Olfactory receptors (ORs) form the largest superfamily of G protein-coupled receptors (GPCRs). Traditionally recognized for their role in the nasal olfactory epithelium, where they mediate the sense of smell, accumulating evidence has firmly established their ectopic expression in non-olfactory tissues, including the intestine, lungs, and kidneys. The intestine, as the primary site for nutrient digestion and absorption, harbors a highly complex chemical environment. To adapt to this environment, the gut employs a sophisticated network of “chemosensors” to monitor luminal contents and maintain homeostasis. Among these sensors, intestinal ORs have emerged as crucial functional components, serving as a molecular bridge that connects environmental chemical signals—such as food-derived odorants—to specific physiological responses. This discovery has significantly deepened our understanding of how dietary flavors and compounds influence intestinal physiology at the molecular level. This review systematically summarizes the expression profiles, ligand classification, and biological functions of ORs within the gastrointestinal tract. Studies indicate that intestinal ORs exhibit distinct spatial distribution patterns across different gut segments and display cell-type specificity, particularly within enterocytes and enteroendocrine cells. These receptors function as versatile sensors capable of recognizing a wide variety of ligands, including exogenous dietary components, gut microbiota metabolites such as short-chain fatty acids, and endogenous small molecules like azelaic acid. Upon activation by specific ligands, intestinal ORs trigger intracellular signaling cascades, primarily involving the AC-cAMP-PKA pathway or calcium influx channels. A major focus of this review is to elucidate the molecular mechanisms by which these receptors regulate the secretion of gut hormones. Activation of specific ORs in enteroendocrine cells has been shown to stimulate the release of hormones such as glucagon-like peptide-1 (GLP-1), peptide YY (PYY), and serotonin (5-HT), thereby modulating systemic energy metabolism, glucose homeostasis, and gastrointestinal motility. Furthermore, the review addresses the critical roles of ORs in immune regulation and pathology. Evidence suggests that specific ORs contribute to the maintenance of intestinal immune homeostasis and may offer protection against inflammation. Beyond their involvement in inflammatory responses, ORs such as Olfr78 have been shown to regulate the differentiation and function of intestinal endocrine cells. Similarly, Olfr544 has been demonstrated to alleviate intestinal inflammation by remodeling the gut microbiome and metabolome. These findings collectively suggest that specific ORs hold promise as therapeutic targets for mitigating intestinal inflammation and maintaining gut homeostasis. Additionally, the review explores the emerging role of ORs in cancer. Although OR expression is often downregulated in tumor tissues compared to normal mucosa, activation of specific ORs by certain ligands can inhibit tumor cell proliferation and migration and induce apoptosis via pathways such as MEK/ERK and p38 MAPK. Conversely, other receptors, such as OR7C1, may serve as biomarkers for cancer-initiating cells. In conclusion, intestinal ORs represent a vital component of the gut’s sensory network. The review also discusses the translational potential of these findings. By elucidating the precise pairing relationships between dietary components and specific ORs, novel therapeutic strategies could be developed. Intestinal ORs may thus emerge as promising targets for nutritional and pharmacological interventions in metabolic diseases, inflammatory bowel diseases, and malignancies.

The c-Jun N-terminal kinase （JNK） signaling pathway， a key member of the mitogen-activated protein kinase （MAPK） family， plays a central role in the pathogenesis and progression of central nervous system （CNS） diseases by regulating core biological processes such as apoptosis， inflammatory responses， synaptic plasticity， and autophagy. This article sorts out and analyzes relevant literature published domestically and internationally in recent years， summarizing the mechanisms of action of the JNK signaling pathway in common CNS diseases and the research progress in traditional Chinese medicine （TCM） interventions in CNS diseases through the regulation of the JNK signaling pathway. Studies have shown that active components of TCM， such as berberine， paeoniflorin， and astragaloside Ⅳ， as well as compound formulations like Heixiaoyao san， Ditan tang， and Buyang huanwu tang， can exert neuroprotective effects in various CNS disorders， including Alzheimer’s disease， Parkinson’s disease， cerebral ischemia-reperfusion injury， and epilepsy， by inhibiting the aberrant activation of the JNK signaling pathway， thereby alleviating neuroinflammation， oxidative stress， and neuronal apoptosis， while improving synaptic function and cognitive behavioral deficits， regulating autophagy， and maintaining blood-brain barrier integrity.

Alzheimer’s disease （AD） is an age-related neurodegenerative disorder. Marrow-sea insufficiency serves as the fundamental basis for the onset of AD. Early syndrome differentiation-based intervention helps to delay disease progression， and improve patients’ cognitive function. Qifu yin is a representative specialized prescription for AD with marrow-sea insufficiency syndrome. Studies demonstrate that Qifu yin exerts neuroprotective effects through multiple pathways， including inhibiting the abnormal deposition of amyloid β -protein and hyperphosphorylation of tau protein， alleviating neuroinflammation， regulating oxidative stress and mitochondrial dysfunction， modulating the cholinergic system， and improving synaptic plasticity. Qifu yin combined with Western medicine such as donepezil， memantine， and butylphthalide， or combined with external therapies such as acupuncture， can effectively improve cognitive function and activities of daily living in AD patients with favorable safety. Future research should focus on the core pathogenesis and key targets of AD with marrow-sea insufficiency syndrome， provide in-depth elucidation of the scientific connotation of Qifu yin’s “tonifying the kidney to produce marrow”， and further conduct high-quality clinical studies to provide scientific evidence for the prevention and treatment of AD with marrow-sea insufficiency syndrome.

Purpose: The optimal sequencing of targeted therapies and the role of primary tumor resection (PTR) in KRAS wild-type metastatic colorectal cancer (mCRC) remain unclear. This study compared survival outcomes in patients treated with first-line cetuximab plus FOLFIRI (folinic acid, 5-fluorouracil, and irinotecan) versus bevacizumab plus FOLFIRI, followed by second-line oxaliplatin-based chemotherapy and later-line trifluridine/tipiracil or regorafenib. Methods: This retrospective cohort study used Taiwan’s National Health Insurance Research Database and the Taiwan Cancer Registry. Patients diagnosed with mCRC between 2013 and 2019 were included if they received first-line cetuximab or bevacizumab plus FOLFIRI, followed by later-line trifluridine/tipiracil or regorafenib. Patients were stratified by PTR status. Primary endpoints were overall survival and survival during trifluridine/tipiracil or regorafenib treatment. Secondary endpoints included time to treatment discontinuation (TTD) and TTD during trifluridine/tipiracil or regorafenib therapy. Stabilized inverse probability of treatment weighting was used for adjustment. Results: Among 559 patients, 278 were assigned to the non-PTR group and 281 to the PTR group. In the non-PTR group, the cetuximab cohort demonstrated significantly longer survival during trifluridine/tipiracil or regorafenib therapy (6.2 months vs. 4.9 months; hazard ratio [HR], 0.72) and longer TTD1 (the interval between initiation of first-line therapy and the start of second-line chemotherapy; 11.8 months vs. 9.5 months; HR, 0.67) than the bevacizumab cohort. Survival differences between regimens were less pronounced among patients who underwent PTR. Conclusion First-line cetuximab plus FOLFIRI may confer a survival advantage over bevacizumab in patients with KRAS wild-type mCRC without PTR, including during later-line therapy with trifluridine/tipiracil or regorafenib, whereas bevacizumab appears to provide more consistent benefits in those with PTR.

Objectives: . Idiopathic sudden sensorineural hearing loss (ISSNHL) is a significant cause of hearing loss. Intratympanic steroid injection (ITSI) is commonly used as an initial or salvage treatment; however, the lack of a standardized treatment protocol has resulted in variability in clinical practice. In addition, no efficient prediction model currently exists to support personalized management. Therefore, this study aimed to develop tailored management strategies for ISSNHL using a machine-learning model. Methods: . This retrospective multicenter cohort study was conducted between January 2015 and December 2020, with data analysis performed between January 2021 and March 2024. Patients were selected based on the International Classification of Diseases, 10th Revision criteria for ISSNHL, along with relevant medication and procedure codes. Patients with pure-tone audiogram results not meeting ISSNHL criteria, better initial hearing in the affected ear, an identifiable etiology, no post-treatment audiogram, or delayed treatment (>6 weeks) were excluded. We included 770 patients diagnosed with ISSNHL who received ITSI. The primary outcome was the area under the receiver operating characteristic curve for prediction performance. Recovery status was determined using the last pure-tone audiogram. Modeling was conducted on the Quanta for Medical Care AI platform using five machine-learning algorithms and a nested cross-validation framework, in which feature selection and hyperparameter tuning were performed in the inner folds and model performance was evaluated in the outer folds. Results: . A random forest classifier outperformed the other models in predicting hearing outcomes, achieving an area under the receiver operating characteristic curve of 0.788. Time to ITSI was the most influential treatment-related factor, with ITSI administered within 10 days of hearing loss being associated with better outcomes. This model can be used to provide personalized prognostic estimates under different treatment protocols. Conclusion . The machine-learning-based prediction model facilitates personalized treatment strategies and timely treatment adjustments for ISSNHL, thereby optimizing the likelihood of complete recovery.

Introduction: The 2021 IDF-DAR risk calculator had been previously evaluated in multiple studies and subsequently widely accepted and applied in clinical practice as a practical standardized tool for patient risk stratification. Recently updated, the 2026 IDF-DAR Risk calculator enables a more individualized, evidence-related evaluation of patientrelated and disease-related risk factors, incorporating modern diabetes technologies, including continuous glucose monitoring (CGM), automated insulin delivery (AID) systems, and advanced insulin formulations to enhance risk stratification. This tool allows medical professionals to tailor Ramadan practices based on overall factors toward promoting safe fasting. Methodology: This prospective multicentre observational study recruited adults with Type 1 and Type 2 diabetes attending public hospitals nationwide. People with diabetes (PwD) intending to perform Ramadan fasting were invited to participate and assessed using the 2026 IDF-DAR Risk Calculator in the 6-week pre-Ramadan period between 30th January and 19th March 2026. Results: A total of 458 PwD were evaluated and stratified into low (15.7%), moderate (41%), and high risk (43.3%) categories. Most participants had Type 2 diabetes (83.6%), with 60.3% having a disease duration exceeding 10 years and 43% exhibiting poor glycemic control (hemoglobin A1c >9%). Insulin therapy was used by 76.4% of participants, including two individuals with Type 1 diabetes using AID systems. Most participants reported no recent hypoglycemia (76.4%), 81.0% performed glucose monitoring, and 3.3% used CGM. Severe comorbidities were uncommon, with 1.1% having unstable macrovascular disease and 4.4% advanced chronic kidney disease (estimated glomerular filtration rate <30). Notably, 72.2% received structured Ramadan education. Conclusion Majority of PwD attending tertiary diabetes clinics were in the moderate- to high-risk category and intended to fast despite medical advice against fasting in some cases. Although most participants were on insulin therapy, hypoglycemia was low in the pre-Ramadan period. Integration of modern technologies, advanced insulin therapies, and structured education may support safer fasting practices.
Risk Assessment ; Diabetes Mellitus ; Hospitals ; Fasting

Glutamine provides carbon and nitrogen to support the proliferation of cancer cells. However, the precise reason why cancer cells are particularly dependent on glutamine remains unclear. In this study, we report that glutamine modulates the tumor suppressor F-box and WD repeat domain-containing 7 (FBW7) to promote cancer cell proliferation and survival. Specifically, lysine 604 (K604) in the sixth of the 7 substrate-recruiting WD repeats of FBW7 undergoes glutaminylation (Gln-K604) by glutaminyl tRNA synthetase. Gln-K604 inhibits SCFFBW7-mediated degradation of c-Myc and Mcl-1, enhances glutamine utilization, and stimulates nucleotide and DNA biosynthesis through the activation of c-Myc. Additionally, Gln-K604 promotes resistance to apoptosis by activating Mcl-1. In contrast, SIRT1 deglutaminylates Gln-K604, thereby reversing its effects. Cancer cells lacking Gln-K604 exhibit overexpression of c-Myc and Mcl-1 and display resistance to chemotherapy-induced apoptosis. Silencing both c-MYC and MCL-1 in these cells sensitizes them to chemotherapy. These findings indicate that the glutamine-mediated signal via Gln-K604 is a key driver of cancer progression and suggest potential strategies for targeted cancer therapies based on varying Gln-K604 status.
Glutamine/metabolism* ; Myeloid Cell Leukemia Sequence 1 Protein/genetics* ; Humans ; Proto-Oncogene Proteins c-myc/genetics* ; Cell Proliferation ; Signal Transduction ; Neoplasms/pathology* ; F-Box-WD Repeat-Containing Protein 7/genetics* ; Cell Survival ; Cell Line, Tumor ; Apoptosis

OBJECTIVE: To explore short-term clinical efficacy of minimally invasive diagnosis and treatment system for hallux valgus in guiding the treatment of hallux valgus. METHODS: From March 2021 to November 2023, 68 patients (136 feet) with hallux valgus were treated under guidance of minimally invasive diagnosis and treatment system, including 12 males and 56 females;aged from 25 to 68 years old with an average of (42.5±8.5) years old, the course of disease ranged from 3.2 to 15.6 years with an average of (10.3±2.6) years. The changes of hallux valgus angle (HVA) and intermetatarsal angle (IMA), visual analog scale (VAS) and American Orthopaedic Foot Ankle Society (AOFAS) forefoot score were recorded and compared before operation and 12 months after operation. RESULTS: Sixty-five patients (130 feet) were followed up for 12 to 15 months with an average of (13.8±0.5) months, 3 patients (6 feet) were not followed up as required. HVA and IMA improved from (35.5±3.5) ° and (12.5±2.0) ° before operation to (10.5±2.5) ° and (8.5±1.5) °12 months after operation, respectively, with statistically significant differences (P<0.05);VAS decreased from (5.5±1.2) before operation to (1.2±0.5) at 12 months after operation, and the difference was statistically significant (P<0.05);AOFAS forefoot score increased from (50.6±5.1) before operation to (93.8±5.6) at 12 months after operation, with a statistically significant difference (P<0.05). Among them, 102 feet were got excellent result, 24 feet good, and 4 feet fair. Two patients were developed calf intermuscular vein thrombosis, and were cured after 3 months of symptomatic treatment. CONCLUSION Under the guidance of minimally invasive diagnosis and treatment system for hallux valgus, the treatment of HV could obviously improve HVA and IMA, and significantly alleviate pain symptoms, and accelerate functional recovery.
Humans ; Hallux Valgus/diagnosis* ; Male ; Female ; Middle Aged ; Adult ; Aged ; Minimally Invasive Surgical Procedures/methods* ; Treatment Outcome

OBJECTIVE: To reveal the molecular basis of knee osteoarthritis (KOA) with Yang deficiency and blood stasis syndrome by analyzing the gene expression profiles in synovial fluid and blood of KOA patients with this syndrome. METHODS: A total of 80 KOA patients were recruited from October 2022 to June 2024, including 40 cases in the non-Yang deficiency and blood stasis group (27 males and 13 females), with an average age of (61.75±3.45) years old;and 40 cases in the Yang deficiency and blood stasis group (22 males and 18 females), with an average age of (62.00±2.76) years old. The levels of body mass index (BMI), high-density lipoprotein (HDL), low-density lipoprotein (LDL), fibrinogen, total cholesterol, and D-dimer were recorded and summarized. Blood and synovial fluid samples from patients were collected for gene expression profile microarray sequencing, and then PCR and immunohistochemistry were used for clinical verification on the patients' synovial fluid and cartilage samples. RESULTS: Logistic regression analysis showed that compared with KOA patients with non-Yang deficiency and blood stasis syndrome, those with Yang deficiency and blood stasis syndrome had increased BMI, LDL, fibrinogen, total cholesterol, and D-dimer, and decreased HDL, with a clear correlation between the two groups. There were 562 differential genes in the blood, among which 322 were up-regulated and 240 were down-regulated;755 differential genes were found in the synovial fluid, with 350 up-regulated and 405 down-regulated. KEGG signaling pathway analysis of synovial fluid revealed changes in lipid metabolism-related pathways, including cholesterol metabolism, fatty acid metabolism, and PPARG signaling pathway. Analysis of the involved differential genes identified 6 genes in synovial fluid that were closely related to lipid metabolism, namely LRP1, LPL, ACOT6, TM6SF2, DGKK, and PPARG. Subsequently, PCR and immunohistochemical verification were performed using synovial fluid and cartilage samples, and the results were consistent with those of microarray sequencing. CONCLUSION This study explores the clinical and genomic correlation between traditional Chinese medicine syndromes and knee osteoarthritis from the perspective of lipid metabolism, and proves that abnormal lipid metabolism is closely related to KOA with Yang deficiency and blood stasis syndrome from both clinical and basic aspects.
Humans ; Male ; Female ; Middle Aged ; Synovial Fluid/metabolism* ; Osteoarthritis, Knee/metabolism* ; Yang Deficiency/complications* ; Aged

OBJECTIVES: To investigate the characteristics and clinical significance of anorectal manometry measurements in children with tethered cord syndrome (TCS) before and after surgery. METHODS: A retrospective study was conducted on 44 children with TCS treated at the Children's Hospital of Zhejiang University School of Medicine from January 2022 to September 2023. These patients were divided into effective subgroup (n=34) and non-effective subgroup (n=10) based on postoperative symptom improvement. Additionally, 34 children with functional constipation were selected as a control group. Baseline data and manometry measurements were compared between the preoperative TCS group and the control group, as well as between the non-effective and effective subgroups. RESULTS: The TCS group had lower short contraction time and defecation relaxation rate compared to the control group (P<0.05), while defecation residual pressure and maximum rectal tolerable threshold were higher than the control group (P<0.05). The length of the anal canal in the high-pressure zone in the effective subgroup was greater postoperatively than preoperatively (P<0.05), and the initial rectal sensation threshold decreased postoperatively (P<0.05). The non-effective subgroup had lower preoperative maximum rectal expulsion pressure compared to the effective subgroup (P<0.05). Postoperative rectal anal inhibition reflex values in the effective subgroup were higher than those in the non-effective subgroup (P<0.05). CONCLUSIONS There are some differences in anorectal dynamics between children with TCS and those with functional constipation. Maximum rectal expulsion pressure may be a key predictor of surgical outcomes. Surgery can alter certain defecation functions in some children.
Humans ; Male ; Anal Canal/physiopathology* ; Female ; Rectum/physiopathology* ; Child ; Child, Preschool ; Retrospective Studies ; Manometry ; Neural Tube Defects/physiopathology* ; Infant ; Defecation ; Adolescent ; Constipation/physiopathology* ; Clinical Relevance