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Breast cancer (BC) remains a leading cause of cancer-related mortality in women, with hormone receptor-positive (HR+) tumors accounting for a significant proportion of cases. Despite advancements in endocrine therapy (ET), resistance remains a challenge in metastatic settings. The use of cyclin-dependent kinases 4/6 (CDK4/6) inhibitors in combination with endocrine therapy has notably improved survival. In China, when patients develop resistance to CDK4/6 inhibitors (CDK4/6i) or face financial constraints that prevent their use, chemotherapy becomes the standard treatment approach. This highlights an urgent need for effective treatments following CDK4/6i therapy. ESG401 is a novel trophoblast cell-surface antigen 2 (Trop2) directed antibody-drug conjugate (ADC) with promising preclinical and early clinical efficacy and safety data. We report a case of a 61-year-old female with HR+HER2- metastatic breast cancer (MBC) who developed resistance to fulvestrant and subsequent chemotherapy but achieved a durable partial response (PR) lasting more than 22.5 months following ESG401 treatment. This case underscores the potential role of Trop2-directed ADCs, such as ESG401, in overcoming endocrine resistance and providing meaningful clinical benefit in heavily pretreated patients with HR+/HER2- MBC. Furthermore, the patient’s exceptionally long clinical benefit distinguishes her from other patients receiving ESG401 treatment. Further exploration of the use of ESG401 in HR+HER2- MBC patients, as well as a deeper understanding of the characteristics of patients that may impact sustained efficacy, in expanded clinical trials is warranted.

Summary: This phase 1a study assesses ESG401 in patients with heavily pretreated locally advanced or metastatic solid tumors, focusing on metastatic breast cancer. Forty patients are enrolled: three experience dose-limiting toxicities, establishing the maximum tolerated dose at 16 mg/kg on days 1, 8, and 15 of a 28-day cycle. The most common grade ≥3 treatment-related adverse events are neutropenia and leukopenia. Among 38 efficacy-evaluable patients, the objective response rate (ORR) is 34.2%, the disease control rate (DCR) is 65.8%, and the clinical benefit rate (CBR) is 50.0% (including stable disease for at least 6 months). The median progression-free survival is 5.1 months, and the median duration of response is 6.3 months. In patients receiving therapeutically relevant doses, the ORR, DCR, and CBR are 40.6%, 75.0%, and 56.3%, respectively. ESG401 demonstrates a favorable safety profile and promising antitumor activity in this heavily treated population. The trial is registered at ClinicalTrials.gov (NCT04892342).

BackgroundPrevious studies reported that endometriosis may have a higher risk of arthritis. However, it remains unclear whether the association between endometriosis and arthritis has genetic correlations, or the relationship is causal. Linkage Disequilibrium Score (LDSC) and Mendelian Randomization (MR) analyses use genetic variation as a natural experiment to explore genetic correlations and causal inferences from observational data, reducing unmeasured confounding factors.MethodParticipants (aged 20-54 years, n = 2,915) for the cross-sectional study were obtained from the National Health and Nutrition Examination Survey (NHANES). Endometriosis and arthritis were diagnosed based on self-reported by reproductive health and medical condition questionnaire. Weighted multivariable logistic regression was used to explore the relationship between endometriosis and arthritis. LDSC and MR analysis were performed using the genome-wide association study (GWAS) summary statistics to identify the causal association.ResultA significant positive association between endometriosis and arthritis was found after multivariable adjustment (OR = 1.89; 95% CI: 1.33, 2.67). When exploring different types of arthritis, a positive association was revealed with rheumatoid arthritis (RA), other types of arthritis, and cases that the arthritis type were unknown, with an OR of 2.07 (95% CI: 1.03, 4.17), 2.78 (95% CI: 1.30, 5.95), and 2.06 (95% CI: 1.36, 3.11), respectively. However, genetic correlation analysis between endometriosis and RA did not reveal any significant findings (all P values > 0.05). Moreover, MR analysis also failed to identify a causal relationship between endometriosis and RA (all P values > 0.05).ConclusionCross-sectional study identified a significant positive association between endometriosis and arthritis among US women, especially among RA, while findings based on LDSC and MR analysis did not support a genetic correlation or causal role. These findings suggest that clinicians should pay more attention to the coexistence of RA in endometriosis patients and explore the shared pathophysiological mechanisms of these two disorders, with a particular focus on extrinsic factors rather than intrinsic genetic inheritance.

BackgroundThe global prevalence of infertility is 9%, with male factors potentially accounting for 40% to 60% of cases. Conventional treatments can be ineffective, invasive, costly, and linked to adverse effects and high risks. Previous studies have shown that, Chinese herbal medicine (CHM) can regulate the hypothalamus-pituitary-testis axis, improve sperm abnormalities and quality, mitigate oxidative stress, and decrease DNA fragmentation index (DFI). Yet, the evidence backing the use of Chinese herbal medicine (CHM) for treating male factor infertility lacks conviction due to study design limitations, and there remains a scarcity of studies on the live birth rate following CHM treatment for male factor infertility. Here, we describe the rationale and design of a randomized waitlist-controlled trial to evaluate the effect of CHM on the live birth rate among males with infertility.MethodsThis study is a single-center, randomized, waitlist-controlled study. A total of 250 couples diagnosed with male factor infertility will be enrolled in this study and then randomly allocated into two groups in a 1:1 ratio. Male participants in CHM group (treatment group) will receive CHM once a day for 3 months. Male participants in the waitlist group (control group) will not receive any treatment for 3 months. After 3 months, participants in both groups need to be followed up for another 12 months. The primary outcome will be the live birth rate; secondary outcomes include semen quality parameters, DFI and pregnancy related outcomes. Safety will also be assessed.DiscussionThe purpose of this trial is to explore the effects and safety of CHM on the live birth rate among couples dealing with male factor infertility. The outcome of this trial may provide a viable treatment option for male factor infertility.Trial registrationChinese Clinical Trial Registry: ChiCTR2200064416. Registered on 7 October 2022, https://www.chictr.org.cn.

Abstract Background Inflammation exerts a critical role in the pathogenesis of infertility. The relationship between inflammatory parameters from peripheral blood and infertility remains unclear. Aim of this study was to investigate the association between inflammatory markers and infertility among women of reproductive age in the United States. Methods Women aged 20–45 were included from the National Health and Nutrition Examination Survey (NHANES) 2013–2020 for the present cross-sectional study. Data of reproductive status was collected from the Reproductive Health Questionnaire. Six inflammatory markers, systemic immune inflammation index (SII), lymphocyte count (LC), product of platelet and neutrophil count (PPN), platelet-lymphocyte ratio (PLR), neutrophil–lymphocyte ratio (NLR) and lymphocyte-monocyte ratio (LMR) were calculated from complete blood counts in mobile examination center. Survey-weighted multivariable logistic regression was employed to assess the association between inflammatory markers and infertility in four different models, then restricted cubic spline (RCS) plot was used to explore non-linearity association between inflammatory markers and infertility. Subgroup analyses were performed to further clarify effects of other covariates on association between inflammatory markers and infertility. Results A total of 3,105 women aged 20–45 was included in the final analysis, with 431 (13.88%) self-reported infertility. A negative association was found between log2-SII, log2-PLR and infertility, with an OR of 0.95 (95% CI: 0.78,1.15; p = 0.60), 0.80 (95% CI:0.60,1.05; p = 0.10), respectively. The results were similar in model 1, model 2, and model 3. Compared with the lowest quartile (Q1), the third quartile (Q3) of log2-SII was negatively correlation with infertility, with an OR (95% CI) of 0.56 (95% CI: 0.37,0.85; p = 0.01) in model 3. Similarly, the third quartile (Q3) of log2-PLR was negatively correlation with infertility, with an OR (95% CI) of 0.61 (95% CI: 0.43,0.88; p = 0.01) in model 3. No significant association was observed between log2-LC, log2-PPN, log2-NLR, log2-LMR and infertility in model 3. A similar U-shaped relationship between log2-SII and infertility was found (p for non-linear

IntroductionStudies have shown that the gut microbiota is associated with male infertility (MI). However, their causal relationship and potential mediators need more evidence to prove. We aimed to investigate the causal relationship between the gut microbiome and MI and the potential mediating role of inflammatory cytokines from a genetic perspective through a Mendelian randomization approach.MethodsThis study used data from genome-wide association studies of gut microbes (Mibiogen, n = 18, 340), inflammatory cytokines (NFBC1966, FYPCRS, FINRISK 1997 and 2002, n=13, 365), and male infertility (Finngen, n=120, 706) to perform two-way Mendelian randomization (MR), mediated MR, and multivariate MR(MVMR) analyses. In this study, the inverse variance weighting method was used as the primary analysis method, and other methods were used as supplementary analysis methods.ResultsIn the present study, two gut microbes and two inflammatory cytokines were found to have a potential causal relationship with MI. Of the two gut microorganisms causally associated with male infertility, Anaerotruncus increased the risk of male infertility (odds ratio = 1.81, 95% confidence interval = 1.18-2.77, P = 0.0062), and Bacteroides decreased the risk of male infertility (odds ratio = 0.57, 95% confidence interval = 0.33-0.96, P = 0.0363). In addition, of the two inflammatory cytokines identified, hepatocyte growth factor(HGF) reduced the risk of male infertility (odds ratio = 0.50, 95% confidence interval = 0.35-0.71, P = 0.0001), Monocyte chemotactic protein 3 (MCP-3) increased the risk of male infertility (odds ratio = 1.28, 95% confidence interval = 1.03-1.61, P = 0.0039). Mediated MR analysis showed that HGF mediated the causal effect of Bacteroides on MI (mediated percentage 38.9%). Multivariate MR analyses suggest that HGF may be one of the pathways through which Bacteroides affects MI, with other unexplored pathways.ConclusionThe present study suggests a causal relationship between specific gut microbiota, inflammatory cytokines, and MI. In addition, HGF may mediate the relationship between Bacteroides and MI.

Abstract Background Cells have been increasingly known to release extracellular vesicles (EVs) to the extracellular environment under physiological and pathological conditions. A plethora of studies have revealed that EVs contain cell-derived biomolecules and are found in circulation, thereby implicating them in molecular trafficking between cells. Furthermore, EVs have an effect on physiological function and disease development and serve as disease biomarkers. Main body Given the close association between EV circulation and vascular disease, this review aims to provide a brief introduction to EVs, with a specific focus on the EV cargoes participating in pathological mechanisms, diagnosis, engineering, and clinical potential, to highlight the emerging evidence suggesting promising targets in vascular diseases. Despite the expansion of research in this field, some noticeable limitations remain for clinical translational research. Conclusion This review makes a novel contribution to a summary of recent advances and a perspective on the future of EVs in vascular diseases. Video Abstract

In recent years, an increasing number of reports have explored the wound healing mechanism of these two traditional Chinese herbal medicines- Panax ginseng and Panax notoginseng, but there is no systematic research on the related core functions and different mechanisms in the treatment of wound healing up to now. Based on network pharmacology and meta-analysis, the present work aimed to comprehensively review the commonality and diversity of P. ginseng and P. notoginseng in wound healing. In this study, a wound healing-related ''ingredients-targets'' network of two herbs was constructed. Thereafter, meta-analysis of the multiple target lists by Metascape showed that these two medicines significantly regulated blood vessel development, responses to cytokines and growth factors and oxygen levels, cell death, cell proliferation and differentiation, and cell adhesion. To better understand the discrepancy between these two herbs, it was found that common signaling pathways including Rap1, PI3K/AKT, MAPK, HIF-1 and Focal adhesion regulated the functions listed above. In parallel, the different pathways including renin-angiotensin system, RNA transport and circadian rhythm, autophagy, and the different metabolic pathways may also explained the discrepancies in the regulation of the above-mentioned functions, consistent with the Traditional Chinese Medicine theory about the effects of P. ginseng and P. notoginseng.

Abstract Problem Interferon epsilon (IFN‐ε) is constitutively expressed in the epithelium of female reproductive tract and confers vital protection against sexually transmitted pathogens in mouse models. However, there is limited insight into the role of IFN‐ε in human sexually transmitted infections such as human papillomavirus (HPV). Method of Study Cervical biopsies were obtained from high‐risk (HR) HPV positive (n = 28) and HR‐HPV negative (n = 10) women. mRNA expression of IFN‐ε in cervical tissues was measured by qPCR. Expression of the IFN‐ε protein was determined by Western blot analysis, immunohistochemistry and immunofluorescence staining. Results mRNA expression of IFN‐ε was higher in the ectocervix than that of other IFNs, and was further upregulated in HR‐HPV positive women compared with HR‐HPV negative women. Expression of the IFN‐ε protein was comparable between HR‐HPV infected patients and healthy controls. Conclusions These results reveal differential expression of IFN‐ε mRNA between individuals with or without HR‐HPV infection, and imply direct or indirect regulatory mechanisms for IFN‐ε transcription by HPV. Expression of IFN‐ε protein in HPV infections would require further validation.

BackgroundDistal symmetric polyneuropathy (DSPN) is the most common chronic complication of type 2 diabetes mellitus (T2DM). DSPN may lead to more serious complications, such as diabetic foot ulcer, amputation, and reduced life expectancy. Observational studies have suggested that vitamin D deficiency may be associated with the development of DSPN in T2DM. However, interventional studies have found that low-dose vitamin D supplementation does not significantly improve neuropathy in DSPN. This study aims to evaluate the efficacy and safety of intramuscular injection of high-dose vitamin D (HDVD) in T2DM with DSPN combined with vitamin D insufficiency.Methods and analysisWe will conduct a multicenter, randomized, double-blinded, and placebo-controlled trial in four large hospitals. All eligible participants will be randomly assigned to either the vitamin D2 supplement or placebo control group and injected intramuscularly monthly for 3 months. Additionally, anthropometric measurements and clinical data will be collected at baseline and 3 months. Adverse events will be collected at 1, 2, and 3 months. The primary outcome measure is the change in the mean Michigan Neuropathy Screening Instrument (MNSI) score at baseline and 3 months post-intervention. We will use the gold-standard liquid chromatography-tandem mass spectrometry method to distinguish between 25(OH)D2 and 25(OH)D3 levels. The MNSN score before the intervention will be used as a covariate to compare the changes between both groups before and after the intervention, and the analysis of covariance will be used to analyze the change in the MNSI score after HDVD supplementation.DiscussionGlycemic control alone does not prevent the progression of DSPN in T2DM. Some studies have suggested that vitamin D may improve DSPN; however, the exact dose, method, and duration of vitamin D supplementation are unknown. Additionally, neuropathy repair requires HDVD supplementation to sustain adequate vitamin D levels. This once-a-month intramuscular method avoids daily medication; therefore, compliance is high. This study will be the first randomized controlled trial in China to analyze the efficacy and safety of HDVD supplementation for patients with T2DM and DSPN and will provide new ideas for pharmacological research and clinical treatment of diabetic neuropathy.Clinical trial registrationhttps://www.chictr.org.cn/, identifier ChiCTR2200062266.

Abstract Background Metabolic reprogramming is one of the essential features of tumorigenesis. Herein, this study aimed to develop a novel metabolism‐related gene signature for head and neck squamous cell carcinoma (HNSCC) patients. Methods The transcriptomic and clinical data of HNSCC samples were collected from The Cancer Genome Atlas (TCGA) and GSE65858 datasets. The metabolism‐related gene‐based prognostic signature (MRGPS) was constructed by the Least Absolute Shrinkage and Selection Operator (LASSO) regression model. The time‐dependent receiver operating characteristic (ROC) and Kaplan‐Meier (K‐M) survival curves were plotted for evaluating its predicting performance. At the same time, univariate along with multivariate analysis was carried out to explore its correlation with clinicopathologic factors. Furthermore, GSEA analysis was performed to explore the signaling pathways affected by MRGPS. We also analyzed the associations of MRGPS with the tumor immune microenvironment (TIME), as well as identified potential compounds via Connectivity Map (CMap) and molecular docking. Results A total of 12 differentially expressed metabolism‐related genes were identified and selected to construct the MRGPS. Notably, this signature performed well in predicting HNSCC patients’ survival and could serve as an independent prognostic factor in multiple datasets. In addition to the metabolism‐related pathway, this signature could also affect some immune‐related pathways. The results indicated that MRGPS is correlated with immune cells infiltration and anti‐cancer immune response. Furthermore, we identified cephaeline as a potential therapeutic compound for HNSCC. Conclusion Taken together, we established an MRGs‐based signature that has the potential to predict the clinical outcome and immune microenvironment, which help to search for potential combination immunotherapy compounds and provide a promising therapeutic strategy for treating HNSCC patients.

Abstract Aims/Introduction To investigate the differential effects of maternal versus paternal history of diabetes on the risks for diabetes and prediabetes, as well as on insulin secretion and resistance in Chinese individuals. Materials and Methods From the 2007 to 2008 China National Diabetes and Metabolism Disorders Study, 39,244 participants were included and divided into four categories: negative parental history, paternal history only (PH), maternal history only (MH), and both paternal and maternal history. Results The age‐ and sex‐standardized prevalence rates of diabetes in the negative parental history, PH, MH, and both paternal and maternal history groups were 8.59, 12.56, 15.86 and 29.81%, respectively. The prevalence rates of impaired glucose metabolism were 24.13, 25.41, 31.13 and 50.80%, with the prevalence in the MH group being significantly higher than that in the PH group. Compared with that in the FH0 group, the risks of diabetes in the PH, MH, and both paternal and maternal history groups were 2.01‐, 2.67‐ and 6.37‐fold greater, and the risks of impaired glucose metabolism were 1.28‐, 1.65‐ and 3.45‐fold greater. In addition, MH had a significantly greater impact on impaired glucose metabolism than PH (PMHvsPH = 0.0292). Regression analyses suggested MH was associated with homeostatic model assessment for β‐cell function (β[SE] = −0.0910[0.0334], P = 0.0065), insulinogenic index (−0.1866[0.0550], P = 0.0007), homeostatic model assessment for insulin resistance (0.0662[0.0227], P = 0.0036) and Matsuda Index [−0.0716(0.0203), P = 0.0004]. PH was specifically associated with homeostatic model assessment for insulin resistance (0.1343[0.0267], P

Immunotherapy has become a promising therapeutic option for Head and neck squamous cell carcinoma (HNSC). However, only a small percentage of patients could benefit from it, and the overall prognosis was far from satisfactory. In this study, by comprehensively computational analyses of hundreds of HNSC samples, a prognostic signature composed of 13 immune-related genes (IRGs) was constructed. The results of the analyses in multiple datasets indicated that our signature had high predictive accuracy and could serve as an independent prognostic predictor. Based on this signature and multiple clinical variables, we also established a prognostic nomogram to quantitatively predict the survival risk of individual patients. Moreover, this signature could accurately predict survival, reflect the immune microenvironment, and predict immunotherapy efficacy among HNSC patients. Two potential drugs (doxorubicin and daunorubicin) were also identified via Connectivity Map and molecular docking, which could be used for HNSC combination therapy. Taken together, we developed and validated a robust IRG-based prognostic signature to monitor the prognosis of HNSC, which could provide a solid foundation for individualized cancer immunotherapy.

Aminopeptidase N (APN, CD13) is closely associated with the development and progression of cancer. Previous studies suggested APN as a biomarker for cancer stem cells. APN inhibitors have been intensively evaluated as chemosensitizers for cancer treatments. In the present study, tetrahydro-β-carboline scaffold was introduced to the structure of APN inhibitors. The synthesized compounds showed potent enzyme inhibitory activities compared with Bestatin, an approved APN inhibitor, in cell-based enzymatic assay. In combination with chemotherapeutic drugs, representative APN inhibitor molecules D12, D14 and D16 significantly improved the antiproliferative potency of anticancer drugs in the in vitro tests. Further mechanistic studies revealed that the anticancer effects of these drug combinations are correlated with decreased APN expression, increased ROS level, and induction of cell apoptosis. The spheroid-formation assay and colony-formation assay results showed effectiveness of Paclitaxel-APN inhibitor combination against breast cancer stem cell growth. The combined drug treatment led to reduced mRNA expression of OCT-4, SOX-2 and Nanog in the cancer stem cells tested, suggesting the reduced stemness of the cells. In the in vivo study, the selected APN inhibitors, especially D12, exhibited improved anticancer activity in combination with Paclitaxel compared with Bestatin. Collectively, potent APN inhibitors were discovered, which could be used as lead compounds for tumor chemo-sensitization and cancer stem cell-based therapies.

As a vital pivot for the human circulatory system, the brain-gut axis is now being considered as an important channel for many of the small immune molecules’ transductions, including interleukins, interferons, neurotransmitters, peptides, and the chemokines penetrating the mesentery and blood brain barrier (BBB) during the development of an ischemic stroke (IS). Hypoxia-ischemia contributes to pituitary and neurofunctional disorders by interfering with the molecular signal release and communication then providing feedback to the gut. Suffering from such a disease on a long-term basis may cause the peripheral system’s homeostasis to become imbalanced, and it can also lead to multiple intestinal complications such as gut microbiota dysbiosis (GMD), inflammatory bowel disease (IBD), necrotizing enterocolitis (NEC), and even the tumorigenesis of colorectal carcinoma (CRC). Correspondingly, these complications will deteriorate the cerebral infarctions and, in patients suffering with IS, it can even ruin the brain’s immune system. This review summarized recent studies on abnormal immunological signal exchange mediated polarization subtype changes, in both macrophages and microglial cells as well as T-lymphocytes. How gut complications modulate the immune signal transduction from the brain are also elucidated and analyzed. The conclusions drawn in this review could provide guidance and novel strategies to benefit remedies for both IS and relative gut lesions from immune-prophylaxis and immunotherapy aspects.

Abstract Schwannomas are homogeneous tumors of schwann cells and occur at peripheral and cranial nerves on the upper limbs, the head and neck area. Rarely, a bronchial schwannoma may appear in the lung and be misdiagnosed as lung neoplasms. Here, we report a 56‐year old woman with a 5.8 × 7.0 × 2.8 cm lesion in her right upper lobe bronchus. The lesion had a maximum standardized uptake value (SUVmax) of 8.5 by 18‐fluorodeoxyglucose positron emission tomography (FDG‐PET). Bronchoscopy showed a mass obstructing the bronchus that bled easily. Despite repeated biopsies, a lung malignancy could not be excluded, and surgical resection was subsequently performed. Pathological examination demonstrated a primary bronchial schwannoma that was positive for molecular markers S‐100 and SOX‐10, negative for immune checkpoint marker PD‐1/PD‐L1 but also demonstrated certain uncommon pathological features. This case highlights the heterogeneity of bronchial masses and the diagnostic challenge for differentiating benign and malignant tumors in the thorax. Key points Rare bronchial schwannoma mimics lung malignancy and poses a diagnostic challenge. This case of bronchial schwannoma, unlike peripheral schwannoma, lacks PD‐L1. Pathological features indicate autonomic nerve origin for pulmonary schwannomas.

Abstract Hereditary hemochromatosis (HH) is a genetic disorder that causes excess absorption of iron and can lead to a variety of complications including liver cirrhosis, arthritis, abnormal skin pigmentation, cardiomyopathy, hypogonadism, and diabetes. Hemojuvelin (HJV) is the causative gene of a rare subtype of HH worldwide. This study aims to systematically review the genotypic and phenotypic spectra of HJV-HH in multiple ethnicities, and to explore the genotype–phenotype correlations. A comprehensive search of PubMed database was conducted. Data were extracted from 57 peer-reviewed original articles including 132 cases with HJV-HH of multiple ethnicities, involving 117 biallelic cases and 15 heterozygotes. Among the biallelic cases, male and female probands of Caucasian ancestry were equally affected, whereas males were more often affected among East Asians (P=1.72×10-2). Hepatic iron deposition and hypogonadism were the most frequently reported complications. Hypogonadism and arthropathy were more prevalent in Caucasians than in East Asians (P=9.30×10-3, 1.69×10-2). Among the recurrent mutations, G320V (45 unrelated cases) and L101P (7 unrelated cases) were detected most frequently and restricted to Caucasians. [Q6H; C321*] was predominant in Chinese patients (6 unrelated cases). I281T (Chinese and Greek), A310G (Brazilian and African American), and R385* (Italian and North African) were reported across different ethnicities. In genotype–phenotype correlation analyses, 91.30% of homozygotes with exon 2-3 mutations developed early-onset HH compared to 66.00% of those with exon 4 mutations (P=2.40×10-2). Hypogonadism occurred more frequently in homozygotes with missense mutations (72.55%) than in those with nonsense mutations (35.71%; P=2.43×10-2). Liver biopsy was accepted by more probands with frame-shift or missense mutations (85.71% and 60.78%, respectively) than by those with nonsense mutations (28.57%; P=2.37×10-2, 3.93×10-2). The present review suggests that patients’ ethnicity, geographical region, and genetic predisposition should be considered in the diagnosis, prognosis and management of HJV-HH.

Background: Obesity is more prevalent in men than in women in China, especially within the middle-aged population. Objectives: The present study aims to determine the contribution of sexual dimorphisms to obesity and related traits in terms of the mechanisms involving the obesity-related genetic variants among patients of Chinese Han ancestry with type 2 diabetes. Method: In the Chinese National Diabetes and Metabolic Disorders Study, 2,555 out of 4,036 patients with type 2 diabetes were treatment naive, including 1,142 men and 1,413 women. Single-nucleotide polymorphisms (SNP) from 18 genomic loci previously found to be associated with obesity-related traits were successfully genotyped, and a genetic risk score (GRS) was constructed by summing the risk alleles for obesity. Results: Single SNP analysis showed that genetic variants in SLC30A10, TMEM18, GNPDA2, PRL, TFAP2B, BDNF, MTCH2, FTO, and MC4R were nominally associated with waist circumference (WC), BMI, and risk for abdominal or general obesity in the untreated patients with type 2 diabetes, as well as in the total group of patients with type 2 diabetes (untreated and treated) (p < 0.05). Interactions between sex and SNP in PRL, MTCH2,and FTO were detected (p < 0.05). In the untreated patients with diabetes, the GRS was nominally associated with WC (β = 0.0032, SE = 0.0011; p = 0.003), BMI (β = 0.0030, SE = 0.0013; p = 0.027), and increased risk for abdominal (OR = 1.08; 95% CI 1.02–1.13; p = 0.004) or general obesity (OR = 1.07; 95% CI 1.02–1.13; p = 0.011) in men but not in women. GRS-sex interactions were detected in the determinant of WC (p = 0.019) and abdominal obesity (p = 0.016). Among patients aged 30–60 years, GRS was found to be significantly associated with WC (β = 0.0050, SE = 0.0016; p = 0.002) and abdominal obesity (OR = 1.10; 95% CI 1.04–1.17; p = 0.001) and nominally associated with BMI (β = 0.0057, SE = 0.0020; p = 0.005) and general obesity (OR = 1.07; 95% CI 1.01–1.14; p = 0.027) in men, whereas in women none of the associations were detected. GRS-sex interactions were present in the determinant of WC (p = 0.015), BMI (p = 0.032), and abdominal obesity (p = 0.012). Among patients aged 60 years or older, neither an association of GRS with obesity-related traits nor GRS-sex interactions were detected. Conclusions: Genetic factors contribute to obesity-related traits in a sex-dependent pattern among middle-aged Chinese, and men tend to be more susceptible to the genetic risk of obesity.

Multidrug resistance (MDR) of hepatocellular carcinoma (HCC) is a serious problem that directly hinders the effect of chemotherapeutics. In this study, we mainly explore the molecular mechanism of ROS-induced CD13 expression using hepatocarcinoma cells as the research object. We show that the drug of fluorouracil (5FU), epirubicin (EPI) and gemcitabine (GEM) can induce ROS generation, activate Ets2 and promote CD13 expression. Meanwhile, CD13 can activate NRF1 and up-regulate ROS scavenging genes transcription, such as SOD1, GPX1, GPX2 and GPX3, leading to down-regulation of intracellular ROS level and reducing the sensitivity of cells to chemotherapy agent. We also detected the anti-tumor effect of the combination therapy, CD13 inhibitor ubenimex and a variety of conventional anti-cancer drugs, such as 5FU, EPI, GEM, pemetrexed (Pem) and paclitaxel (PTX) were employed in combination. Ubenimex enhances the sensitivity of different chemotherapeutic agents and cooperates with chemotherapeutic agents to suppress tumor growth in vitro and in vivo. In general, overexpression of CD13 can lead to chemotherapy resistance, and CD13 inhibitor can reverse this effect. Combination of chemotherapy agent and ubenimex will become a potential treatment strategy for liver cancer resistance.

Aims. The current study aims to explore if a family history of diabetes can influence the efficiency of lifestyle intervention on insulin secretion and study the insulin resistance in Chinese men and women with metabolic syndrome in a cohort with a 2-year follow-up. Methods. 151 individuals (90 individuals did not have a family history of diabetes (DMFH (-)) and 61 with a family history of diabetes (DMFH (+)) with metabolic syndrome participated in the lifestyle intervention program at baseline and finished with 1-year follow-up. 124 individuals have two-year follow-up data. A family history of diabetes was ascertained by self-report. Lifestyle interventions were individual sessions on lifestyle changes. Results. During the 1-year follow-up, Ln Insulinogenic index (Δbaseline−1year=0.29±0.65, P=0.001) and 30-min glucose (Δbaseline−1year=−0.41±1.71, P=0.024) changed significantly in the DMFH(-) group; in the DMFH(+) group, Ln ISIm (Δbaseline−1year=−0.22±0.60, P=0.022) and 30-min glucose (Δbaseline−1year=0.53±1.89, P=0.032) changed significantly, and there was no significant change of other parameters. The change of 30 min glucose during a 1-year intervention has shown a significant difference between the two groups (P=0.002). During the 2 years intervention, Ln Insulinogenic index changed significantly in the DMFH(-) group (Δbaseline−1year=0.33±0.66, P

Cardiovascular autonomic neuropathy (CAN) is a debilitating condition occurring among diabetic patients especially those with long duration of disease. Whereas incidences and treatment of CAN has been well described for Western populations, fewer studies have been conducted among the Chinese. This study, therefore, aimed to assess the prevalence of CAN among sampled Chinese diabetic patients. Accordingly, 2,048 participants with a history of type 1 diabetes mellitus (T1DM, 73) and type 2 diabetes mellitus (T2DM, 1975) were randomly sampled from 13 hospitals. Patients’ biodata were recorded, and autonomic nervous system function tests performed to aid in the preliminary diagnosis of CAN. The final CAN diagnosis was based on the Ewing’s test in which heart rate variation (HRV) values were evaluated through deep-breathing (DB), lying-to-standing (LS), and Valsalva (V) tests. Systolic blood pressure (SBP) variation values were also evaluated through LS. In the T1DM group, 61.6% patients were diagnosed with CAN and no differences were observed in the baseline and clinical data between this group and those without CAN (P > 0.05). In the T2DM group, 62.6% patients were diagnosed with CAN and statistically significant differences were found between the CAN and non- CAN group with regards to age, duration of diabetes, metformin treatment, retinopathy, and hypertension history (P < 0.05). The most common manifestations of CAN included weakness (28.6%), dizziness (23.4%), frequent urination (19.6%), upper body sweating (18.3%), and nocturia (15.9%). Additionally, duration of disease and age were independent risk factors for CAN in T1DM and T2DM, respectively. On diagnosis, a combination of the V test + LS test provided the highest sensitivity of detecting CAN among T1DM group (sensitivity = 97.6%, AUC = 0.887) while for T2DM category, DB test had the highest sensitivity (83.6%), and maximal AUC (0.856) was found with V test + DB test. The overall prevalence of diabetes with CAN in the study was up to 63%.

Diabetic peripheral neuropathy (DPN) is the most common complication of diabetes, and its progression significantly worsens the patient's quality of life. This study investigated the prevalence and risk factors associated with DPN in a large sample of Beijing individuals with type 1 and 2 diabetes, as well as compared the diagnostic methods for DPN. A total of 2,048 diabetic patients from 13 centers in Beijing were assessed for DPN through questionnaires and examination. Patients were divided into DPN group and suspected DPN/non-DPN group. The demographic, clinical and biological characteristics between the two groups were compared. Binary logistic regression analysis was performed to identify potential variables associated with DPN in diabetic patients. The diagnostic methods for DPN were also compared. Among the 2,048 diabetic patients, 73 cases of type 1 diabetes mellitus, 1,975 cases of type 2 diabetes were included in this study. Among them, 714 (34.86%) were identified with DPN, 537 (26.22%) were suspected of having DPN, and 797 (38.92%) were identified without DPN. Patient's age, duration of diabetes, and diabetic retinopathy were the significant independent risk factor for DPN among patients with type 2 diabetes. The odds ratio (OR) was 1.439 (95% confidence interval (CI): 1.282–1.616, P < 0.001), 1.297 (95% CI: 1.151–1.462, P < 0.001), and 0.637 (95% CI: 0.506–0.802, P < 0.001), respectively. Ankle reflex, temperature sensation plus vibration sensation are the best screening test for patients with type 1 and 2 diabetes. The Youden indexes were 62.2 and 69.8%, respectively. The prevalence rates of DPN in the Chinese patients with type 1 and type 2 diabetes in Beijing were 21.92 and 35.34%, respectively. Patient's age, duration of diabetes, and diabetic retinopathy are the independent risk factors for DPN.

The high acidity and complex components of Hibiscus sabdariffa have provided major challenges for sensitive determination of trace aflatoxins. In this study, sample pretreatment of H. sabdariffa was systematically developed for sensitive high performance liquid chromatography-fluorescence detection (HPLC-FLD) after ultrasonication-assisted extraction, immunoaffinity column (IAC) clean-up and on-line post-column photochemical derivatization (PCD). Aflatoxins B1, B2, G1, G2 were extracted from samples by using methanol/water (70:30, v/v) with the addition of NaCl. The solutions were diluted 1:8 with 0.1 M phosphate buffer (pH 8.0) to negate the issues of high acidity and matrix interferences. The established method was validated with satisfactory linearity (R > 0.999), sensitivity (limits of detection (LODs) and limits of quantitation (LOQs) of 0.15–0.65 and 0.53–2.18 μg/kg, respectively), precision (RSD

Background: Guanxin Danshen formulation (GXDSF) is a traditional Chinese herbal recipe recorded in the Chinese Pharmacopeia since 1995 edition, which consists of Salviae miltiorrhizae Radix et Rhizoma, Notoginseng Radix et Rhizoma and Dalbergiae odoriferae Lignum. Our previous research suggested GXDSF had positive effect on cardiovascular disease. Therefore, the aim of this study was to elucidate the effects of GXDSF on myocardial ischemia reperfusion injury-induced left ventricular remodelling (MIRI-LVR).Methods: The effects of GXDSF on cardiac function were detected by haemodynamics and echocardiograms. The effects of GXDSF on biochemical parameters (AST, LDH and CK-MB) were analyzed. Histopathologic examinations were performed to evaluate the effect of GXDSF on cardiac structure. In addition, the Traditional Chinese Medicine Systems Pharmacology (TCMSP) database was used to predict the main target of GXDSF. Target validation was conducted by using western blots and immunofluorescent double staining assays.Results: We found that +dp/dt and LVSP were significantly elevated in the GXDSF-treated groups compared with the MIRI-LVR model group. Left ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS) were increased in the GXDSF-treated groups compared with the model group. All biochemical parameters (AST, LDH and CK-MB) were considerably decreased in the GXDSF-treated groups compared with the model group. Fibrosis parameters (collagen I and III, α-SMA, and left ventricular fibrosis percentage) were decreased to different degrees in the GXDSF-treated groups compared with the model group, and the collagen III/I ratio was elevated by the same treatments. TCMSP database prediction and western blot results indicated that estrogen receptor β (ERβ) could be the main target of GXDSF. PHTPP, a selective antagonist of ERβ, could inhibit the expression of ERβ and the phosphorylation of PI3K and Akt in myocardial tissue induced by GXDSF, and partly normalize the improving effects of GXDSF on +dp/dt, LVEF, LVFS, LDH, CK-MB, α-SMA and myocardial fibrosis.Conclusion: Collectively, GXDSF showed therapeutic potential for use in the prevention and treatment of myocardial ischemia reperfusion injury-induced ventricular remodeling by upregulating ERβ via PI3K/Akt signaling. Moreover, these findings may be valuable in understand the mechanism of disease and provide a potential therapy of MIRI-IVR.

In this study, an improved UPLC-MS (Ultra-high performance liquid chromatography-tandem mass spectrometry) method for simultaneously quantifying twelve major components belonging to two chemical types was developed and validated, and was applied to quantitatively compare the quality of sulfur-fumigated Astragali Radix of different durations and of the fresh reference sample. The results showed that the contents of triterpenes astragaloside III and astragaloside IV decreased moderately, while the flavonoids calycosin, formononetin, and 7,2′-dihydroxy-3′,4′-dimethoxyisoflavane decreased significantly. The corresponding flavonoid glycosides increased accordingly, which indicated the occurrence of chemical transformation of flavonoids and glycosides in the process of sulfur-fumigation. These transformations were further confirmed by the synthesis of flavonoid glycosides under simulated sulfur-fumigation circumstances. Furthermore, the sulfur-fumigated duration varied in proportion with the contents of compounds 7, 11, and 12. These results suggest that the established method was precise, accurate and sensitive enough for the global quality evaluation of sulfur-fumigated Astragali Radix. Further, sulfur-fumigation not only changes the proportions of bioactive components, but also causes chemical transformation in Astragali Radix.

Dyslipidemia is a strong risk factor for cardiovascular disease among patients with type 2 diabetes (T2D). The aim of this study was to identify lipid-related genetic variants in T2D patients of Han Chinese ancestry. Among 4,908 Chinese T2D patients who were not taking lipid-lowering medications, single nucleotide polymorphisms (SNPs) in seven genes previously found to be associated with lipid traits in genome-wide association studies conducted in populations of European ancestry (ABCA1, GCKR, BAZ1B, TOMM40, DOCK7, HNF1A, and HNF4A) were genotyped. After adjusting for multiple covariates, SNPs in ABCA1, GCKR, BAZ1B, TOMM40, and HNF1A were identified as significantly associated with triglyceride levels in T2D patients (P < 0.05). The associations between the SNPs in ABCA1 (rs3890182), GCKR (rs780094), and BAZ1B (rs2240466) remained significant even after correction for multiple testing (P = 8.85×10(-3), 7.88×10(-7), and 2.03×10(-6), respectively). BAZ1B (rs2240466) also was associated with the total cholesterol level (P = 4.75×10(-2)). In addition, SNP rs157580 in TOMM40 was associated with the low-density lipoprotein cholesterol level (P = 6.94×10(-3)). Our findings confirm that lipid-related genetic loci are associated with lipid profiles in Chinese patients with type 2 diabetes.

AIM:To investigate the association between different family history risk categories and prevalence of diabetes in the Chinese population. METHODS:The family history of diabetes was obtained from each subject, and an oral glucose tolerance test was performed for measuring the fasting and postload glucose and insulin levels based on a national representative cross-sectional survey of 46,239 individuals (age ≥ 20 years) in the 2007-2008 China National Diabetes and Metabolism Disorders Study. The family history risk categories of diabetes were high, moderate, and average (FH2 and FH1: at least two generations and one generation of first-degree relatives with diabetes, respectively; FH0: no first-degree relatives with diabetes). RESULTS:The age- and gender-adjusted prevalence rates of diabetes were 32.7% (95% confidence interval (CI): 26.4-39.7%) in FH2, 20.1% (95% CI: 18.2-22.1%) in FH1, and 8.4% (95% CI: 7.9-8.9%) in FH0 (P < 0.0001). The calculated homeostatic model assessment-estimated insulin resistance (HOMA-IR), Matsuda insulin sensitivity index (ISI), and insulinogenic index (ΔI30/ΔG30) values showed significant trending changes among the three risk categories, with the most negative effects in FH2. Multivariate logistic regression analysis showed that the odds ratios of having diabetes were 6.16 (95% CI: 4.46-8.50) and 2.86 (95% CI: 2.41-3.39) times higher in FH2 and FH1, respectively, than in FH0 after adjustment for classical risk factors for diabetes. CONCLUSIONS:Family history risk categories of diabetes have a significant, independent, and graded association with the prevalence of this disease in the Chinese population.

The sex difference in the prevalence rates of diabetes and cardiovascular diseases (CVDs) among the middle-aged population in China remain largely unknown. Therefore, we analyzed differences in the prevalence of diabetes, self-reported CVDs, and some CVD risk factors among men and women in the middle-aged population (30-49 years) and in individuals aged 50 years and older using data from the China National Diabetes and Metabolic Disorders Study of 2007-2008. Middle-aged men appeared to have significantly a higher prevalence of diabetes and self-reported CVDs than middle-aged women (8.07% vs 5.06% for diabetes, P < 0.001; 0.64% vs 0.22% for CVDs, P < 0.001). Men also showed higher rates of central obesity, hypertension, and dyslipidemia than women (all P < 0.01). Compared with women, men were more likely to drink alcohol and smoke cigarettes but less likely to be under diet control. The sex-specific differences in prediabetes, CVD, and CVD risk factors between men and women were diminished or even reversed in the population aged 50 years and older. No sex-specific differences were found in the prevalences of a family history of diabetes, coronary heart disease, and hypertension (P > 0.05) in middle-aged population. Specific strategies to reduce modifiable risk factors for the prevention and control of diabetes and CVD may be warranted in this population.

Metabolic syndrome (MetS) is prevalent in type 2 diabetes (T2D) patients. The comorbidity of MetS and T2D increases the risk of cardiovascular complications. The aim of the present study was to determine the T2D-related genetic variants that contribute to MetS-related components in T2D patients of Chinese ancestry. We successfully genotyped 25 genome wide association study validated T2D-related single nucleotide polymorphisms (SNPs) among 5,169 T2D individuals and 4,560 normal glycemic controls recruited from the Chinese National Diabetes and Metabolic Disorders Study (DMS). We defined MetS in this population using the harmonized criteria (2009) combined with the Chinese criteria for abdominal obesity. The associations between SNPs and MetS-related components, as well as the associations between SNPs and risk for T2D with or without MetS, were subjected to logistic regression analysis adjusted for age and sex. Results showed that the T2D risk alleles of rs243021 located near BCL11A, rs10830963 in MTNR1B, and rs2237895 in KCNQ1 were related to a lower risk for abdominal obesity in T2D patients (rs243021: 0.92 (0.84, 1.00), P = 4.42 × 10-2; rs10830963: 0.92 (0.85, 1.00), P = 4.07 × 10-2; rs2237895: 0.89 (0.82, 0.98), P = 1.29 × 10-2). The T2D risk alleles of rs972283 near KLF14 contributed to a higher risk of elevated blood pressure (1.10 (1.00, 1.22), P = 4.48 × 10-2), while the T2D risk allele of rs7903146 in TCF7L2 was related to a lower risk for elevated blood pressure (0.74 (0.61, 0.90), P = 2.56 × 10-3). The T2D risk alleles of rs972283 near KLF14 and rs11634397 near ZFAND6 were associated with a higher risk for elevated triglycerides (rs972283: 1.11 (1.02, 1.24), P = 1.46 × 10-2; rs11634397: 1.14 (1.00, 1.29), P = 4.66 × 10-2), while the T2D risk alleles of rs780094 in GCKR and rs7903146 in TCF7L2 were related to a lower risk of elevated triglycerides (rs780094: 0.86 (0.80, 0.93), P = 1.35 × 10-4; rs7903146: 0.82 (0.69, 0.98), P = 3.18 × 10-2). The genotype risk score of the 25 T2D-related SNPs was related to a lower risk for abdominal obesity (Ptrend = 1.29 × 10-2) and lower waist circumference (P = 2.20 × 10-3). Genetic variants of WFS1, CDKAL1, CDKN2BAS, TCF7L2, HHEX, KCNQ1, TSPAN8/LGR5, FTO, and TCF2 were associated with the risk for T2D with MetS, as well as the risk for development of T2D with at least one of the MetS components (P < 0.05). In addition, genetic variants of BCL11A, GCKR, ADAMTS9, CDKAL1, KLF14, CDKN2BAS, TCF7L2, CDC123/CAMK1D, HHEX, MTNR1B, and KCNQ1 contributed to the risk for T2D without MetS (P < 0.05). In conclusion, these findings highlight the contribution of T2D-related genetic loci to MetS in a Chinese Han population. The study also provides insight into the pleotropic effects of genome-wide association loci of diabetes on metabolic regulation.

Monocytes can be activated by incubation with opsonized zymosan (Zop), and under these conditions can oxidize low density lipoprotein (LDL). We have characterized the biochemical changes in the lipoprotein after this oxidation. We found that monocyte-oxidized LDL has increased mobility on agarose gels, increased absorbance at 234 nm, increased content of lysophosphatidylcholine, and fluorescence at 430 nm when excited at 350 nm. All these features were somewhat less pronounced in monocyte-oxidized LDL than in LDL oxidized by 5 μm CuSO4. Under appropriate conditions, Zop-stimulated monocytes oxidized LDL to a form recognized by macrophage scavenger receptors. Monocytes stimulated by Zop produced superoxide and also oxidized LDL, whereas monocytes stimulated by phorbol ester produced slightly more superoxide but did not oxidize LDL. We found that the chelators EDTA and diethylenetriaminepentaacetic acid inhibited LDL oxidation by Zop-stimulated monocytes, implying a requirement for transition metal ions. We found that Zop contained approximately 5 nmol iron per mg, probably as Fe3+. Zop stripped of its iron supported superoxide production by monocytes, but did not support LDL oxidation. Furthermore, Fe2+ appeared in the medium when monocytes were incubated with Zop, but not with iron-stripped Zop. Taken together, these results imply that monocytes stimulated by Zop are able to oxidize LDL only because of contaminating iron in the commercial zymosan preparations. —Xing, X., J. Baffic, and C. P. Sparrow. LDL oxidation by activated monocytes: characterization of the oxidized LDL and requirement for transition metal ions. J. Lipid. Res. 1998. 39: 2201–2208.

Danshen formulation (GXDSF) is a traditional Chinese herbal recipe recorded in the Chinese Pharmacopeia since 1995 edition, which consists of Salviae miltiorrhizae Radix et Rhizoma, Notoginseng Radix et Rhizoma and Dalbergiae odoriferae Lignum. Our previous research suggested GXDSF had positive effect on cardiovascular disease. Therefore, the aim of this study was to elucidate the effects of GXDSF on myocardial ischemia reperfusion injury-induced left ventricular remodelling (MIRI-LVR). Methods: The effects of GXDSF on cardiac function were detected by haemodynamics and echocardiograms. The effects of GXDSF on biochemical parameters (AST, LDH and CK-MB) were analyzed. Histopathologic examinations were performed to evaluate the effect of GXDSF on cardiac structure. In addition, the Traditional Chinese Medicine Systems Pharmacology (TCMSP) database was used to predict the main target of GXDSF. Target validation was conducted by using western blots and immunofluorescent double staining assays. Results: We found that Cdp/dt and LVSP were significantly elevated in the GXDSFtreated groups compared with the MIRI-LVR model group. Left ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS) were increased in the GXDSF-treated groups compared with the model group. All biochemical parameters (AST, LDH and CK-MB) were considerably decreased in the GXDSF-treated groups compared with the model group. Fibrosis parameters (collagen I and III, a-SMA, and left ventricular fibrosis percentage) were decreased to different degrees in the GXDSFtreated groups compared with the model group, and the collagen III/I ratio was elevated by the same treatments. TCMSP database prediction and western blot results indicated that estrogen receptor b (ERb) could be the main target of GXDSF. PHTPP, a selective antagonist of ERb, could inhibit the expression of ERb and the phosphorylation of PI3K and Akt in myocardial tissue induced by GXDSF, and partly normalize the improving effects of GXDSF on Cdp/dt, LVEF, LVFS, LDH, CK-MB, a-SMA and myocardial fibrosis. Conclusion: Collectively, GXDSF showed therapeutic potential for use in the prevention and treatment of myocardial ischemia reperfusion injury-induced ventricular remodeling by upregulating ERb via PI3K/Akt signaling. Moreover, these findings may be valuable in understand the mechanism of disease and provide a potential therapy of MIRI-IVR. [ABSTRACT FROM AUTHOR]