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.

Alzheimer’s disease (AD) is a central neurodegenerative disease characterized by progressive cognitive decline and memory impairment in clinical. Currently, there are no effective treatments for AD. In recent years, a variety of therapeutic approaches from different perspectives have been explored to treat AD. Although the drug therapies targeted at the clearance of amyloid β-protein (Aβ) had made a breakthrough in clinical trials, there were associated with adverse events. Neuroinflammation plays a crucial role in the onset and progression of AD. Continuous neuroinflammatory was considered to be the third major pathological feature of AD, which could promote the formation of extracellular amyloid plaques and intracellular neurofibrillary tangles. At the same time, these toxic substances could accelerate the development of neuroinflammation, form a vicious cycle, and exacerbate disease progression. Reducing neuroinflammation could break the feedback loop pattern between neuroinflammation, Aβ plaque deposition and Tau tangles, which might be an effective therapeutic strategy for treating AD. Traditional Chinese herbs such as Polygonum multiflorum and Curcuma were utilized in the treatment of AD due to their ability to mitigate neuroinflammation. Non-steroidal anti-inflammatory drugs such as ibuprofen and indomethacin had been shown to reduce the level of inflammasomes in the body, and taking these drugs was associated with a low incidence of AD. Biosynthetic nanomaterials loaded with oxytocin were demonstrated to have the capability to anti-inflammatory and penetrate the blood-brain barrier effectively, and they played an anti-inflammatory role via sustained-releasing oxytocin in the brain. Transplantation of mesenchymal stem cells could reduce neuroinflammation and inhibit the activation of microglia. The secretion of mesenchymal stem cells could not only improve neuroinflammation, but also exert a multi-target comprehensive therapeutic effect, making it potentially more suitable for the treatment of AD. Enhancing the level of TREM2 in microglial cells using gene editing technologies, or application of TREM2 antibodies such as Ab-T1, hT2AB could improve microglial cell function and reduce the level of neuroinflammation, which might be a potential treatment for AD. Probiotic therapy, fecal flora transplantation, antibiotic therapy, and dietary intervention could reshape the composition of the gut microbiota and alleviate neuroinflammation through the gut-brain axis. However, the drugs of sodium oligomannose remain controversial. Both exercise intervention and electromagnetic intervention had the potential to attenuate neuroinflammation, thereby delaying AD process. This article focuses on the role of drug therapy, gene therapy, stem cell therapy, gut microbiota therapy, exercise intervention, and brain stimulation in improving neuroinflammation in recent years, aiming to provide a novel insight for the treatment of AD by intervening neuroinflammation in the future.

Objective: To investigate the expression and functional role of FK506 binding protein 10 (FKBP10) in oral squamous cell carcinoma (OSCC), and to provide a research basis for the estimated prognosis and targeted therapy of OSCC. Methods: A total of 284 OSCC samples and 19 normal samples were selected from the Cancer Genome Atlas (TCGA) database, and diagnostic analysis was performed to determine mRNA expression. Survival analysis for FKBP10 and OSCC was conducted on a gene expression profile interaction analysis website. Real-time fluorescence quantitative PCR and Western Blot were used to detect the mRNA and protein expression of FKBP10 in four OSCC cell lines and SAS and SCC9 cells transfected with siRNA. The cell proliferation ability of FKBP10-silenced cells was detected using the CCK8 method, and the cell cycle distribution and apoptosis were detected by flow cytometry. Cell migration and invasion ability were detected through wound healing and invasion experiments. The expression changes of total protein and phosphatidylinositol 3-kinase (PI3K)-serine/threonine kinase (AKT) after FKBP10 silencing were analyzed by proteomics and Western Blot. Results: According to the analysis of gene expression levels, the mRNA expression level of FKBP10 in OSCC was significantly higher than that in normal tissues (P < 0.001). In terms of diagnosis, the expression level of FKBP10 has unique diagnostic value for OSCC (P < 0.05). The survival analysis of FKBP10 and OSCC showed that a high expression of FKBP10 led to a decrease in patient survival and poor prognosis (P < 0.05). The expression of FKBP10 mRNA and protein in OSCC cell lines was higher than that in normal oral keratinocytes (P < 0.001). Silencing FKBP10 can reduce the proliferation, invasion, and migration ability of SAS and SCC9 (P < 0.001), and also block their cell cycle in the G0/G1 phase (P < 0.001), with a significant increase in apoptosis (P < 0.05). Protein mass spectrometry and Western blot analysis revealed that FKBP10 silencing significantly downregulated the expression of multiple proteins in the RAP1 signaling pathway, mainly RAP guanine nucleotide exchange factor 1 (RAPGEF1) (P < 0.05) and the phosphorylation of PI3K-AKT proteins (P < 0.05). Conclusion FKBP10 is highly expressed in OSCC, leading to poor prognosis for patients. Downregulated FKBP10 expression can inhibit the proliferation, migration, and invasion ability of OSCC cells, hinder cell cycle progression, and promote apoptosis via the RAP1-PI3K-AKT axis. FKBP10 is a potential therapeutic target and prognostic biomarker for OSCC.

Objective: To analyze the effects of blue light on the formation of kidney stones. Methods: A total of 40 rats were randomly divided into 4 groups：A，B，C，and D，with 10 rats in each group.Rats in groups C and D were administered with a mixture of 10 g/L ethylene glycol，20 g/L ammonium chloride，and 100 g/L calcium gluconate via gavage (2 mL per mouse)，while rats in groups A and B received an equal volume of physiological saline via gavage.From the second day after gavage，rats in groups A and C were subjected to twice-daily blue light irradiation (one hour per session) as an intervention，while rats in groups B and D were subjected to fluorescent lamp irradiation using the same method.After 4 weeks of intervention，the 24-hour urine samples were collected，and the rats were then euthanized for the collection of blood and kidney tissue samples.Serum levels of antidiuretic hormone (ADH)，urinary Ca ，and urinary oxalate (Oxa) were measured.Levels of malondialdehyde (MDA) and superoxide dismutase (SOD) in kidney tissues were detected using ELISA.Von Kossa staining was performed to observe pathological changes in kidney tissues and the presence of calcium salt crystals in the kidneys. Results: Compared with groups A and B，groups C and D showed higher accumulation of calcium salt crystals in renal tissues，as well as elevated levels of ADH，urinary Ca ，urinary Oxa，and MDA in renal tissues, additionally，the SOD level in renal tissues was lower (P<0.05).Compared with group D，group C exhibited higher accumulation of calcium salt crystals in renal tissues，along with increased levels of ADH，urinary Ca ，urinary Oxa，and MDA in renal tissues；conversely，the SOD level in renal tissues was lower (P<0.05). Conclusion: Blue light may increase the formation of kidney stones in rats by promoting the secretion of ADH in serum and oxidative stress in kidney tissues through the brain-kidney axis.

OBJECTIVE To compare the efficacy of ceftazidime and avibactam （CZA） monotherapy and combination therapy in the treatment of carbapenem-resistant Gram-negative bacteria （CRGNB） infections， and analyze the influencing factors. METHODS The data of patients with CRGNB infection who received CZA treatment from January 2020 to March 2025 were collected retrospectively. The patients were divided into the CZA monotherapy group （52 cases） and the CZA combination therapy group （85 cases） according to treatment regimen. The therapeutic effects of the two groups were compared， and the drug susceptibility results of isolated strains were recorded. The multivariate Logistic regression model was used to analyze the factors influencing clinical efficacy of CRGNB patients. RESULTS The bacterial clearance rate of patients was significantly higher in the CZA combination therapy group than in the CZA monotherapy group （P＝0.012）. However， when comparing the 30-day mortality rate and the clinical response rate between the two groups， no statistically significant differences were observed （P＞0.05）. Among the isolates， carbapenem-resistant Klebsiella pneumoniae had the highest sensitivity to tigecycline （87.3%） and carbapenem-resistant Pseudomonas aeruginosa showed 90.9% sensitivity to amikacin. Five isolates were resistant to CZA. The multivariate Logistic regression showed， lung infection， receiving continuous renal replacement therapy （CRRT）， and inadequate treatment courses were significantly correlated with clinical treatment failure （P＜0.05）. CONCLUSIONS For CRGNB infection， the clinical efficacy of CZA combination therapy is similar to that of monotherapy， but the combination therapy has a higher bacterial clearance rate. Lung infections， receiving CRRT and inadequate treatment courses （No. are independent risk factors for clinical treatment failure.

Objective:To explore the effects of Tongdu Tiaoshen acupuncture on vascular endothelial function and inflammatory factors in patients with mild cognitive impairment (MCI) after ischemic stroke (IS).Methods:A retrospective analysis was performed on the clinical data of 71 patients with MCI after IS in the hospital between January 2020 and September 2022. According to different treatment methods, they were divided into Tongdu Tiaoshen acupuncture group ( n=31, Tongdu Tiaoshen acupuncture + oral nimodipine tables) and routine body-acupuncture group ( n=40, routine body-acupuncture group + oral nimodipine tables). Both groups were treated for 2 courses (14 d/course). Before and after treatment, levels of serum NO and endothelin-1 (ET-1) were detected by radioimmunoassay, and levels of serum basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF), plasma homocysteine (Hcy) and IL-6 were detected by ELISA. The cognitive function of patients was evaluated and intelligence level by Montreal Cognitive Assessment Scale (MoCA), Mini-Mental State Examination(MMSE) and the clinical curative effect was also evaluated. Results:The total response rates in Tongdu Tiaoshen acupuncture group and routine body-acupuncture group were 90.32% (28/31) and 70.00% (28/40), and the difference between the two groups was statistically significant ( χ2=4.33, P=0.037). After treatment, levels of plasma Hcy and IL-6 in Tongdu Tiaoshen acupuncture group were lower than those in the routine body-acupuncture group ( t=2.57, 9.36, P<0.05 or P<0.01). After treatment, levels of serum bFGF, VEGF and NO in Tongdu Tiaoshen acupuncture group were significantly higher than those in the routine body-acupuncture group ( t=10.03, 9.29, 8.17, P<0.01), while ET-1 level was significantly lower than that of the routine body-acupuncture group ( t=2.41, P=0.019). After treatment, MoCA score [(28.24±4.45) vs. (25.32±4.34), t=2.78], MMSE score [(28.73±1.44) vs. (28.02±1.22), t=2.25] in Tongdu Tiaoshen acupuncture group were higher than those in the routine body-acupuncture group ( P<0.01). Conclusion:Tongdu Tiaoshen acupuncture is beneficial to improve vascular endothelial function, reduce levels of inflammatory factors, promote the recovery of cognitive function and improve curative effect in patients with MCI after IS.

Objective To observe the clinical efficacy of Lingnan Traditional Vesiculating Moxibustion No.4 Recipe(mainly composed of Brassicae Junceae Semen,Euodiae Fructus,and Curcumae Radix)in the treatment of mild depressive disorder(DD),and to provide a novel approach to the treatment of mild DD population.Methods Sixty-one patients with mild DD were randomly divided into 31 cases in the trial group and 30 cases in the control group.The trial group was given medicinal vesiculation treatment with Lingnan Traditional Vesiculating Moxibustion No.4 Recipe,and the control group was given medicinal vesiculation treatment with the placebo of Lingnan Traditional Vesiculating Moxibustion No.4 Recipe.The treatment was performed twice a week and with an interval of 3-4 days between the treatment,and the course of treatment covered 6 weeks.The changes of Hamilton Depression Scale-17(HAMD-17)scores and Patient Health Questionnaire-9(PHQ-9)scores in the two groups were observed before and after the treatment.After treatment,the clinical efficacy and safety of the patients in the two groups were evaluated.Results(1)After 6 weeks of treatment,the total efficacy rate of the trial group was 77.42%(24/31),and that of the control group was 26.67%(8/30).The intergroup comparison(tested by rank sum test)showed that the efficacy of the trial group was significantly superior to that of the control group,and the difference was statistically significant(P＜0.01).(2)After treatment,the HAMD-17 scores and PHQ-9 scores of patients in the two groups were lower than those before treatment(P＜0.01),and the decrease of HAMD-17 and PHQ-9 scores in the trial group was significantly superior to that of the control group,the difference being statistically significant(P＜0.01).(3)During the trial,there were 5 cases of adverse events related to the vesiculating moxibustion treatment,and all 5 cases of adverse events occurred in the trial group,manifested as minor blisters at the acupoint application region.The 5 cases kept on participating in the trial after relevant treatment.Conclusion Lingnan Traditional Vesiculating Moxibustion No.4 Recipe can effectively relieve the clinical symptoms of patients with mild DD,and has high safety.

Objective To analyze the antigen recognition sites of commercial and homemade antibodies against aquaporin(AQP)9,and to identify the application effect.Methods Western blotting was used to compare the efficacy of three commercial antibodies and self-made antibody in identifying AQP9 genotypes.The antigen recognition sites of four antibodies and their specificities in practical applications were analyzed.Results Western blotting showed that protein bands of three commercial antibodies were detected in both WT and Aqp9-/-mice.The keyhole limpet hemocyanin(KLH)conjugated synthetic peptides corresponding to the three commercial antibodies were derived from rat,human and human,respectively.And The sequences of these three synthetic peptides were different from those of mice.AQP3/7 and AQP9 have similar molecular weight and were expressed in the liver with high homology.An obvious band of self-made antibody was observed at the 27 kD position in WT mice,but no band was observed at the corresponding position in Aqp9-/-mice.Conclusion Commercial antibodies 1 and 3 can be used to assist in the identification of genotypes in Aqp9-/-mice.Homemade antibodies can accurately identify genotypes at the protein level.

Objective: To investigate the prevalence of osteoporosis (OP) and its influencing factors among people aged 60 years and above, so as to provide insights into OP prevention and treatment among the elderly. Methods: People aged 60 years and above who underwent physical examinations were selected from Hangzhou First People's Hospital from January to October 2023. Demographic information, lifestyle and physical examination data were collected through field surveys and hospital information systems. Bone density was measured by dual-energy X-ray densitometer, and OP was diagnosed with reference to the Guidelines for the Diagnosis and Treatment of Primary Osteoporosis (2022). Factors affecting the OP were identified using a multivariable logistic regression model. Results: A total of 482 participants were included and had a mean age of (69.10±6.52) years. There were 217 men (45.02%) and 265 women (54.98%). The prevalence of OP was 43.36%. Multivariable logistic regression analysis identified gender (women, OR=3.791, 95%CI: 1.726-8.314), age (70 to 79 years, OR=1.260, 95%CI: 1.018-1.559; 80 years and above, OR=3.083, 95%CI: 1.546-6.147), body mass index (≥24 kg/m2, OR=0.358, 95%CI: 0.205-0.626), family history of fracture (OR=1.475, 95%CI: 1.073-2.030), diabetes (OR=1.626, 95%CI: 1.109-2.382), regular exercise (OR=0.457, 95%CI: 0.287-0.726), intake of milk products (OR=0.511, 95%CI: 0.335-0.780), intake of calcium supplements (OR=0.473, 95%CI: 0.287-0.778) and vitamin D deficiency (OR=2.132, 95%CI: 1.309-3.473) as factors affecting OP. Conclusion The prevalence of OP is associated with gender, age, body mass index, family history of fracture, diabetes, diet and vitamin D deficiency.

Alzheimer’s disease (AD) is a central neurodegenerative disease characterized by progressive cognitive dysfunction and behavioral impairment, and there is a lack of effective drugs to treat AD clinically. Existing medications for the treatment of AD, such as Tacrine, Donepezil, Rivastigmine, and Aducanumab, only serve to delay symptoms and but not cure disease. To add insult to injury, these medications are associated with very serious adverse effects. Therefore, it is urgent to explore effective therapeutic drugs for AD. Recently, studies have shown that a variety of enzyme inhibitors, such as cholinesterase inhibitors, monoamine oxidase (MAO)inhibitors, secretase inhibitors, can ameliorate cholinergic system dysfunction, Aβ production and deposition, Tau protein hyperphosphorylation, oxidative stress damage, and the decline of synaptic plasticity, thereby improving AD symptoms and cognitive function. Some plant extracts from natural sources, such as Umbelliferone, Aaptamine, Medha Plus, have the ability to inhibit cholinesterase activity and act to improve learning and cognition. Isochromanone derivatives incorporating the donepezil pharmacophore bind to the catalytic active site (CAS) and peripheral anionic site (PAS) sites of acetylcholinesterase (AChE), which can inhibit AChE activity and ameliorate cholinergic system disorders. A compound called Rosmarinic acid which is found in the Lamiaceae can inhibit monoamine oxidase, increase monoamine levels in the brain, and reduce Aβ deposition. Compounds obtained by hybridization of coumarin derivatives and hydroxypyridinones can inhibit MAO-B activity and attenuate oxidative stress damage. Quinoline derivatives which inhibit the activation of AChE and MAO-B can reduce Aβ burden and promote learning and memory of mice. The compound derived from the combination of propargyl and tacrine retains the inhibitory capacity of tacrine towards cholinesterase, and also inhibits the activity of MAO by binding to the FAD cofactor of monoamine oxidase. A series of hybrids, obtained by an amide linker of chromone in combine with the benzylpiperidine moieties of donepezil, have a favorable safety profile of both cholinesterase and monoamine oxidase inhibitory activity. Single domain antibodies (such as AAV-VHH) targeted the inhibition of BACE1 can reduce Aβ production and deposition as well as the levels of inflammatory cells, which ultimately improve synaptic plasticity. 3-O-trans-p-coumaroyl maslinic acid from the extract of Ligustrum lucidum can specifically inhibit the activity of γ-secretase, thereby rescuing the long-term potentiation and enhancing synaptic plasticity in APP/PS1 mice. Inhibiting γ-secretase activity which leads to the decline of inflammatory factors (such as IFN-γ, IL-8) not only directly improves the pathology of AD, but also reduces Aβ production. Melatonin reduces the transcriptional expression of GSK-3β mRNA, thereby decreasing the levels of GSK-3β and reducing the phosphorylation induced by GSK-3β. Hydrogen sulfide can inhibitGSK-3β activity via sulfhydration of the Cys218 site of GSK-3β, resulting in the suppression of Tau protein hyperphosphorylation, which ameliorate the motor deficits and cognitive impairment in mice with AD. This article reviews enzyme inhibitors and conformational optimization of enzyme inhibitors targeting the regulation of cholinesterase, monoamine oxidase, secretase, and GSK-3β. We are hoping to provide a comprehensive overview of drug development in the enzyme inhibitors, which may be useful in treating AD.