Diabetes is a very complex endocrine disease whose common feature is the increase in blood glucose concentration. Persistent hyperglycemia can lead to blindness, kidney and heart disease, neurodegeneration, and many other serious complications that have a significant impact on human health and quality of life. The number of people with diabetes is increasing yearly. The global diabetes prevalence in 20-79 year olds in 2021 was estimated to be 10.5% (536.6 million), and it will rise to 12.2% (783.2 million) in 2045. The main modes of intervention for diabetes include medication, dietary management, and exercise conditioning. Medication is the mainstay of treatment. Marketed diabetes drugs such as metformin and insulin, as well as GLP-1 receptor agonists, are effective in controlling blood sugar levels to some extent, but the preventive and therapeutic effects are still unsatisfactory. Peptide drugs have many advantages such as low toxicity, high target specificity, and good biocompatibility, which opens up new avenues for the treatment of diabetes and other diseases. Currently, insulin and its analogs are by far the main life-saving drugs in clinical diabetes treatment, enabling effective control of blood glucose levels, but the risk of hypoglycemia is relatively high and treatment is limited by the route of delivery. New and oral anti-diabetic drugs have always been a market demand and research hotspot. Inhibitor cystine knot (ICK) peptides are a class of multifunctional cyclic peptides. In structure, they contain three conserved disulfide bonds (C3-C20, C7-C22, and C15-C32) form a compact “knot” structure, which can resist degradation of digestive protease. Recent studies have shown that ICK peptides derived from legume, such as PA1b, Aglycin, Vglycin, Iglycin, Dglycin, and aM₁, exhibit excellent regulatory activities on glucose and lipid metabolism at the cellular and animal levels. Mechanistically, ICK peptides promote glucose utilization by muscle and liver through activation of IR/AKT signaling pathway, which also improves insulin resistance. They can repair the damaged pancrease through activation of PI3K/AKT/Erk signaling pathway, thus lowering blood glucose. The biostability and hypoglycemic efficacy of the ICK peptides meet the requirements for commercialization of oral drugs, and in theory, they can be developed into natural oral anti-diabetes peptide drugs. In this review, the structural properties, activity and mechanism of ICK pattern peptides in regulating glucose and lipid metabolism were summaried, which provided a reference for the development of new oral peptides for diabetes.

The tumor microenvironment is a crucial factor in tumor occurrence and progression. The hypoxic microenvironment is widely present in tumor tissue and is a key endogenous factor accelerating tumor deterioration. The "blood stasis toxin" theory, as an emerging perspective in tumor research, is regarded as the unique "soil" in tumor progression from the perspective of traditional Chinese medicine(TCM) due to its dynamic evolution mechanism, which closely resembles the formation of the hypoxic microenvironment. Scientifically integrating TCM theories with the biological characteristics of tumors and exploring precise syndrome differentiation and treatment strategies are key to achieving comprehensive tumor prevention and control. This article focused on the hypoxic microenvironment of the tumor, elucidating its formation mechanisms and evolutionary processes and carefully analyzing the internal relationship between the "blood stasis toxin" theory and the hypoxic microenvironment. Additionally, it explored the interaction among blood stasis, toxic pathogens, and hypoxic environment and proposed micro-level prevention and treatment strategies targeting the hypoxic microenvironment based on the "blood stasis toxin" theory, aiming to provide TCM-based theoretical support and therapeutic approaches for precise regulation of the hypoxic microenvironment.
Humans ; Tumor Microenvironment/drug effects* ; Neoplasms/therapy* ; Animals ; Medicine, Chinese Traditional ; Disease Progression ; Drugs, Chinese Herbal

The prelimbic cortex (PL) plays a critical role in processing both the sensory and affective components of pain. However, the underlying molecular mechanisms remain poorly understood. In this study, we observed a reduction in hyperpolarization-activated cation current (I_h) in layer V pyramidal neurons of the contralateral PL in a mouse model of spared nerve injury (SNI). The expression of hyperpolarization-activated cyclic nucleotide-gated 2 (HCN2) channels was also decreased in the contralateral PL. Conversely, microinjection of fisetin, a partial agonist of HCN2, produced both analgesic and anxiolytic effects. Additionally, we found that cyclin-dependent kinase 5 (CDK5) was activated in the contralateral PL, where it formed a complex with HCN2 and phosphorylated its C-terminus. Knockdown of CDK5 restored HCN2 expression and alleviated both pain hypersensitivity and anxiety-like behaviors. Collectively, these results indicate that CDK5-mediated dysfunction of HCN2 in the PL underlies nerve injury-induced mechanical hypersensitivity and anxiety.
Animals ; Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels/metabolism* ; Hyperalgesia/metabolism* ; Cyclin-Dependent Kinase 5/metabolism* ; Neuralgia/metabolism* ; Male ; Anxiety/metabolism* ; Mice ; Potassium Channels/metabolism* ; Mice, Inbred C57BL ; Disease Models, Animal ; Pyramidal Cells/metabolism*

OBJECTIVE: To identify prognostic genes associated with lysosome-dependent cell death (LDCD) in patients with gastric cancer (GC). METHODS: Differentially expressed genes (DEGs) were identified using The Cancer Genome Atlas - Stomach Adenocarcinoma. Weighted gene co-expression network analysis was performed to identify the key module genes associated with LDCD score. Candidate genes were identified by DEGs and key module genes. Univariate Cox regression analysis, and least absolute shrinkage and selection operator regression and multivariate Cox regression analyses were performed for the selection of prognostic genes, and risk module was established. Subsequently, key cells were identified in the single-cell dataset (GSE183904), and prognostic gene expression was analyzed. Cell proliferation and migration were assessed using the Cell Counting Kit-8 assay and the wound healing assay. RESULTS: A total of 4,465 DEGs, 95 candidate genes, and 4 prognostic genes, including C19orf59, BATF2, TNFAIP2, and TNFSF18, were identified in the analysis. Receiver operating characteristic curves indicated the excellent predictive power of the risk model. Three key cell types (B cells, chief cells, and endothelial/pericyte cells) were identified in the GSE183904 dataset. C19orf59 and TNFAIP2 exhibited predominant expression in macrophage species, whereas TNFAIP2 evolved over time in endothelial/pericyte cells and chief cells. Functional experiments confirmed that interfering with C19orf59 inhibited proliferation and migration in GC cells. CONCLUSION C19orf59, BATF2, TNFAIP2, and TNFSF18 are prognostic genes associated with LDCD in GC. Furthermore, the risk model established in this study showed robust predictive power.
Stomach Neoplasms/pathology* ; Humans ; Prognosis ; Lysosomes/physiology* ; RNA-Seq ; Cell Death ; Single-Cell Analysis ; Gene Expression Regulation, Neoplastic ; Cell Proliferation ; Single-Cell Gene Expression Analysis

This study was aimed at comparing performance differences among three metagenomic sequencing platforms,MGISEQ-2000,Illumina NextSeq 2000,and Ion GeneStudio S5 Plus,to optimize the sequencing process for trace samples.The three sequencing platforms were used to perform high-throughput sequencing on DNA standards and simulated samples.Through analysis of the quality of raw data and microbial detection capabilities,systematic differences among platforms were compared.The sequencing results were optimized for trace samples by incorporation of exogenous nucleic acids during the li-brary preparation process.In terms of data output per batch and base quality,MGISEQ-2000 surpassed the other two plat-forms.Illumina NextSeq 2000 had the lowest proportion of duplicate reads,whereas Ion GeneStudio S5 Plus had the highest proportion,and significant differences were observed across platforms(P＜0.001).In sequencing uniformity,MGISEQ-2000 and Illumina NextSeq 2000 were superior to Ion GeneStudio S5 Plus.MGISEQ-2000 provided a substantial advantage in microbial detection capability(P＜0.001),but the advantage diminished with decreasing bacterial fluid concentration.Ion GeneStudio S5 Plus had the shortest duration for single-batch sequencing.Moreo-ver,for trace samples with DNA content ≤0.05 ng,the experi-mental group(with added exogenous nucleic acids)achieved a higher number of reads than the control group(without exogenous nucleic acids),with a 11.09±8.03 fold increase.In conclu-sion,the different sequencing platforms each had advantages and disadvantages,thus allowing researchers to choose the appro-priate platform according to specific needs.Furthermore,the addition of exogenous nucleic acids improved the microorganism detection efficiency,and provided better support for subsequent diagnosis and evaluation of results.

Ophiopogonis Radix, a well-known Chinese herb, is dominantly cultivated in Zhejiang and Sichuan provinces, with the Zhejiang Ophiopogonis Radix acting as one of the eight Zhejiang-based traditional medical materials. Phytochemical studies have shown that Ophiopogonis Radix is rich in steroidal saponins, homoisoflavonoids, terpenoids, and polysaccharides, which collectively confer it with cardiovascular protection, anti-inflammation, anticancer, antioxidation, and immune regulation activities. Studies also show that Ophiopogonis Radix originated from Zhejiang and Sichuan is discriminated in both chemical components and clinical efficacy, while the existing reviews of Ophiopogonis Radix appear to pose a particular focus on Sichuan species, but not for Zhejiang origin. This article systematically summarizes the structures and bioactivities of the compounds sourced from Zhejiang Ophiopogonis Radix as well as its molecular pharmacognosy and it will set the stage for a comprehensive understanding of geo-authentic Ophiopogonis Radix.
Drugs, Chinese Herbal/chemistry* ; Humans ; Animals ; Pharmacognosy ; Ophiopogon/chemistry* ; China

Objective: To propose a new staging system for presacral recurrence of rectal cancer and explore the factors influencing radical resection of such recurrences based on this staging system. Methods: In this retrospective observational study, clinical data of 51 patients with presacral recurrence of rectal cancer who had undergone surgical treatment in the Department of Gastrointestinal Surgery, Peking University People's Hospital between January 2008 and September 2022 were collected. Inclusion criteria were as follows: (1) primary rectal cancer without distant metastasis that had been radically resected; (2) pre-sacral recurrence of rectal cancer confirmed by multi-disciplinary team assessment based on CT, MRI, positron emission tomography, physical examination, surgical exploration, and pathological examination of biopsy tissue in some cases; and (3) complete inpatient, outpatient and follow-up data. The patients were allocated to radical resection and non-radical resection groups according to postoperative pathological findings. The study included: (1) classification of pre-sacral recurrence of rectal cancer according to its anatomical characteristics as follows: Type I: no involvement of the sacrum; Type II: involvement of the low sacrum, but no other sites; Type III: involvement of the high sacrum, but no other sites; and Type IV: involvement of the sacrum and other sites. (2) Assessment of postoperative presacral recurrence, overall survival from surgery to recurrence, and duration of disease-free survival. (3) Analysis of factors affecting radical resection of pre-sacral recurrence of rectal cancer. Non-normally distributed measures are expressed as median (range). The Mann-Whitney U test was used for comparison between groups. Results: The median follow-up was 25 (2-96) months with a 100% follow-up rate. The rate of metachronic distant metastasis was significantly lower in the radical resection than in the non-radical resection group (24.1% [7/29] vs. 54.5% [12/22], χ²=8.333, P=0.026). Postoperative disease-free survival was longer in the radical resection group (32.7 months [3.0-63.0] vs. 16.1 [1.0-41.0], Z=8.907, P=0.005). Overall survival was longer in the radical resection group (39.2 [3.0-66.0] months vs. 28.1 [1.0-52.0] months, Z=1.042, P=0.354). According to univariate analysis, age, sex, distance between the tumor and anal verge, primary tumor pT stage, and primary tumor grading were not associated with achieving R0 resection of presacral recurrences of rectal cancer (all P>0.05), whereas primary tumor pN stage, anatomic staging of presacral recurrence, and procedure for managing presacral recurrence were associated with rate of R0 resection (all P<0.05). According to multifactorial analysis, the pathological stage of the primary tumor pN1-2 (OR=3.506, 95% CI: 1.089-11.291, P=0.035), type of procedure (transabdominal resection: OR=29.250, 95% CI: 2.789 - 306.811, P=0.005; combined abdominal perineal resection: OR=26.000, 95% CI: 2.219-304.702, P=0.009), and anatomical stage of presacral recurrence (Type III: OR=16.000, 95% CI: 1.542 - 166.305, P = 0.020; type IV: OR= 36.667, 95% CI: 3.261 - 412.258, P = 0.004) were all independent risk factors for achieving radical resection of anterior sacral recurrence after rectal cancer surgery. Conclusion: Stage of presacral recurrences of rectal cancer is an independent predictor of achieving R0 resection. It is possible to predict whether radical resection can be achieved on the basis of the patient's medical history.
Humans ; Neoplasm Recurrence, Local/diagnosis* ; Rectal Neoplasms/therapy* ; Retrospective Studies ; Pelvis/pathology* ; Recurrence ; Treatment Outcome

Objective: This cross-sectional investigation aimed to determine the incidence, clinical characteristics, prognosis, and related risk factors of olfactory and gustatory dysfunctions related to infection with the SARS-CoV-2 Omicron strain in mainland China. Methods: Data of patients with SARS-CoV-2 from December 28, 2022, to February 21, 2023, were collected through online and offline questionnaires from 45 tertiary hospitals and one center for disease control and prevention in mainland China. The questionnaire included demographic information, previous health history, smoking and alcohol drinking, SARS-CoV-2 vaccination, olfactory and gustatory function before and after infection, other symptoms after infection, as well as the duration and improvement of olfactory and gustatory dysfunction. The self-reported olfactory and gustatory functions of patients were evaluated using the Olfactory VAS scale and Gustatory VAS scale. Results: A total of 35 566 valid questionnaires were obtained, revealing a high incidence of olfactory and taste dysfunctions related to infection with the SARS-CoV-2 Omicron strain (67.75%). Females(χ2=367.013, P<0.001) and young people(χ2=120.210, P<0.001) were more likely to develop these dysfunctions. Gender(OR=1.564, 95%CI: 1.487-1.645), SARS-CoV-2 vaccination status (OR=1.334, 95%CI: 1.164-1.530), oral health status (OR=0.881, 95%CI: 0.839-0.926), smoking history (OR=1.152, 95%CI=1.080-1.229), and drinking history (OR=0.854, 95%CI: 0.785-0.928) were correlated with the occurrence of olfactory and taste dysfunctions related to SARS-CoV-2(above P<0.001). 44.62% (4 391/9 840) of the patients who had not recovered their sense of smell and taste also suffered from nasal congestion, runny nose, and 32.62% (3 210/9 840) suffered from dry mouth and sore throat. The improvement of olfactory and taste functions was correlated with the persistence of accompanying symptoms(χ2=10.873, P=0.001). The average score of olfactory and taste VAS scale was 8.41 and 8.51 respectively before SARS-CoV-2 infection, but decreased to3.69 and 4.29 respectively after SARS-CoV-2 infection, and recovered to 5.83and 6.55 respectively at the time of the survey. The median duration of olfactory and gustatory dysfunctions was 15 days and 12 days, respectively, with 0.5% (121/24 096) of patients experiencing these dysfunctions for more than 28 days. The overall self-reported improvement rate of smell and taste dysfunctions was 59.16% (14 256/24 096). Gender(OR=0.893, 95%CI: 0.839-0.951), SARS-CoV-2 vaccination status (OR=1.334, 95%CI: 1.164-1.530), history of head and facial trauma(OR=1.180, 95%CI: 1.036-1.344, P=0.013), nose (OR=1.104, 95%CI: 1.042-1.171, P=0.001) and oral (OR=1.162, 95%CI: 1.096-1.233) health status, smoking history(OR=0.765, 95%CI: 0.709-0.825), and the persistence of accompanying symptoms (OR=0.359, 95%CI: 0.332-0.388) were correlated with the recovery of olfactory and taste dysfunctions related to SARS-CoV-2 (above P<0.001 except for the indicated values). Conclusion: The incidence of olfactory and taste dysfunctions related to infection with the SARS-CoV-2 Omicron strain is high in mainland China, with females and young people more likely to develop these dysfunctions. Active and effective intervention measures may be required for cases that persist for a long time. The recovery of olfactory and taste functions is influenced by several factors, including gender, SARS-CoV-2 vaccination status, history of head and facial trauma, nasal and oral health status, smoking history, and persistence of accompanying symptoms.
Female ; Humans ; Adolescent ; SARS-CoV-2 ; Smell ; COVID-19/complications* ; Cross-Sectional Studies ; COVID-19 Vaccines ; Incidence ; Olfaction Disorders/etiology* ; Taste Disorders/etiology* ; Prognosis

COVID-19 has been prevalent for three years. The virulence of SARS-CoV-2 is weaken as it mutates continuously. However, elderly patients, especially those with underlying diseases, are still at high risk of developing severe infections. With the continuous study of the molecular structure and pathogenic mechanism of SARS-CoV-2, antiviral drugs for COVID-19 have been successively marketed, and these anti-SARS-CoV-2 drugs can effectively reduce the severe rate and mortality of elderly patients. This article reviews the mechanism, clinical medication regimens, drug interactions and adverse reactions of five small molecule antiviral drugs currently approved for marketing in China, so as to provide advice for the clinical rational use of anti-SARS-CoV-2 in the elderly.

ObjectiveTo investigate the nephroprotective and anti-inflammatory effects of Fufang Shelong capsules （FFSL） in rats with membranous nephropathy （MN）， and the role of the p38 mitogen-activated protein kinase （MAPK） signaling pathway. MethodMale SD rats of SPF grade were divided into a normal group and an experimental group. The MN model was induced by tail vein injection of cationized bovine serum albumin in the experimental group. After screening， the eligible model rats were included and divided into a positive control group （tripterygium glycosides tablets） and low-， medium-， and high-dose FFSL groups （0.375， 0.75， 1.5g·kg^-1）. The rats were treated correspondingly for eight weeks， and urine protein was detected during drug intervention. Renal function and inflammation-related indicators were detected after drug intervention. The changes in 24-hour urine total protein （24 h UP）， interleukin-6 （IL-6）， interleukin-8 （IL-8）， tumor necrosis factor-α （TNF-α）， creatinine （Cr）， blood urea nitrogen （BUN）， total protein （TP）， albumin （Alb）， and total cholesterol （TC） were detected. Flow cytometry was used to detect CD4⁺/CD8⁺ changes. Kidney tissues were collected to observe pathological changes under a light microscope and an electron microscope. The protein expression of p38 MAPK and phosphorylated p38 MAPK （p-p38 MAPK） in kidney tissues was detected by Western blot. ResultCompared with the normal group， the model group showed increased 24 h UP （P<0.01）， elevated serum Cr， BUN， TC， IL-6， IL-8， and TNF-α （P<0.05，P<0.01）， decreased serum Alb and TP levels （P<0.05，P<0.01）， increased CD4⁺/CD8⁺ in the peripheral blood （P<0.01）， and up-regulated protein expression of p38 MAPK and p-p38 MAPK in kidney tissues （P<0.05）. Additionally， in the model group， immune complex deposition and foot process fusion， accompanied by infiltration of inflammatory cells， were observed on the epithelial side of the basement membrane in the pathological kidney tissues. Compared with the model group， the groups with drug intervention showed declining 24 h UP levels at six weeks （P<0.05，P<0.01）， decreased serum Cr， BUN， TC， IL-6， IL-8， and TNF-α （P<0.05，P<0.01）， increased serum Alb and TP levels （P<0.05，P<0.01）， reduced CD4⁺/CD8⁺ in the peripheral blood （P<0.01）， improved renal pathological damage， and down-regulated p38 MAPK and p-p38 MAPK in kidney tissues （P<0.05，P<0.01）. ConclusionFFSL can decrease the expression of inflammatory factors， reduce proteinuria， delay kidney damage， and protect kidney function by inhibiting the expression of the p38 MAPK signaling pathway.