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.

Nonobstructive azoospermia (NOA), one of the most severe types of male infertility, etiology often remains unclear in most cases. Therefore, this study aimed to detect four biallelic detrimental variants (0.5%) in the minichromosome maintenance domain containing 2 ( MCMDC2 ) genes in 768 NOA patients by whole-exome sequencing (WES). Hematoxylin and eosin (H&E) demonstrated that MCMDC2 deleterious variants caused meiotic arrest in three patients (c.1360G>T, c.1956G>T, and c.685C>T) and hypospermatogenesis in one patient (c.94G>T), as further confirmed through immunofluorescence (IF) staining. The single-cell RNA sequencing data indicated that MCMDC2 was substantially expressed during spermatogenesis. The variants were confirmed as deleterious and responsible for patient infertility through bioinformatics and in vitro experimental analyses. The results revealed four MCMDC2 variants related to NOA, which contributes to the current perception of the function of MCMDC2 in male fertility and presents new perspectives on the genetic etiology of NOA.
Humans ; Male ; Azoospermia/genetics* ; Meiosis/genetics* ; Spermatogenesis/genetics* ; Adult ; Exome Sequencing ; Microtubule-Associated Proteins/genetics* ; Alleles ; Infertility, Male/genetics*

The Janus kinase/signal transducers and activators of transcription (JAK-STAT) control natural killer (NK) cells development and cytotoxic functions, however, whether long non-coding RNAs (lncRNAs) are involved in this pathway remains unknown. We found that miR155HG was elevated in activated NK cells and promoted their proliferation and effector functions in both NK92 and induced-pluripotent stem cells (iPSCs)-derived NK (iPSC-NK) cells, without reliance on its derived miR-155 and micropeptide P155. Mechanistically, miR155HG bound to miR-6756 and relieved its repression of JAK3 expression, thereby promoting the JAK-STAT pathway and enhancing NK cell proliferation and function. Further investigations disclosed that upon cytokine stimulation, STAT3 directly interacts with miR155HG promoter and induces miR155HG transcription. Collectively, we identify a miR155HG-mediated positive feedback loop of the JAK-STAT signaling. Our study will also provide a power target regarding miR155HG for improving NK cell generation and effector function in the field of NK cell adoptive transfer therapy against cancer, especially iPSC-derived NK cells.

Cemental tear is a rare and indetectable condition unless obvious clinical signs present with the involvement of surrounding periodontal and periapical tissues. Due to its clinical manifestations similar to common dental issues, such as vertical root fracture, primary endodontic diseases, and periodontal diseases, as well as the low awareness of cemental tear for clinicians, misdiagnosis often occurs. The critical principle for cemental tear treatment is to remove torn fragments, and overlooking fragments leads to futile therapy, which could deteriorate the conditions of the affected teeth. Therefore, accurate diagnosis and subsequent appropriate interventions are vital for managing cemental tear. Novel diagnostic tools, including cone-beam computed tomography (CBCT), microscopes, and enamel matrix derivatives, have improved early detection and management, enhancing tooth retention. The implementation of standardized diagnostic criteria and treatment protocols, combined with improved clinical awareness among dental professionals, serves to mitigate risks of diagnostic errors and suboptimal therapeutic interventions. This expert consensus reviewed the epidemiology, pathogenesis, potential predisposing factors, clinical manifestations, diagnosis, differential diagnosis, treatment, and prognosis of cemental tear, aiming to provide a clinical guideline and facilitate clinicians to have a better understanding of cemental tear.
Humans ; Dental Cementum/injuries* ; Consensus ; Diagnosis, Differential ; Cone-Beam Computed Tomography ; Tooth Fractures/therapy*

Hypertriglyceridemia-associated acute pancreatitis is an inflammatory disorder of exocrine pancreas caused by metabolism disturbances of triglyceride-rich lipoproteins.Currently,hypertriglyceridemia-associated acute pancreatitis is characterized by an escalating incidence rate,a tendency for more severe cases,and a lack of therapeutic drugs.Traditional Chinese medicine has distinct advantages in treating this disease,but its theoretical framework has not yet been established.Hypertriglyceridemia-associated acute pancreatitis manifests itself as a febrile disease,aberrant accumulation of fat and turbidity may stem from dietary imbalances and visceral dysfunction in ordinary individuals.The prolonged accumulation of fat and turbidity can transform into turbid pathogen,subsequently engendering heat,constituting a pivotal pathogenic factor.Throughout the progression of the disease,the fiery pathogen consumes the fat and turbidity,resulting in the generation of toxic heat,which is a crucial mechanism in the exacerbation of the disease severity.Thus,this article posits therapeutic principles aimed at averting the transformation of fat and turbidity into turbid pathogen and counteracting toxic heat in this disease.This article reviews two key theories from traditional Chinese medicine classics relevant to hypertriglyceridemia-associated acute pancreatitis:the theory of fat-turbidity associated with hypertriglyceridemia and the febrile disease related to acute pancreatitis.Combining these traditional theories with modern research on the mechanisms that intensify hypertriglyceridemia-associated acute pancreatitis and the corresponding targets of traditional Chinese medicine,it suggests that the pathogenesis of"fat-turbidity-toxic heat"serves as the theoretical basis of traditional Chinese medicine for the aggravated severity of hypertriglyceridemia-associated acute pancreatitis.The article aims to offer new insights for the treatment of hypertriglyceridemia-associated acute pancreatitis.

Objective:In chronic hepatitis B (CHB) patients with previous 96-week treatment with tenofovir amibufenamide (TMF) or tenofovir disoproxil fumarate (TDF), we investigated the efficacy of sequential TMF treatment from 96 to 144 weeks.Methods:Enrolled subjects who were previously assigned (2:1) to receive either 25 mg TMF or 300 mg TDF with matching placebo for 96 weeks received extended or switched TMF treatment for 48 weeks. Efficacy was evaluated based on virological, serological, biological parameters, and fibrosis staging. Statistical analysis was performed using the McNemar test, t-test, or Log-Rank test according to the data. Results:593 subjects from the initial TMF group and 287 subjects from the TDF group were included at week 144, with the proportions of HBV DNA<20 IU/ml at week 144 being 86.2% and 83.3%, respectively, and 78.1% and 73.8% in patients with baseline HBV DNA levels ≥8 log10 IU/ml. Resistance to tenofovir was not detected in both groups. For HBeAg loss and seroconversion rates, both groups showed a further increase from week 96 to 144 and the 3-year cumulative rates of HBeAg loss were about 35% in each group. However, HBsAg levels were less affected during 96 to 144 weeks. For patients switched from TDF to TMF, a substantial further increase in the alanine aminotransferase (ALT) normalization rate was observed (11.4%), along with improved FIB-4 scores.Conclusion:After 144 weeks of TMF treatment, CHB patients achieved high rates of virological, serological, and biochemical responses, as well as improved liver fibrosis outcomes. Also, switching to TMF resulted in significant benefits in ALT normalization rates (NCT03903796).

Objective:In chronic hepatitis B (CHB) patients with previous 96-week treatment with tenofovir amibufenamide (TMF) or tenofovir disoproxil fumarate (TDF), we investigated the safety profile of sequential TMF treatment from 96 to 144 weeks.Methods:Enrolled subjects that previously assigned (2:1) to receive either 25 mg TMF or 300 mg TDF with matching placebo for 96 weeks received extending or switching TMF treatment for 48 weeks. Safety profiles of kidney, bone, metabolism, body weight, and others were evaluated.Results:666 subjects from the initial TMF group and 336 subjects from TDF group with at least one dose of assigned treatment were included at week 144. The overall safety profile was favorable in each group and generally similar between extended or switched TMF treatments from week 96 to 144. In subjects switching from TDF to TMF, the non-indexed estimated glomerular filtration rate (by non-indexed CKD-EPI formula) and creatinine clearance (by Cockcroft-Gault formula) were both increased, which were (2.31±8.33) ml/min and (4.24±13.94) ml/min, respectively. These changes were also higher than those in subjects with extending TMF treatment [(0.91±8.06) ml/min and (1.30±13.94) ml/min]. Meanwhile, switching to TMF also led to an increase of the bone mineral density (BMD) by 0.75% in hip and 1.41% in spine. On the other side, a slight change in TC/HDL ratio by 0.16 (IQR: 0.00, 0.43) and an increase in body mass index (BMI) by (0.54±0.98) kg/m 2 were oberved with patients switched to TMF, which were significantly higher than that in TMF group. Conclusion:CHB patients receiving 144 weeks of TMF treatment showed favorable safety profile. After switching to TMF, the bone and renal safety was significantly improved in TDF group, though experienceing change in metabolic parameters and weight gain (NCT03903796).

Objective:Non-alcoholic fatty liver disease(NAFLD)is a common metabolic disorder in overweight and obese children,and its etiology and pathogenesis remain unclear,lacking effective preventive and therapeutic measures.This study aims to explore the association between whole blood copper,zinc,calcium,magnesium and iron levels and NAFLD in overweight and obese children aged 6 to 17 years,providing a scientific basis for the prevention and intervention of early NAFLD in overweight and obese children. Methods:A cross-sectional study design was used to collect relevant data from overweight and obese children who visited the Hunan Children's Hospital from January 2019 to December 2021 through questionnaire surveys.Fasting blood samples were collected from the subjects,and various indicators such as blood glucose,blood lipid,and mineral elements were detected.All children were divided into an overweight group(n=400)and a NAFLD group(n=202).The NAFLD group was divided into 2 subgroups according to the ALT level:A non-alcoholic fatty liver(NAFL)group and a non-alcoholic steatohepatitis(NASH)group.Logistic regression analysis was used to analyze the association between minerals(copper,zinc,calcium,magnesium,and iron)and NAFLD,NAFL and NASH. Results:A total of 602 subjects were included,of whom 73.6%were male,with a median age of 10(9,11)years,and a body mass index(BMI)of 24.9(22.7,27.4)kg/m2.The intergroup comparison results showed that compared with the overweight group,the NAFLD group had higher levels of age,BMI,diastolic blood pressure(DBP),systolic blood pressure(SBP),triglyceride(TG),low density lipoprotein(LDL),alanine transaminase(ALT)and aspartate aminotransferase(AST),and lower level of high density lipoprotein(HDL).The NAFL group had higher levels of age,BMI,DBP,SBP,ALT,and AST,and lower levels of HDL compared with the overweight group.The levels of age,BMI,DBP,SBP,TG,LDL,ALT,and AST of NASH were higher than those in the overweight group,while the level of HDL was lower than that in overweight group(all P<0.017).After adjusting for a variety of confounders,the OR of NAFLD for the highest quantile of iron was 1.79(95%CI 1.07 to 3.00)compared to the lowest quantile,and no significant association was observed between copper,zinc,calcium,and magnesium,and NAFLD.The subgroup analysis of NAFLD showed that the OR for the highest quantile of iron in children with NAFL was 2.21(95%CI 1.26 to 3.88),while no significant association was observed between iron level and NASH.In addition,no significant associations were observed between copper,zinc,calcium,and magnesium levels and NAFL or NASH. Conclusion:High iron level increases the risk of NAFLD(more likely NAFL)in overweight and obese children,while copper,zinc,calcium,magnesium,and other elements are not associated with the risk of NAFLD in overweight and obese children.

This article reported a typical case of paroxysmal kinesigenic dyskinesia(PKD).The patient was a 26-year-old female with a medical history of 10 years.The patient manifested as paroxysmal choreoathetosis of the limb and head triggered by sudden movement in a quiet state,without sensory aura.The symptoms resolved spontaneously after tens of seconds.She was conscious during and between attacks,had a clear family history and a normal neurological examination.No abnormalities were found in brain magnetic resonance image and electroencephalogram.Genetic test showed a frame-shift mutation of c.776del in PRRT2 gene of the proband and her father with similar phenotype.The patient was diagnosed with PKD according to the diagnostic criteria for PKD.The symptoms were significantly relieved after one month of oxcarbazepine treatment with good prognosis.PKD is a rare movement disorder.The patient has typical symptoms,and the mutation site has not been reported in the Human Gene Mutation Database.Therefore,this article enriched the pathogenic gene mutation spectrum of PKD,provided a basis for genetic counseling of PKD and increased the awareness of this rare disease among physicians.

Gastric cancer(GC)is one of the most common malignancies worldwide.In our country,the majority of patients are diagnosed with GC at alocally advanced stage.Fortunately,clinical studies have demonstrated that minimally invasive radical gastrectomy,particularly laparoscopic surgery,is just as effective as traditional open surgery in terms of both short-and long-term outcomes.Consequently,minim-ally invasive surgery has become the primary surgical approach for patients with locally advanced gastric cancer(LAGC).Advancements in surgical techniques and technologies are enabling even more precise and minimally invasive approaches to GC surgery.Based on recent do-mestic and international studies,this study aimed to review and elaborate on the development of minimally invasive surgery for LAGC.