Refractory pruritus caused by sintilimab and its clinical management: A case report.

Several immune related adverse events (irAEs) were reported with the wide application of immune checkpoint inhibitors (ICIs) in tumors. ICI-related skin reactions are the most common, which are manifested as maculopapules, rash, pruritus, vitiligo, psoriasis, and lichenoid rash.Among them, the incidence of pruritus is second only to maculopapule/rash, but both often co-exist. The severity of pruritus is mostly mild to moderate and can be relieved after symptomatic treatment with antihistamines. Symptoms are slightly relieved after conventional treatment in patients with severe pruritus, but it easily recurs and eventually develops into refractory pruritus.The patient's quality of life may be affected and may also be life-threatening. We report a case of a patient with postoperative recurrence of gallbladder neuroendocrine carcinoma,who developed refractory pruritus after sintilimab use, which was relieved after naloxone infusion after unsuccessful conventional drug therapy. By analyzing the treatment plan of this typical case of immune-related refractory pruritus after using sintilimab, this report discusses how clinical pharmacists can provide individualized treatment of patients by using their expertise and clinicians' cooperation and complementation in treating clinically difficult cases. This case report may be used as a reference in treating patients with refractory pruritus after the clinical use of sintilimab.

[The Roles of N6-Methyladenosine Modification and Its Regulators in Male Reproduction]. / N6-ç”²åŸºè ºå˜Œå‘¤ä¿®é¥°åŠå ¶è°ƒæŽ§å› å­åœ¨ç”·æ€§ç”Ÿæ®–ä¸­çš„ä½œç”¨.

Infertility affects an estimated 10 to 15 percent of couples worldwide, with approximately half of the cases attributed to male-related issues. Most men diagnosed with infertility exhibit symptoms such as oligospermia, asthenospermia, azoospermia, and compromised sperm quality. Spermatogenesis is a complex and tightly coordinated process of germ cell differentiation, precisely regulated at transcriptional, posttranscriptional, and translational levels to ensure stage-specific gene expression during the development of spermatogenic cells and normal spermiogenesis. N6-methyladenosine (m6A) stands out as the most prevalent modification on eukaryotic mRNA, playing pivotal roles in various biological processes, including mRNA splicing, transportation, and translation. RNA methylation modification is a dynamic and reversible process primarily mediated by "writers", removed by "erasers", and recognized by "readers". In mammals, the aberrant methylation modification of m6A on mRNA is associated with a variety of diseases, including male infertility. However, the precise involvement of disrupted m6A modification in the pathogenesis of human male infertility remains unresolved. Intriguingly, a significant correlation has been found between the expression levels of m6A regulators in the testis and the severity of sperm concentration, motility, and morphology. Aberrant expression patterns of m6A regulatory proteins have been detected in anomalous human semen samples, including those of oligospermia, asthenozoospermia, and azoospermia. Furthermore, the examination of both sperm samples and testicular tissues revealed abnormal mRNA m6A modification, leading to reduced sperm motility and concentration in infertile men. Consequently, it is hypothesized that dysregulation of m6A modification might serve as an integral link in the mechanism of male infertility. This paper presents a comprehensive review of the recent discoveries regarding the spatial and temporal expression dynamics of m6A regulators in testicular tissues and the correlation between deregulated m6A regulators and human male infertility. Previous studies predominantly utilized constitutive or conditional knockout animal models for testicular phenotypic investigations. However, gene suppression in additional tissues could potentially influence the testis in constitutive knockout models. Furthermore, considering the compromised spermatogenesis observed in constitutive animals, distinguishing between the indirect effects of gene depletion on testicular development and its direct impact on the spermatogenic process is challenging, due to their intricate relationship. Such confounding factors might compromise the validity of the findings. To address this challenge, an inducible and conditional gene knockout model may serve as a superior approach. To date, nearly all reported studies have concentrated solely on the level changes of m6A and its regulators in germs cells, while the understanding of the function of m6A modification in testicular somatic cells remains limited. Testicular somatic cells, including peritubular myoid cells, Sertoli cells, and Leydig cells, play indispensable roles during spermatogenesis. Hence, comprehensive exploration of m6A modification within these cells as an additional crucial regulatory mechanism is warranted. In addition, exploration into the presence of unique methylation mechanisms or m6A regulatory factors within the testes is warranted. To elucidate the role of m6A modification in germ cells and testicular somatic cells, detailed experimental strategies need to be implemented. Among them, manipulation of the levels of key enzymes involved in m6A methylation and demethylation might be the most effective approach. Moreover, comprehensive analysis of the gene expression profiles involved in various signaling pathways, such as Wnt/ß-catenin, Ras/MAPK, and Hippo, in m6A-modified germ cells and testicular somatic cells can provide more insight into its regulatory role in the spermatogenesis process. Further research in this area could provide valuable insights for developing innovative strategies to treat male infertility. Finally, considering the mitigation impact of m6A imbalance regulation on disease, investigation concerning whether restoring the equilibrium of m6A modification regulation can restore normal spermatogenesis function is essential, potentially elucidating the pivotal clinical significance of m6A modulation in male infertility.

miR-22 negatively regulating NOD-like receptor protein 3 gene in the proliferation, invasion, and migration of malignant melanoma cells.

Introduction: Malignant melanoma (MM) is a highly aggressive skin tumour. Aim: To investigate whether miR-22 is involved in the proliferation, invasion, and migration of melanoma cells (MCs) by negatively regulating NOD-like receptor protein 3 (NLRP3) gene. Material and methods: Human MCs (WM239a) and human epidermal melanocytes (HEM) were used as study material. The expression levels of miR-22 and NLRP3 were detected by qRT-PCR. The expression of NLRP3 protein was determined by Western blot (WB) analysis. The effects of miR-22 and NLRP3 on the proliferation, invasion, and migration of MCs were evaluated by cell counting kit-8 (CCK-8), Transwell cell invasion assay, and scratch assay. Results: The expression of miR-22 was clearly lower in WM239a than in HEM. Up-regulation of miR-22 expression in WM239a clearly raised the expression of miR-22, Caspase-1, and E-cadherin and the apoptotic rate of WM239a; however, the levels of interleukin-1ß (IL-1ß) and NLRP3, cell proliferation activity, invasion and migration ability were clearly decreased. The negative regulation of NLRP3 by miR-22 may play a major role in activities of MM. Conclusions: Further studies will help to reveal the molecular details of this regulatory mechanism and provide new therapeutic strategies.

Analgesic treatment for refractory cancer pain caused by gastric cancer bone metastasis: A case report and literature review.

RATIONALE: Patients with bone metastasis-associated cancer pain often experience a complex mix of pain types. Consequently, the use of multimodal combination therapy is essential. While monitoring for common adverse reactions in pain treatment, it is also crucial to be vigilant for the rare but serious serotonin syndrome. PATIENT CONCERNS: A 53-year-old female with metastatic gastric cancer was hospitalized due to severe, uncontrolled thoracic and cervical pain. During the titration of her cancer pain medication, she developed serotonin syndrome. DIAGNOSES: He was diagnosed with refractory cancer pain and serotonin syndrome. INTERVENTIONS: The complete process of cancer pain medication in a patient with gastric cancer and bone metastasis was analyzed, with a primary focus on the selection of analgesic medications, adjustment of opioid dosages, and prevention and treatment of medication-associated adverse reactions. OUTCOMES: The patient's cancer pain was well controlled, with the prompt management of adverse reactions. Furthermore, by adjusting the medication regimen, intolerable adverse reactions were prevented. LESSONS: In clinical settings, personalized analgesic regimens must be developed for patients with cancer pain to enhance patient compliance with medication, prevent the occurrence of severe adverse reactions, and improve the overall quality of life of patients with cancer. Healthcare professionals should pay increased attention to ADRs associated with opioid medications, whereas pharmacists should assist them in promptly identifying ADRs.

Identifying therapeutic targets for breast cancer: insights from systematic Mendelian randomization analysis.

Background: Breast cancer (BC) exhibits a high incidence rate, imposing a substantial burden on healthcare systems. Novel drug targets are urgently needed for BC. Mendelian randomization (MR) has gained widespread application for identifying fresh therapeutic targets. Our endeavor was to pinpoint circulatory proteins causally linked to BC risk and proffer potential treatment targets for BC. Methods: Through amalgamating protein quantitative trait loci from 2,004 circulating proteins and comprehensive genome-wide association study data from the Breast Cancer Association Consortium, we conducted MR analyses. Employing Steiger filtering, bidirectional MR, Bayesian colocalization, phenotype scanning, and replication analyses, we further solidified MR study outcomes. Additionally, protein-protein interaction (PPI) network was harnessed to unveil latent associations between proteins and prevailing breast cancer medications. The phenome-wide MR (Phe-MR) was employed to assess potential side effects and indications for the druggable proteins of BC. Finally, we further affirmed the drugability of potential drug targets through mRNA expression analysis and molecular docking. Results: Through comprehensive analysis, we identified five potential drug targets, comprising four (TLR1, A4GALT, SNUPN, and CTSF) for BC and one (TLR1) for BC_estrogen receptor positive. None of these five potential drug targets displayed reverse causation. Bayesian colocalization suggested that these five latent drug targets shared variability with breast cancer. All drug targets were replicated within the deCODE cohort. TLR1 exhibited PPI with current breast cancer therapeutic targets. Furthermore, Phe-MR unveiled certain adverse effects solely for TLR1 and SNUPN. Conclusion: Our study uncovers five prospective drug targets for BC and its subtypes, warranting further clinical exploration.

Pueraria lobata antioxidant extract ameliorates non-alcoholic fatty liver by altering hepatic fat accumulation and oxidative stress.

ETHNOPHARMACOLOGICAL RELEVANCE: Pueraria lobata is essential medicinal and edible homologous plants widely cultivated in Asian countries. Therefore, P. lobata is widely used in the food, health products and pharmaceutical industries and have significant domestic and international market potential and research value. P. lobata has remarkable biological activities in protecting liver, relieving alcoholism, antioxidation, anti-tumor and anti-inflammation in clinic. However, the potential mechanism of ethyl acetate extract of Pueraria lobata after 70% alcohol extraction (APL) ameliorating nonalcoholic fatty liver disease (NAFLD) has not been clarified. AIM OF THE STUDY: This study aimed to investigate the ameliorative effect of P. lobata extract on human hepatoma cells and injury in rats, and to evaluate its therapeutic potential for ameliorating NAFLD. METHODS: Firstly, the effective part of P. lobata extract was determined as APL by measuring its total substances and antioxidant activity. And then the in vitro and in vivo models of NAFLD were adopted., HepG2 cells were incubated with palmitic acid (PA) and hydrogen peroxide (H2O2). In order to evaluate the effect of APL, Simvastatin and Vitamin C (VC) were used as positive control. Various parameters related to lipogenesis and fatty acid ß-oxidation were studied, such as intracellular lipid accumulation, reactive oxygen species (ROS), Western Blot, mitochondrial membrane potential, apoptosis, and the mechanism of APL improving NAFLD. The chemical components of APL were further determined by HPLC and UPLC-MS, and molecular docking was carried out with Keap1/Nrf2/HO-1 pathway related proteins. RESULTS: APL significantly reduced lipid accumulation and levels of oxidative stress-related factors in vitro and in vivo. Immunohistochemical、Western Blot and PCR analysis showed that the expressions of Nrf2 and HO-1 were up-regulated in APL treatment. The Nrf2 inhibitor ML385 can block the rescue by APL of cellular oxidative stress and lipid accumulation induced by H2O2 and PA, demonstrating its dependence on Nrf2. UPLC/MS analysis showed that there were 3'-hydroxyl puerarin, puerarin, 3'-methoxy puerarin, daidzein, genistin, ononin, daidzin and genistein. CONCLUSION: This study further clarified the mechanism of P. lobata extract in improving NAFLD, which provided a scientific basis for developing new drugs to protect liver injury and laid a solid foundation for developing P. lobata Chinese herbal medicine resources.

Standardised protocol for a prospective international multicentre clinical-based evaluation of point-of-care tests for the screening of genital and extragenital chlamydial and gonococcal infections in men who have sex with men and for the screening of genital chlamydial, gonococcal and Trichomonas vaginalis infections in at risk women.

INTRODUCTION: In 2016, WHO estimated there were roughly 374 million new infections among adults of the following four curable sexually transmitted infections (STIs): chlamydia (caused by Chlamydia trachomatis (CT)), gonorrhoea (Neisseria gonorrhoeae (NG)), syphilis (Treponema pallidum) and trichomoniasis (Trichomonas vaginalis (TV)). Accurate point-of-care tests (POCTs) for screening of genital and extragenital CT, NG and TV infections are of great value and have been developed during recent decade. Several tests are commercially available and have shown encouraging performance compared with 'gold-standard' reference tests in laboratory-based studies. However, there is limited data on their clinical performance, including at the POC. Key populations, such as men who have sex with men (MSM), are at higher risk of these STIs at genital and extragenital sites and these STIs are often asymptomatic, especially in extragenital sites and in women. We will conduct a clinical-based evaluation to assess the performance characteristics and acceptability to end-users of molecular-based diagnostic technology for POC/near patient use of the Xpert CT/NG (Cepheid, Sunnyvale, California, USA) test for screening of genital, anorectal and pharyngeal CT and NG infections in MSM and the Xpert CT/NG and Xpert TV (Cepheid, Sunnyvale, California, USA) for screening of genital CT, NG and TV among women at risk for these STIs compared with gold-standard reference nucleic acid amplification tests. This master protocol outlines the overall research approach that will be used in seven countries. METHOD AND ANALYSES: Consecutive MSM and women at risk presenting at the clinical sites in high, and low- and middle-income countries will be enrolled. The POCTs to be evaluated are Xpert CT/NG and Xpert TV. All procedures will be carried out by trained healthcare staff and tests performed in strict accordance with the manufacturer's instructions. The sensitivity, specificity, positive and negative predictive values for each POCT will be calculated. The study is ongoing with recruitment expected to be completed in all countries by mid-2022 to late-2022. ETHICS AND DISSEMINATION: Prior to enrolment, this core protocol was independently peer-reviewed and approved by the research project review panel (RP2) of the WHO Department of Sexual and Reproductive Health and Research and by the WHO Ethics Review Committee (ERC). The core protocol has been slightly adapted accordingly to individual countries and adaptations approved by both RP2 and ERC, as well as all relevant institutional review boards at each participating site. Results will be disseminated through peer-reviewed journals and presented at relevant national/international conferences.

Paediatric Drug Development in China: Current Status and Future Prospects.

For more than two decades, regulatory agencies throughout the world released guidelines, rules and laws to stimulate and assist in paediatric drug development. In 2014, the National Health and Family Planning Commission (now known as the National Health Commission, NHC) and five other departments in China jointly issued 'Several Opinions on Safeguarding Medication for Children', after which several policies and regulations were issued to implement the priority review and approval of paediatric medicinal products and support the development of new drugs, including new dosage forms and strengths, for children. A total of 172 special medicinal products for children were approved from 2018 to 2022. Since 2016, the NHC, together with relevant administrative departments, has formulated and issued four paediatric drug lists containing 129 medicinal products to encourage research and development. At present, approximately 25 of these drugs (at exactly the same dosage forms and strengths as on the lists) have been approved for marketing, including antitumour drugs and immunomodulators, nervous system drugs, drugs for mental disorders and drugs for rare diseases. In this review, we analysed the regulations issued for promoting paediatric drug development in China, including the priority review and approval system, technical guidelines, data protection and financial support policies and general profiles of paediatric drug approval, clinical trials and the addition of information for children in the labels of marketed medicinal products. Finally, we discussed the challenges and possible strategies in the research and development of paediatric drugs in China.

Association of Cytokines with Clinical Indicators in Patients with Drug-Induced Liver Injury.

Objective: To explore characteristics of clinical parameters and cytokines in patients with drug-induced liver injury (DILI) caused by different drugs and their correlation with clinical indicators. Method: The study was conducted on patients who were up to Review of Uncertainties in Confidence Assessment for Medical Tests (RUCAM) scoring criteria and clinically diagnosed with DILI. Based on Chinese herbal medicine, cardiovascular drugs, non-steroidal anti-inflammatory drugs (NSAIDs), anti-infective drugs, and other drugs, patients were divided into five groups. Cytokines were measured by Luminex technology. Baseline characteristics of clinical biochemical indicators and cytokines in DILI patients and their correlation were analyzed. Results: 73 patients were enrolled. Age among five groups was statistically different ( P = 0.032). Alanine aminotransferase (ALT) ( P = 0.033) and aspartate aminotransferase (AST) ( P = 0.007) in NSAIDs group were higher than those in chinese herbal medicine group. Interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α) in patients with Chinese herbal medicine (IL-6: P < 0.001; TNF-α: P < 0.001) and cardiovascular medicine (IL-6: P = 0.020; TNF-α: P = 0.001) were lower than those in NSAIDs group. There was a positive correlation between ALT ( r = 0.697, P = 0.025), AST ( r = 0.721, P = 0.019), and IL-6 in NSAIDs group. Conclusion: Older age may be more prone to DILI. Patients with NSAIDs have more severe liver damage in early stages of DILI, TNF-α and IL-6 may partake the inflammatory process of DILI.

Building a novel TRUCK by harnessing the endogenous IFN-gamma promoter for cytokine expression.

Despite the remarkable success of chimeric antigen receptor (CAR) T therapy in hematological malignancies, its efficacy in solid tumors remains limited. Cytokine-engineered CAR T cells offer a promising avenue, yet their clinical translation is hindered by the risks associated with constitutive cytokine expression. In this proof-of-concept study, we leverage the endogenous interferon (IFN)-γ promoter for transgenic interleukin (IL)-15 expression. We demonstrate that IFN-γ expression is tightly regulated by T cell receptor signaling. By introducing an internal ribosome entry site IL15 into the 3' UTR of the IFN-γ gene via homology directed repair-mediated knock-in, we confirm that IL-15 expression can co-express with IFN-γ in an antigen stimulation-dependent manner. Importantly, the insertion of transgenes does not compromise endogenous IFN-γ expression. In vitro and in vivo data demonstrate that IL-15 driven by the IFN-γ promoter dramatically improves CAR T cells' antitumor activity, suggesting the effectiveness of IL-15 expression. Last, as a part of our efforts toward clinical translation, we have developed an innovative two-gene knock-in approach. This approach enables the simultaneous integration of CAR and IL-15 genes into TRAC and IFN-γ gene loci using a single AAV vector. CAR T cells engineered to express IL-15 using this approach demonstrate enhanced antitumor efficacy. Overall, our study underscores the feasibility of utilizing endogenous promoters for transgenic cytokines expression in CAR T cells.

Immune cells mediated the causal relationship between the gut microbiota and lung cancer: a Mendelian randomization study.

Introduction: The gut microbiota (GM) influences the occurrence and progression of lung cancer (LC), with potential involvement of immune cells (IC). We aimed to investigate the causal impact of GM on LC and identify potential immune cell mediators. Methods: The utilized data for the Genome-Wide Association Studies (GWAS) were summarized as follows: gut microbiota data from the Dutch Microbiome Project (DMP) (N = 7,738), lung cancer data from the Transdisciplinary Research in Cancer of the Lung (TRICL) and International Lung Cancer Consortium (ILCCO) (Ncase = 29,266, Ncontrol = 56,450) included four types of cancer: NSCLC, LUAD, LUSC, and SCLC, and immune cell data from European populations (N = 3,757). We employed bi-directional two-sample univariable Mendelian randomization (UVMR), multivariable Mendelian randomization (MVMR), and mediation analysis to assess the causal relationship between GM and LC and potential immune cell mediators. Results: Bi-directional UVMR analysis revealed that 24 gut microbiota species can affect LC, while LC can affect the abundance of 17 gut microbiota species. Mediation analysis demonstrated that six immune cells mediated the causal relationships of seven gut microbiota species on LC: "CCR7 on naive CD8+ T cell" mediated the causal relationship between s_Alistipes_putredinis and LUAD, with a mediation proportion of 9.5% and P = 0.018; "IgD- CD27- B cell %lymphocyte" mediated the causal relationships between g_Gordonibacter and s_Gordonibacter_pamelaeae with LUSC, with mediation proportions of 11.8% and 11.9%, respectively and P = 0.029; "CD20- CD38- B cell %lymphocyte" mediated the causal relationship between s_Bacteroides_clarus and SCLC, with a mediation proportion of 13.8% and P = 0.005; "CD20 on IgD+ CD38- unswitched memory B cell" mediated the causal relationship between s_Streptococcus_thermophilus and SCLC, with a mediation proportion of 14.1% and P = 0.023; "HLA DR on CD14- CD16+ monocyte" mediated the causal relationship between s_Bifidobacterium_bifidum and SCLC, with a mediation proportion of 8.7% and P = 0.012; "CD45 on Granulocytic Myeloid-Derived Suppressor Cells" mediated the causal relationship between f_Lactobacillaceae and SCLC, with a mediation proportion of 4.0% and P = 0.021. Conclusion: This Mendelian randomization study identified several specific gut microbiotas that exhibit causal relationships with lung cancer and potentially mediate immune cells.

Klinefelter syndrome: Etiology and clinical considerations in male infertility.

Klinefelter syndrome (KS) is the most prevalent chromosomal disorder occurring in males. It is defined by an additional X chromosome, 47,XXY, resulting from errors in chromosomal segregation during parental gametogenesis. A major phenotype is impaired reproductive function, in the form of low testosterone and infertility. This review comprehensively examines the genetic and physiological factors contributing to infertility in KS, in addition to emergent assisted reproductive technologies, and the unique ethical challenges KS patients face when seeking infertility treatment. The pathology underlying KS is increased susceptibility for meiotic errors during spermatogenesis, resulting in aneuploid or even polyploid gametes. Specific genetic elements potentiating this susceptibility include polymorphisms in checkpoint genes regulating chromosomal synapsis and segregation. Physiologically, the additional sex chromosome also alters testicular endocrinology and metabolism by dysregulating interstitial and Sertoli cell function, collectively impairing normal sperm development. Additionally, epigenetic modifications like aberrant DNA methylation are being increasingly implicated in these disruptions. We also discuss assisted reproductive approaches leveraged in infertility management for KS patients. Application of assisted reproductive approaches, along with deep comprehension of the meiotic and endocrine disturbances precipitated by supernumerary X chromosomes, shows promise in enabling biological parenthood for KS individuals. This will require continued multidisciplinary collaboration between experts with background of genetics, physiology, ethics and clinical reproductive medicine.

Research Progress in the Use of Small Molecule Smac Mimetics in Combination Therapy of Cancer.

Inhibitors of Apoptosis Proteins (IAP) are inhibitors that can block programmed cell death, are expressed at high levels in various cancers, and are recognized as a therapeutic target for cancer therapy. In the past few years, several small molecule IAP protein inhibitors have been designed to mimic the endogenous IAP antagonist, but no IAP inhibitors have been approved for marketing worldwide. Previously, xevinapant has been awarded a breakthrough therapy designation by the FDA. In addition, a combination of Smac-mimetics and chemotherapeutic compounds has been reported to improve anticancer efficacy. According to the phase II clinical data, xevinapant has the potential to significantly enhance the standard therapy for patients with head and neck cancer, which is expected to be approved as an innovative therapy for cancer patients. Therefore, this paper briefly describes the mechanism of IAPs (AT-406, APG-1387, GDC- 0152, TL32711, and LCL161) as single or in combination for cancer treatment, their application status as well as the synthetic pathway, and explores the research prospects and challenges of IAPs antagonists in the tumor combination therapy, with the hope of providing strong insights into the further development of Smac mimics in tumor therapy.

Exploring the HIF-1α signalling pathway and the mechanism of YiQiHuoXue decoction against Precancerous Lesions of Gastric Cancer based on Network Pharmacology and Molecular Docking.

Precancerous Lesions of Gastric Cancer (PLGC) are an essential step in the advancement of Gastric cancer (GC). Early intervention represents the most effective strategy to impede the development of PLGC. However, additional research is necessary to comprehend the molecular mechanism of PLGC. YQHXD is originated from Si Wu Decoction, has been utilized as an empirical formula for the treatment of PLGC for several years. In this study, we employed network pharmacology, molecular docking, and experimental validation to examine the inhibitory and ameliorative properties of YQHXD on PLGC. Multiple databases were utilized to gather genetic information on drugs in PLGC and YQHXD, in order to obtain cross-targets. We discovered 142 common targets between YQHXD and PLGC. GO and KEGG enrichment analyses indicate that YQHXD treatment of PLGC might be linked with cellular response to oxygen levels and the HIF-1α signaling pathway. Finally, we performed in vitro experiments, of which the results reveal that YQHXD mitigates gastric mucosal atrophy, intestinalization, and heterogeneous hyperplasia, and reduces the expression of inflammatory factors in rats. Therefore, we considered that YQHXD has the potential to delay the PLGC process by inhibiting the HIF-1α signaling pathway.

Polyketides with α-glucosidase inhibitory and neuroprotective activities from Aspergillus versicolor associated with Pedicularis sylvatica.

Aspergillus versicolor, an endophytic fungus associated with the herbal medicine Pedicularis sylvatica, produced four new polyketides, aspeversins A-D (1-2 and 5-6) and four known compounds, O-methylaverufin (2), aversin (3), varilactone A (7) and spirosorbicillinol A (8). Their structures were elucidated by extensive spectroscopic data analysis, and their absolute configurations were determined by calculated electronic circular dichroism (ECD) and Mo2(AcO)4-induced CD data. Compound 5 was found to exhibit α-glucosidase inhibitory activity with an IC50 value of 25.57 µM. An enzyme kinetic study indicated that 5 was a typical uncompetitive inhibitor toward α-glucosidase, which was supported by a molecular docking study. Moreover, compounds 1-3 and 5 also improved the cell viability of PC12 cells on a 1-methyl-4-phenylpyridinium (MPP+)-induced Parkinson's disease model, indicating their neuroprotective potential as antiparkinsonian agents.

Detection of chromosomal instability using ultrasensitive chromosomal aneuploidy detection in the diagnosis of precancerous lesions of gastric cancer.

Background: The diagnosis of Precancerous Lesions of Gastric Cancer (PLGC) is challenging in clinical practice. We conducted a clinical study by analyzing the information of relevant chromosome copy number variations (CNV) in the TCGA database followed by the UCAD technique to evaluate the value of Chromosomal Instability (CIN) assay in the diagnosis of PLGC. Methods: Based on the screening of gastric cancer related data in TCGA database, CNV analysis was performed to explore the information of chromosome CNV related to gastric cancer. Based on the gastroscopic pathology results, 12 specimens of patients with severe atrophy were screened to analyze the paraffin specimens of gastric mucosa by UCAD technology, and to explore the influence of related factors on them. Results: The results of CNV in TCGA database suggested that chromosome 7, 8, and 17 amplification was obvious in patients with gastric cancer. UCAD results confirmed that in 12 patients with pathologic diagnosis of severe atrophy, five of them had positive results of CIN, with a positive detection rate of 41.7%, which was mainly manifested in chromosome seven and chromosome eight segments amplification. We also found that intestinalization and HP infection were less associated with CIN. And the sensitivity of CIN measurement results was significantly better than that of tumor indicators. Conclusion: The findings suggest that the diagnosis of PLGC can be aided by UCAD detection of CIN, of which Chr7 and 8 may be closely related to PLGC.

Associations between hyperuricemia and ultrasound-detected knee synovial abnormalities in middle-aged and older population: a cross-sectional study.

OBJECTIVES: Knee synovial abnormalities, potentially treatment targets for knee pain and osteoarthritis, are common in middle-aged and older population, but its etiology remains unclear. We examined the associations between hyperuricemia and knee synovial abnormalities detected by ultrasound in a general population sample. METHODS: Participants aged ≥ 50 years were from a community-based observational study. Hyperuricemia was defined as serum urate (SU) level > 416 µmol/L in men and > 357 µmol/L in women. Ultrasound of both knees was performed to determine the presence of synovial abnormalities, i.e., synovial hypertrophy, effusion, or Power Doppler signal (PDS). We examined the relation of hyperuricemia to prevalence of knee synovial abnormalities and its laterality, and the dose-response relationships between SU levels and the prevalence of knee synovial abnormalities. RESULTS: In total, 3,405 participants were included in the analysis. Hyperuricemia was associated with higher prevalence of knee synovial abnormality (adjusted odds ratio [aOR] = 1.21, 95% confidence interval [CI]: 1.02 to 1.43), synovial hypertrophy (aOR = 1.33, 95% CI: 1.05 to 1.68), and effusion (aOR = 1.21, 95% CI: 1.02 to 1.44), respectively. There were dose-response relationships between SU levels and synovial abnormalities. Additionally, the hyperuricemia was more associated with prevalence of bilateral than with that of unilateral knee synovial abnormality, synovial hypertrophy, or effusion; however, no significant association was observed between hyperuricemia and PDS. CONCLUSION: In this population-based study we found that hyperuricemia was associated with higher prevalence of knee synovial abnormality, synovial hypertrophy and effusion, suggesting that hyperuricemia may play a role in pathogenesis of knee synovial abnormalities.

Diagnostic accuracy and cellular origin of pleural fluid CXCR3 ligands for tuberculous pleural effusion.

BACKGROUND: Pleural biomarkers represent potential diagnostic tools for tuberculous pleural effusion (TPE) due to their advantages of low cost, short turnaround time, and less invasiveness. This study evaluated the diagnostic accuracy of two CXCR3 ligands, C-X-C motif chemokine ligand 9 (CXCL9) and CXCL11, for TPE. In addition, we investigated the cellular origins and biological roles of CXCL9 and CXCL11 in the development of TPE. METHODS: This double-blind study prospectively enrolled patients with undiagnosed pleural effusion from two centers (Hohhot and Changshu) in China. Pleural fluid on admission was obtained and levels of CXCL9 and CXCL11 were measured by an enzyme-linked immunosorbent assay (ELISA). The receiver operating characteristic (ROC) curve and the decision curve analysis (DCA) were used to evaluate their diagnostic accuracy and net benefit, respectively. THP-1 cell-derived macrophages were treated with Bacillus Calmette-Guérin (BCG), and quantitative real-time PCR (qRT-PCR) and ELISA were used to determine the mRNA and protein levels of CXCL9 and CXCL11. The chemoattractant activities of CXCL9 and CXCL11 for T helper (Th) cells were analyzed by a transwell assay. RESULTS: One hundred and fifty-three (20 TPEs and 133 non-TPEs) patients were enrolled in the Hohhot Center, and 58 (13 TPEs and 45 non-TPEs) were enrolled in the Changshu Center. In both centers, we observed increased CXCL9 and CXCL11 in TPE patients. The areas under the ROC curves (AUCs) of pleural CXCL9 and CXCL11 in the Hohhot Center were 0.70 (95 % CI: 0.55-0.85) and 0.68 (95 % CI: 0.52-0.84), respectively. In the Changshu Center, the AUCs of CXCL9 and CXCL11 were 0.96 (95 % CI: 0.92-1.00) and 0.97 (95 % CI: 0.94-1.00), respectively. The AUCs of CXCL9 and CXCL11 decreased with the advancement of age. The decision curves of CXCL9 and CXCL11 showed net benefits in both centers. CXCL9 and CXCL11 were upregulated in BCG-treated macrophages. Pleural fluid from TPE and conditioned medium from BCG-treated macrophages were chemotactic for Th cells. Anti-CXCL9 or CXCL11 neutralizing antibodies could partly block the chemotactic activity. CONCLUSIONS: Pleural CXCL9 and CXCL11 are potential diagnostic markers for TPE, but their diagnostic accuracy is compromised in elderly patients. CXCL9 and CXCL11 can promote the migration of peripheral Th cells, thus representing a therapeutic target for the treatment of TPE.

Identification and quantification of N6-methyladenosine by chemical derivatization coupled with 19F NMR spectroscopy.

N 6-Methyladenosine (6mA) is a well-known prokaryotic DNA modification that has been shown to play epigenetic roles in eukaryotic DNA. Accurate detection and quantification of 6mA are prerequisites for molecular understanding of the impact of 6mA modification on DNA. However, the existing methods have several problems, such as high false-positive rate, time-consuming and complex operating procedures. Chemical sensors for the selective detection of 6mA modification are rarely reported in the literature. Fluorinated phenylboronic acid combined with 19F NMR analysis is an effective method for determining DNA or RNA modification. In this study, we presented a simple and fast chemical method for labelling the 6th imino group of 6mA using a boric-acid-derived probe. Besides, the trifluoromethyl group of trifluoromethyl phenylboronic acid (2a) could detect 6mA modification through 19F NMR. Combined with this sensor system, 6mA modification could be detected well and quickly in 6 types of deoxynucleoside mixtures and DNA samples. Taken together, the method developed in the current study has potential for specific detection of 6mA in biological samples.

Revealing the role of the gut microbiota in enhancing targeted therapy efficacy for lung adenocarcinoma.

Lung adenocarcinoma (LUAD) is the leading cause of cancer-related death globally. Although the gut microbiota's role in the antitumor efficacy of many cancers has been revealed, its involvement in the response to gefitinib therapy for LUAD remains unclear. To fill this gap, we conducted a longitudinal study that profiled gut microbiota changes in PC-9 tumor-bearing mice under different treatments, including gefitinib monotherapy and combination therapies with probiotics, antibiotics, or Traditional Chinese Medicine (TCM). Our findings demonstrated that combining probiotics or TCM with gefitinib therapy outperformed gefitinib monotherapy, as evidenced by tumor volume, body weight, and tumor marker tests. By contrast, antibiotic intervention suppressed the antitumor efficacy of gefitinib. Notably, the temporal changes in gut microbiota were strongly correlated with the different treatments, prompting us to investigate whether there is a causal relationship between gut microbiota and the antitumor efficacy of gefitinib using Mediation Analysis (MA). Finally, our research revealed that thirteen mediators (Amplicon Sequence Variants, ASVs) regulate the antitumor effect of gefitinib, regardless of treatment. Our study provides robust evidence supporting the gut microbiota's significant and potentially causal role in mediating gefitinib treatment efficacy in mice. Our findings shed light on a novel strategy for antitumor drug development by targeting the gut microbiota.