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.

Aim To investigate the intervention effect of Rehmannia radix water extract on bleomycin(BLM)-induced pulmonary fibrosis in mice combined with metabolomics and to reveal the potential mechanism,in order to provide new ideas for clinical treatment of pul-monary fibrosis.Methods Male C57BL/6N mice were randomly divided into the control group,model group,pirfenidone group(positive control,PFD,270 mg·kg-1),and low dose(DH-L,4.55 g·kg-1)group,medium dose(DH-M,9.1 g·kg-1)group and high dose(DH-H,18.2 g·kg-1)group of Rehman-nia.Except for the control group,BLM(5 mg·kg-1)was instilled into the trachea to establish the model of pulmonary fibrosis in the other groups.The survival rate,lung index and blood oxygen saturation of mice in each group were evaluated.HE and Masson staining were used to observe the pathological changes of lung tissue.WBP was used to detect lung function.Flow cytometry was used to detect the apoptosis of primary lung cells,ROS and immune cells.ELISA was used to detect the levels of fibrosis markers and inflammatory factors(α-SMA,collagen Ⅰ,collagen Ⅲ,TGF-β1,TNF-α,IL-1 β,and IL-6).Biochemical method was employed to detect the contents of GSH-Px,T-SOD and MDA.Liquid chromatograph mass spectrometer(LC-MS)metabolomics was used to analyze the changes of serum metabolic profile.Results Water extract of Re-hmannia significantly increased the survival rate,oxy-gen saturation and lung function of mice with pulmona-ry fibrosis,reduced the lung coefficient,ameliorated pathological damage and collagen deposition in lung tissue,reduced the levels of apoptosis and oxidative stress,and down-regulated the levels of inflammatory factors in lung tissue.It regulated the levels of metabo-lites such as bile acid metabolism,sphingolipid metabo-lism,and unsaturated fatty acid metabolism.Conclu-sions Water extract of Rehmannia inhibits lung injury and collagen deposition in mice with pulmonary fibrosis by inhibiting inflammatory response,which may be a-chieved by regulating the levels of inflammatory factors through the metabolic pathways of bile acid and sphin-golipid.

Objective To systematically evaluate of the effect of autoimmune diseases(AIDs)on early spontaneous abortion(ESA).Methods Several databases such as Ovid and Web of Science were searched from January 2000 to May 2024 for retrospective analysis.Furthermore,subgroup analysis was conducted in terms of AIDs,continent and assisted reproduction.Results Total of 73 eligible studies were included in this study.There was a statistically significant difference in the risk of ESA between the population with AIDs and the population with normal pregnancy(OR=1.832,95％CI:1.619-2.073).When subgroup studies of AIDs were performed,the increased risk of ESA in patients with some AIDs was statistically significant:e.g.,thyroid autoimmunity,antiphospholipid syndrome,systemic lupus erythematosus,desiccation syndrome,antinuclear antibody positivity and rheumatoid arthritis.While the impact of some AIDs on ESA was still uncertain,e.g.inflammatory bowel disease,ulcerative colitis,Crohn's disease,autoimmune skin diseases,neuromyelitis optica spectrum disorders.In addition,patients with antiphospholipid syndrome who had underwent assisted reproductive technologies were at higher risk of ESA.Furthermore,compared to other continents,there is a difference in the risk of ESA in patients with AIDs in Africa.Conclusion AIDs are associated with the risk of ESA.

Objective:To evaluate the role of necroptosis in paclitaxel-induced cognitive dysfunction in mice.Methods:Thirty SPF healthy male C57BL/6N mice, aged 6-8 weeks, weighing 20-25 g, were divided into 3 groups ( n=10 each) using a random number table method: vehicle control group (Veh group), paclitaxel group (PTX group), and paclitaxel+ a specific inhibitor of necroptosis Necrostatin-1 group (P+ N group). In PTX group and P+ N group, paclitaxel 10 mg/kg (diluted to 5 mg/ml in anhydrous ethanol and castor oil [1∶1], and further diluted to 1 mg/ml in 0.9% normal saline before use) was intraperitoneally injected daily for 7 consecutive days to induce cognitive dysfunction. P+ N group received an intraperitoneal injection of Necrostatin-1 6.5 mg/kg (diluted to 10 mg/ml in dimethyl sulfoxide, and further diluted to 1 mg/ml in 0.9% normal saline before use) at 2 h before paclitaxel administration every other day, 4 times in total. Veh group received the equal volume of solvent at the matched time points as previously described in P+ N group. After establishment of the model, spontaneous locomotor activity was assessed using the open field test, followed by the novel object recognition test and the Morris water maze to evaluate the cognitive function. The animals were sacrificed after the end of the Morris water maze test, and the hippocampal tissues were collected for determination of the expression of necroptosis-related proteins receptor-interacting serine/threonine-protein kinase 1 (RIPK1), RIPK3, mixed lineage kinase domain-like protein (MLKL), and phospho-MLKL (p-MLKL) (by Western blot analysis) and contents of tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) (double immunofluorescence staining) and for observation of the localization of programmed necrosis cells (using enzyme-linked immunosorbent assay). Results:There were no significant differences in the total distance traveled and mean movement speed in the open field test or swimming speed in the Morris water maze test among the three groups ( P>0.05). Compared to Veh group, the time spent in the central zone in the open field and time spent in the original platform quadrant were significantly shortened, the discrimination index was decreased, the escape latency was prolonged, the number of crossing the original platform was reduced, the expression of RIPK1, RIPK3, MLKL and p-MLKL was up-regulated, the contents of TNF-α and IL-1β were increased, and the number of RIPK1-positive neurons was increased in PTX group ( P<0.05). Compared to PTX group, the time spent in the central zone in the open field test and time spent in the original platform quadrant were significantly prolonged, the discrimination index was increased, the escape latency was shortened, the number of crossing the original platform was increased, the expression of RIPK1, RIPK3, MLKL and p-MLKL was down-regulated, the contents of TNF-α and IL-1β were decreased, and the number of RIPK1-positive neurons was decreased in P+ N group ( P<0.05). Conclusions:Necroptosis in hippocampal neurons can lead to neuroinflammation, thus contributeing to paclitaxel-induced cognitive dysfunction in mice.

Objective:To review and analyze the results of cervical cancer screening for women aged 30-65 years in Tianjin from 2018—2023, and to explore the choice of cervical cancer screening strategies.Methods:The results of free cervical cancer screening in Tianjin from January 2018 to December 2023 were collected and divided into two periods: group A [2018—2020; screening programs included cervical cytology, Thinprep cytologic test (TCT), and human papillomavirus (HPV) DNA+TCT combined screening] and group B (2021—2023; the screening scheme of HPV E6/E7 mRNA primary screening and TCT diversion, referred to as “HPV E6/E7 mRNA primary screening”) according to the policy changes, and according to the primary screening method of cervical cancer, it was divided into four methods: cervical smear primary screening, TCT primary screening, HPV DNA+TCT combined primary screening and HPV E6/E7 mRNA primary screening. Cervical cancer and precancerous lesion detection rate, cervical cancer early diagnosis rate were analyzed.Results:(1) A total of 1 634 155 women of eligible age were screened, and the detection rate of cervical cancer and precancerous lesion was 216.3/100 000 (3 535/1 634 155), among which the detection rate of precancerous lesion was 200.3/100 000 (3 274/1 634 155) and cervical cancer was 16.0/100 000 (261/1 634 155). (2) The cervical cancer and precancerous lesion detection rate and cancer early diagnosis rate in group B were significantly higher than those in group A [480.3/100 000 (2 132/443 924) vs 117.9/100 000 (1 403/1 190 231), 97.56% (2 080/2 132) vs 92.37% (1 296/1 403); both P<0.001]. (3) The detection rates of cervical cancer and precancerous lesions in women who underwent initial screening with cervical cytology, TCT, HPV DNA+TCT combined screening, and HPV E6/E7 mRNA screening were 106.8/100 000 (10 980/1 028 227), 167.7/100 000 (190/113 319), 236.2/100 000(115/48 685) and 480.3/100 000 (2 132/443 924), respectively. HPV E6/E7 mRNA primary screening had the highest cervical cancer and precancerous lesion detection rate among the four screening methods ( χ2=2 017.59, P<0.001). Conclusion:After 2021, the cervical cancer screening method of HPV E6/E7 mRNA primary screening and TCT triage adopted in Tianjin is suitable for general screening of large populations and is an effective method for initial screening of cervical cancer.

The ventral anterior (VA) nucleus of the thalamus is a major target of the basal ganglia and is closely associated with the pathogenesis of Parkinson's disease (PD). Notably, the VA receives direct innervation from the hypothalamic histaminergic system. However, its role in PD remains unknown. Here, we assessed the contribution of histamine to VA neuronal activity and PD motor deficits. Functional magnetic resonance imaging showed reduced VA activity in PD patients. Optogenetic activation of VA neurons or histaminergic afferents significantly alleviated motor deficits in 6-OHDA-induced PD rats. Furthermore, histamine excited VA neurons via H1 and H2 receptors and their coupled hyperpolarization-activated cyclic nucleotide-gated channels, inward-rectifier K⁺ channels, or Ca²⁺-activated K⁺ channels. These results demonstrate that histaminergic afferents actively compensate for Parkinsonian motor deficits by biasing VA activity. These findings suggest that targeting VA histamine receptors and downstream ion channels may be a potential therapeutic strategy for PD motor dysfunction.
Animals ; Histamine/metabolism* ; Male ; Oxidopamine/toxicity* ; Rats ; Ventral Thalamic Nuclei/physiopathology* ; Rats, Sprague-Dawley ; Disease Models, Animal ; Parkinson Disease/metabolism* ; Neurons/physiology* ; Humans ; Optogenetics

In recent years, gastrointestinal stromal tumors (GIST) have increased incidence and mortality, and most GIST is caused by the activation mutation of the c-KIT gene. Therefore, c-KIT has become a promising therapeutic target of GIST. At present, the drugs approved for the treatment of GIST including imatinib, sunitinib, regorafenib and ripretinib, are mostly prone to developing resistance and accompanied by various degrees of adverse reactions. Therefore, there is an urgent need to develop new c-KIT inhibitors to solve the problem of resistance. In this study, we investigated the anti-tumor effect of a novel c-KIT inhibitor PN17-1 on gastrointestinal stromal tumor GIST-882 cells in vitro. We found that PN17-1 significantly inhibited the proliferation, colony formation and migration ability of GIST-882 cells, and significantly downregulated the protein expression levels of p-c-KIT and its downstream signals p-AKT, p-STAT5 and p-ERK in GIST-882 cells. In addition, PN17-1 induced apoptosis in GIST-882 cells, and the apoptosis may be mainly related to the mitochondrial-dependent endogenous pathway. In conclusion, the novel c-KIT inhibitor PN17-1 is a promising anti-GIST drug, and this study provides new ideas for further development of c-KIT inhibitors in the future.

Objective:To explore the clinical efficacy of super-selective ophthalmic artery thrombolysis in the treatment of central retinal artery occlusion (CRAO).Methods:This is a retrospective case series study,based on the analysis of clinical data of 50 non-arteritic CRAO patients. The patients were advised to be treated with super-selective intra-ocular arterial thrombolysis at the Neurosurgery Department, Shenyang No. 4 People′s Hospital from May to December 2024, and treated with intra-arterial thrombolysis and postoperative management guidance by the Department of Neurosurgery, General Hospital of the Northern Theater Command. There were 36 males and 14 females, aged (59.5±10.2)years (range: 41 to 75 years). There were 5 cases of complete obstruction of the central retinal artery and 45 cases of subtotal obstruction.Before the operation, all patients underwent optical coherence tomography angiography (OCTA)+ocular vascular ultrasonography, and their visual acuity was measured using a standard visual acuity logarithmic scale, visual field was measured using the contrast visual field examination method;One week after the operation, all patients were rechecked for OCTA, visual acuity and visual field. The patients′ preoperative and postoperative visual field recovery status were compared. Significant effect was defined as an improvement of more than 3 lines of visual acuity or a complete improvement of visual field defects after treatment compared with pretreatment visual acuity; effectiveness was defined as an improvement of 1 to 2 lines of visual acuity or an improvement of visual field defects after treatment compared with pretreatment visual acuity.Results:The overall effective rate of 50 patients with CRAO treated with super-selective ophthalmic artery urokinase thrombolysis was 94.0% (47/50), with 29 very effective, 18 effective and 3 ineffective. The time from onset to surgery was 0 to 6 hours in 5 patients, with an effective rate of 5/5; >6 to 24 hours in 11 patients, with an effective rate of 10/11; >1 to 7 days in 21 patients, with an effective rate of 90.5%(19/21); >7 to 14 days in 9 patients, with an effective rate of 9/9; and >14 to 21 days in 4 patients, with an effective rate of 4/4, and the difference in effective rate between the different time windows of thrombolytic therapy was not statistically significant ( P=0.961). There were 3 cases of intraoperative and postoperative complications, including 1 case of ophthalmic artery entrapment, 1 case of femoral artery pseudoaneurysm and 1 case of fundus hemorrhage, but all of them were cured after symptomatic treatment. Conclusions:Intra-arterial thrombolysis for CRAO patients has a high effective rate and a low complication rate. The surgical time window can be extended to 21 days after the onset, which is of positive significance for the recovery and improvement of the patient′s final visual acuity.

Objective:To investigate the value of midtreatment 18F-FDG PET/CT metabolic parameters for predicting the pathological response in patients with locally advanced gastric cancer (LAGC) after neoadjuvant immunochemotherapy (NICT). Methods:Twenty-five LAGC patients (19 males, 6 females, age: (64.8±8.6) years) who underwent 18F-FDG PET/CT after NICT in Henan Cancer Hospital from August 2019 to June 2024 were retrospectively analyzed. The lesion′s ROI was delineated, then the SUV max and metabolic tumor volume (MTV) were measured, and the SUV max was divided by SUV mean of the descending aorta to obtain the tumor-to-background ratio (TBR). Patients underwent surgery after PET/CT imaging. Based on the tumor regression grade (TRG) system by the American Joint Committee on Cancer (AJCC) criteria on surgical specimen, patients were divided into responders (TRG0+ 1) and non-responders (TRG2+ 3). Independent-sample t test, Mann-Whitney U test, one-way analysis of variance, and Kruskal-Wallis rank-sum test were used to compare the differences of data. The predictive efficacy of PET/CT metabolic parameters was assessed by the ROC curve analysis. Results:Postsurgical pathology showed that 9 patients were responders and 16 were non-responders. The SUV max (3.10±1.95) and TBR (2.44±1.54) of primary lesions in responders were lower than those in non-responders (7.40±4.68, 5.85±3.74; t values: -2.61, -2.59, both P<0.05), while the MTV of primary tumors and short diameter and metabolic parameters of positive lymph nodes were not significantly different between those 2 groups ( t=-1.50, Z values: -1.09 to -0.75, all P>0.05). No significant relation was found between PET/CT parameters and pathological differentiation or Lauren classification, or other pathological features ( t values: -1.55 to 1.38, Z values: -1.84 to 0, F values: 0.12-2.43, H values: 0.13-0.98, all P>0.05). ROC curve showed that the cut-off value of SUV max for predicting postoperative TRG was 5.40, and the AUC reached 0.77 (95% CI: 0.56-0.91), with the sensitivity and specificity of 9/16, 9/9, respectively. With TBR=3.54 as the cut-off value, its AUC reached 0.77 (95% CI: 0.56-0.91), and the sensitivity and specificity were 11/16, 8/9, respectively. The sensitivity and specificity of PET/CT for predicting lymph node positivity of patients were 8/12 and 13/13, respectively. Conclusion:Interim 18F-FDG PET/CT metabolic parameters can accurately predict the pathological response of LAGC patients after NICT.

Objective:To develop a bacterial endotoxin detection method suitable for mRNA vaccines based on lipid nanoparticle（LNP）delivery system.Methods:The gel clot limit test outlined in the third section of the Chinese Pharmacopoeia（2020 edition）was utilized. Taking the human herpesvirus type 2 mRNA vaccine as the detection object，the optimal conditions for bacterial endotoxin detection were established by evaluating sample dilution factors，diluents，and other interfering elements. The results were validated using the recombinant C factor method. Finally，the applicability of the established method was validated through testing the respiratory syncytial virus mRNA vaccine and the shingles mRNA vaccine.Results:Increasing the sample dilution factor to 480 times with a magnesium-containing buffer and using 0.06 EU/ml tachypleus amebocyte lysate effectively mitigated the interference caused by LNP on the test results of the human herpesvirus type 2 mRNA vaccine，the respiratory syncytial virus mRNA vaccine，and the shingles mRNA vaccine. The results from recombinant C factor method and the gel clot limit method were consistent.Conclusion:A bacterial endotoxin gel clot limit detection method tailored for human herpesvirus type 2 mRNA vaccine，respiratory syncytial virus mRNA vaccine，and shingles mRNA vaccine is successfully developed based on existing protocols in the Chinese Pharmacopoeia（2020 edition）. This study offers insights for the detection of bacterial endotoxin in LNP-based biological products.