG2, and HeLa) to assess their cytotoxic potential. Among the tested molecules, some of the analogues showed better cytotoxic activity than that shown by the 7-hydroxy-4-phenylchromen-2-one (1a). Of the synthesised 1,2,4-triazoles,the 7-((4-(4-Chlorophenyl)-4H-1,2,4-triazol-3-yl)methoxy)-4-phenyl-2H-chromen-2-one (4d) showed the best activity, with an IC50 of 2.63 ± 0.17 µM against AGS cells. Further flow cytometry assays demonstrated that compound 4d exerts its antiproliferative effects by arresting cells in the G2/M phase of the cell cycle and by inducing apoptosis. Collectively, our results indicate that the 1,2,4-triazole derivatives have a significantly stronger antitumour activity than 1,2,3-triazole derivatives. Most of the compounds exhibited better antitumour activity than the positive control drug 5-fluorouracil.

Broad-spectrum antiviral strategy: Host-targeting antivirals against emerging and re-emerging viruses.

Viral infections are amongst the most prevalent diseases that pose a significant threat to human health. Targeting viral proteins or host factors represents two primary strategies for the development of antiviral drugs. In contrast to virus-targeting antivirals (VTAs), host-targeting antivirals (HTAs) offer advantages in terms of overcoming drug resistance and effectively combating a wide range of viruses, including newly emerging ones. Therefore, targeting host factors emerges as an extremely promising strategy with the potential to address critical challenges faced by VTAs. In recent years, extensive research has been conducted on the discovery and development of HTAs, leading to the approval of maraviroc, a chemokine receptor type 5 (CCR5) antagonist used for the treatment of HIV-1 infected individuals, with several other potential treatments in various stages of development for different viral infections. This review systematically summarizes advancements made in medicinal chemistry regarding various host targets and classifies them into four distinct catagories based on their involvement in the viral life cycle: virus attachment and entry, biosynthesis, nuclear import and export, and viral release.

Association between Serum Phosphorus Levels and Diabetic Retinopathy: A Cross-Sectional Study.

Background and Aims: The aim of this study was to investigate the association between serum phosphate levels and diabetic retinopathy (DR) in patients with type 2 diabetes mellitus (T2DM). Methods and Results: The study sample consisted of 1657 T2DM patients hospitalized between 2017 and 2019. Patients were categorized into quartiles based on their serum phosphate levels (Q1-Q4). An increasing trend in the prevalence of DR was observed across these quartiles. Subsequently, logistic regression analysis was employed to adjust for potential confounders, such as gender, age, BMI, and duration of diabetes, and to evaluate the odds ratios (ORs) associated with these quartiles. The prevalence of DR showed an increasing trend with elevated serum phosphate levels. Logistic regression further confirmed that serum phosphate levels remain an independent risk factor for DR. Conclusion: Elevated serum phosphate levels are closely associated with the prevalence of DR in hospitalized T2DM patients. Further studies are needed to establish causality. This trial is registered with chiCTR2000032374.

Analysis of an adult diabetes mellitus caused by a rare mutation of the gene: A case report.

BACKGROUND: This study presents the clinical and genetic mutation characteristics of an unusual case of adult-onset diabetes mellitus occurring in adolescence, featuring a unique mutation in the peroxisome proliferator-activated receptor gamma (PPARG) gene. Data Access Statement: Research data supporting this publication are available from the NN repository at www.NNN.org/download/. CASE SUMMARY: The methodology employed entailed meticulous collection of comprehensive clinical data from the probands and their respective family members. Additionally, high-throughput sequencing was conducted to analyze the PPARG genes of the patient, her siblings, and their offspring. The results of this investigation revealed that the patient initially exhibited elevated blood glucose levels during pregnancy, accompanied by insulin resistance and hypertriglyceridemia. Furthermore, these strains displayed increased susceptibility to diabetic kidney disease without any discernible aggregation patterns. The results from the gene detection process demonstrated a heterozygous mutation of guanine (G) at position 284 in the coding region of exon 2 of PPARG, which replaced the base adenine (A) (exon2c.284A>Gp.Tyr95Cys). This missense mutation resulted in the substitution of tyrosine with cysteine at the 95th position of the translated protein. Notably, both of her siblings harbored a nucleotide heterozygous variation at the same site, and both were diagnosed with diabetes. CONCLUSION: The PPARG gene mutation, particularly the p.Tyr95Cys mutation, may represent a newly identified subtype of maturity-onset diabetes of the young. This subtype is characterized by insulin resistance and lipid metabolism disorders.

[Research progress of relationship in long-novel coronavirus syndrome and sarcopenia].

At present, the major public health challenges caused by novel coronavirus infection have gradually subside. However, a large number of people are still suffering from long-novel coronavirus syndrome or post-novel coronavirus syndrome. The clinical manifestations of long coronavirus syndrome are related to multiple systems, such as respiratory, circulatory, nervous, digestive and musculoskeletal systems, with various long-term persistent symptoms after novel coronavirus infection. At the same time, the infection of the novel coronavirus is an important cause of frailty and sarcopenia in the elderly population. However, at present, the scholars have not paid enough attention to the skeletal muscle weakness caused by the novel coronavirus. Therefore, this paper focuses on the long-novel coronavirus syndrome and sarcopenia to explore the pathological mechanism of skeletal muscle attenuation caused by the SARS-CoV-2 mediated "cytokine storm", mitochondrial damage, hypoxia state and other links,so as to raise the attention of clinical and academic researchers and improve the clinical strategy of frailty and sarcopenia after novel coronavirus infection.

Recent advances of phenotypic screening strategies in the application of anti-influenza virus drug discovery.

Seasonal and pandemic influenza virus infections not only pose a serious threat to human health but also cause tremendous economic losses and social burdens. However, due to the inherent high variability of influenza virus RNA genomes, the existing anti-influenza virus drugs have been frequently faced with the clinical issue of emerging drug-resistant mutants. Therefore, there is an urgent need to develop efficient and broad-spectrum antiviral agents against wild-type and drug-resistant mutant strains. Phenotypic screening has been widely employed as a reliable strategy to evaluate antiviral efficacy of novel agents independent of their modes of action, either directly targeting viral proteins or regulating cellular factors involved in the virus life cycle. Here, from the point of view of medicinal chemistry, we review the research progress of phenotypic screening strategies by focusing direct acting antivirals against influenza virus. It could provide scientific insights into discovery of a distinctive class of therapeutic candidates that ensure high efficiency but low cytotoxicity, and address issues from circulation of drug-resistant influenza viruses in the future.

Risk Factors and Oncologic Outcomes for Clinical T1 Renal Cell Carcinoma Upstaging to Pathological T3a and The Construction of Predictive Model: A Retrospective Study.

PURPOSE: The study is intended to identify the independent predictors of clinical T1 (cT1) renal cell carcinoma upstaging to pathological T3a (pT3a) and construct the predictive nomogram model. METHODS: The data of cT1 renal cell carcinoma was collected from patients who were treated in the Second Hospital of Tianjin Medical University from January 2010 to December 2016. Mann-Whitney U and chi-square tests were performed to analyze continuous and categorical variables respectively. Univariate and multivariate logistic regression were used to identify the predictors of upstaging. Kaplan-Meier method, log-rank test and Cox regression were performed to analyze survival materials. RESULTS: Among 1,376 cT1 renal cell carcinoma patients, 75 patients were observed upstaging to pT3a, accounting for 5.5%. There were 6 potential predictors of upstaging, i.e age, clinical symptom, tumor size, Fuhrman grade, tumor necrosis and tumor edge regularity. The 5-year recurrence free survival probabilities of upstaging and non-upstaging patients were 73.3% and 91.1%, respectively and upstaging was an independent predictor of recurrence free survival. Two predictive nomograms were constructed and the C-index of them were 0.842 and 0.806, and the calibration curve and decision curve analysis showed highly clinical accuracy of the nomograms. CONCLUSION: Two nomogram models were built to predict the probability of cT1 renal cell carcinoma upstaging to pT3a with highly accuracy and specificity. Upstaging was an independent risk factor of recurrence free survival for cT1 renal cell carcinoma patients.

The role of C-peptide in diabetes and its complications: an updated review.

Worldwide, diabetes and its complications have seriously affected people's quality of life and become a serious public health problem. C-peptide is not only an indicator of pancreatic ß-cell function, but also a biologically active peptide that can bind to cell membrane surface signaling molecules and activate downstream signaling pathways to play antioxidant, anti-apoptotic and inflammatory roles, or regulate cellular transcription through internalization. It is complex how C-peptide is related to diabetic complications. Both deficiencies and overproduction can lead to complications, but their mechanisms of action may be different. C-peptide replacement therapy has shown beneficial effects on diabetic complications in animal models when C-peptide is deficient, but results from clinical trials have been unsatisfactory. The complex pattern of the relationship between C-peptide and diabetic chronic complications has not yet been fully understood. Future basic and clinical studies of C-peptide replacement therapies will need to focus on baseline levels of C-peptide in addition to more attention also needs to be paid to post-treatment C-peptide levels to explore the optimal range of fasting C-peptide and postprandial C-peptide maintenance.

The risk of nonalcoholic fatty liver disease in gout patients with frequent flares: a retrospective cohort study.

OBJECTIVE: Nonalcoholic fatty liver disease (NAFLD) is a common chronic disease that is related to high serum uric acid; however, the association between the frequency of gout flares and NAFLD risk remains unclear. This study aimed to investigate whether frequent gout flares were associated with incident NAFLD and analyze the interaction of frequency of gout flares and Adipo-IR on NAFLD in the gout Chinese population. METHODS: A total of 350 cases of gout patients were enrolled in this retrospective cohort study. Cox proportional hazard regression analyses were performed to determine the association between frequent gout flares and NAFLD during follow-up and analyze the interaction of frequency of gout flares and Adipo-IR on NAFLD. Receiver operating curves (ROC) were plotted to explore the diagnostic value of frequent gout flares and Adipo-IR on the occurrence of NAFLD. RESULTS: NAFLD developed in 78 participants (22.3%) during follow-up. Logistic regression showed that Adipo-IR was an independent factor associated with frequent gout flares risk. The multivariate Cox regression analysis revealed that frequent gout flares and Adipo-IR were associated with NAFLD risk (HR: 7.88, 95% CI: 2.11-29.48, p < 0.01; HR: 1.058, 95% CI: 1.01-1.2, p < 0.05). And ROC showed that both of them had a great discriminant ability to diagnose NAFLD. CONCLUSIONS: Our data showed an independent association between the frequency of gout flares or Adipo-IR and incident NAFLD. Frequent gout flares and elevated Adipo-IR had a good predictive capability towards NAFLD development and played a synergistic role in the development of NAFLD. KEY POINTS: • Frequent gout flares and elevated Adipo-IR had a good diagnostic capability towards NAFLD development. • Frequent gout flares and Adipo-IR played a synergistic role in the development of NAFLD.

Progesterone levels associated with proteinuria in male diabetes mellitus patients: A cross-sectional retrospective study.

INTRODUCTION: The relationship between progesterone (P) and diabetic nephropathy (DKD) is unclear. Herein, we investigated the relationship between progesterone and DKD in men and postmenopausal women with type 2 diabetes mellitus. MATERIALS AND METHODS: We recruited 3,556 male and postmenopausal female patients and obtained the dominance ratio (OR) and corresponding 95% confidence intervals (CIs) associated with progesterone by logistic regression analysis after adjusting for potentially confounding variants. RESULTS: We found that progesterone levels were significantly lower in the massive proteinuria and microproteinuria groups compared with the non-DKD group for male patients. Also, microproteinuria and massive proteinuria prevalence were higher in the first (lowest) progesterone quartile than in the second to fourth quartiles. After adjusting for confounders, compared with the first (lowest) progesterone quartile group, the OR for the second to fourth quartiles in the male microproteinuria subgroup, were: Q2: 0.846 (95% CI: 0.581-1.233, P = 0.385); Q3: 0.667 (95% CI: 0.45-0988, P = 0.044); Q4: 0.597 (95% CI: 0.393-0.907, P = 0.016). In the male massive proteinuria subgroup, the OR for the third quartile group was 0.418 (95% CI: 0.201-0.867, P = 0.019). In contrast, no significant association was detected between progesterone and DKD prevalence in the female group. CONCLUSIONS: Progesterone levels were negatively associated with DKD incidence in hospitalized male patients with type 2 diabetes mellitus.

Emerging drug design strategies in anti-influenza drug discovery.

Influenza is an acute respiratory infection caused by influenza viruses (IFV), According to the World Health Organization (WHO), seasonal IFV epidemics result in approximately 3-5 million cases of severe illness, leading to about half a million deaths worldwide, along with severe economic losses and social burdens. Unfortunately, frequent mutations in IFV lead to a certain lag in vaccine development as well as resistance to existing antiviral drugs. Therefore, it is of great importance to develop anti-IFV drugs with high efficiency against wild-type and resistant strains, needed in the fight against current and future outbreaks caused by different IFV strains. In this review, we summarize general strategies used for the discovery and development of antiviral agents targeting multiple IFV strains (including those resistant to available drugs). Structure-based drug design, mechanism-based drug design, multivalent interaction-based drug design and drug repurposing are amongst the most relevant strategies that provide a framework for the development of antiviral drugs targeting IFV.