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.

Objective To investigate the feasibility of magnetic tracer technique for locating pulmonary nodules.Methods A tracer magnet and a matching puncture instrument were designed by ourselves for locating pulmonary nodules.After preliminarily verifying the feasibility of the operation in the isolated lung,four beagle dogs were used as animal models to perform puncture localization of the assumed lesions in the upper lobe of the right lung under the guidance of X-ray by using self-designed tracer magnets and puncture instruments,and the positioning effect was observed and evaluated after thorax opening.The operation time required for the tracer magnet implantation,whether there is bleeding at the puncture site,whether the tracer magnet is displaced,and the positioning time of pulmonary nodules after thorax opening were recorded.Results Two tracer magnets were successfully inserted into the upper lobe of the right lung under X-ray guidance in four beagle dogs,and the magnets were successfully attracted and fixed.The median insertion time of the tracer magnet was 5 minutes(4 to 7 minutes),and the insertion process was smooth without bleeding at the puncture site.After thorax opening,oval forceps were used to conveniently locate the location of the tracer magnet,achieving accurate positioning of pulmonary nodules with a median positioning time of 13 seconds(10 to 17 seconds),and the tracer magnet did not shift during the whole process.Conclusion The magnetic tracer technique is simple to operate and pricise for localization of pulmonary nodules.With further optimization of the operation process,this technique is expected to be applied in clinic.

With the extended survival period of breast cancer patients and the increasing health demands, the concomitant diseases of breast cancer have gradually attracted the attention of both doctors and patients, and it is imperative to conduct comprehensive management of these diseases, in which the general practitioners, as the more comprehensive and complex medical talents, have not yet played their due roles. In this article, we report two cases of comprehensive management of concomitant diseases of breast cancer through collaboration of general practitioners and specialists (integrated general and specialist care). The role and function of general practitioners in this process were deeply analyzed, and the establishment of a consultation-liaison general practice model to further promote the role of integrated general and specialist care in integrated oncology care was advocated.

Objective To investigate the feasibility of magnetic tracer technique for locating pulmonary nodules.Methods A tracer magnet and a matching puncture instrument were designed by ourselves for locating pulmonary nodules.After preliminarily verifying the feasibility of the operation in the isolated lung,four beagle dogs were used as animal models to perform puncture localization of the assumed lesions in the upper lobe of the right lung under the guidance of X-ray by using self-designed tracer magnets and puncture instruments,and the positioning effect was observed and evaluated after thorax opening.The operation time required for the tracer magnet implantation,whether there is bleeding at the puncture site,whether the tracer magnet is displaced,and the positioning time of pulmonary nodules after thorax opening were recorded.Results Two tracer magnets were successfully inserted into the upper lobe of the right lung under X-ray guidance in four beagle dogs,and the magnets were successfully attracted and fixed.The median insertion time of the tracer magnet was 5 minutes(4 to 7 minutes),and the insertion process was smooth without bleeding at the puncture site.After thorax opening,oval forceps were used to conveniently locate the location of the tracer magnet,achieving accurate positioning of pulmonary nodules with a median positioning time of 13 seconds(10 to 17 seconds),and the tracer magnet did not shift during the whole process.Conclusion The magnetic tracer technique is simple to operate and pricise for localization of pulmonary nodules.With further optimization of the operation process,this technique is expected to be applied in clinic.

Icaritin(ICT)is an 8-isopentenylflavonoid,which is the main effective component of the tra-ditional Chinese medicine Epimedium.Previously,we found that Icaritin inhibits the growth of glioblasto-ma(GBM)cells.Herein we aim to study the in vivo anti-GBM effectiveness of Icaritin and explore its mechanism.The results of MTT assay,flow cytometry,comet assay and cellular immunofluorescence as-say in vitro showed that ICT inhibited the proliferation of four kinds of GBM cells,U87,U251,U118 and A172,induced early apoptosis(P＜0.001)and late apoptosis(P＜0.05)in U87 cells,induced DNA damage in U87 cells,and blocked the growth of U87 cells at the G0/G1 phase(P＜0.0001)in a concen-tration-time-dependent manner.In vivo subcutaneous tumor transplantation tumor experiments showed that feeding 200 mg/kg(P＜0.01)and 400 mg/kg(P＜0.001)ICT had a significant inhibitory effect on the growth of GBM subcutaneous tumors,and had no significant toxic effects on heart,liver,spleen,lung and kidney tissues.The results of network pharmacological analysis,molecular docking and cellular thermodynamic experiments showed that there were 26 possible target proteins between ICT and GBM,a-mong which the expression of p53 in GBM tissues was significantly(P＜0.001)higher than in normal tis-sues,and the binding energy of ICT and p53 was lower;cellular thermodynamic experiments verified that ICT significantly enriched the level of p53 in the living cells of GBM,which indicated that ICT could tar-get p53.The expression of key proteins in the DNA damage repair and apoptosis-associated FOXO signa-ling pathway was detected by ICT.The results showed that the expression of ATR(P＜0.01),P53(P＜0.001),P21(P＜0.05)and γ-H2AX(P＜0.05)was up-regulated,whereas the expression of Cyc-lin E1(P＜0.01),E2F1(P＜0.05),CDK2(P＜0.01),Rb(P＜0.001),p-Rb(P＜0.0001)and WRN(P＜0.0001)expression were down-regulated.There was no significant change in the expres-sion of FOXO 1 in the FOXO pathway or a significant down-regulation of its phosphorylation level.This study demonstrated that ICT could effectively inhibit the growth of GBM cells in vivo.It targets p53 to regulate the DNA damage repair pathway and FOXO signaling pathway to induce GBM cell cycle arrest and apoptosis.

Immunometabolism studies focus on the relationships between immune cell functions and cellular energy metabolism pathways.Immunometabolism plays an important regulatory role in immune-related diseases.Mycobacterium tuberculosis(M.tb),an important intracellular pathogenic bacterium,enters alveolar macrophages after infection.The confrontation between M.tb and the host is a complex and dynamic process involving multiple aspects and mechanisms,such as the immune response,granuloma formation,and immune evasion.M.tb effector proteins play key roles in maintaining bacterial virulence and regulating host cell metabolism.This article reviews the reprogramming process of glucose metabolism,lipid metabolism,and immunometabolism,as well as changes in mi-tochondrial function in M.tb-infected host cells,thereby revealing the relationship between M.tb pathogenicity and host metabolic regu-lation,which is important for understanding tuberculosis.

ObjectiveTo explore the clinical safety of Feilike Mixture （FLK） in the real world. MethodsThe safety of all children who received FLK from 29 institutions in 12 provinces between January 21，2021 and December 25，2021 was evaluated through prospective centralized surveillance and a nested case control study. ResultsA total of 3 035 juveniles were included. There were 29 research centers involved，which are distributed across 12 provinces，including one traditional Chinese medicine （TCM） hospital and 28 general hospitals. The average age among the juveniles was （4.77±3.56） years old，and the average weight was （21.81±12.97） kg. Among them，119 cases （3.92%） of juveniles had a history of allergies. Acute bronchitis was the main diagnosis for juveniles，with 1 656 cases （54.46%）. FLK was first used in 2 016 cases （66.43%），and 142 juvenile patients had special dosages，accounting for 4.68%. Among them，92 adverse drug reactions （ADRs） occurred，including 73 cases of gastrointestinal system disorders，10 cases of metabolic and nutritional disorders，eight cases of skin and subcutaneous tissue diseases，two cases of vascular and lymphatic disorders，and one case of systemic diseases and various reactions at the administration site. The manifestations of ADRs were mainly diarrhea，stool discoloration，and vomiting，and no serious ADRs occurred. The results of multi-factor analysis indicated that special dosages （the use of FLK）［odds ratio （OR） of 2.642， 95% confidence interval （CI） of 1.105-6.323］，combined administration： spleen aminopeptide （OR of 4.978， 95%CI of 1.200-20.655），and reason for combined administration： anti-infection （OR of 1.814， 95%CI of 1.071-3.075） were the risk factors for ADRs caused by FLK. Conclusion92 ADRs occurred among 3 035 juveniles using FLK. The incidence of ADRs caused by FLK was 3.03%，and the severity was mainly mild or moderate. Generally，the prognosis was favorable after symptomatic treatment such as drug withdrawal or dosage reduction，suggesting that FLK has good clinical safety.

Objective:To compare the treatment time stability, inter- and intra-fraction errors, and clinical target volume (CTV) to planning target volume (PTV) margin expansions under different gated window settings in deep inspiration breath hold (DIBH) radiotherapy for breast cancer, and to analyze the correlation between organ at risk (OAR) dose optimization and changes in lung volume.Methods:A retrospective analysis was conducted on 65 patients with left-sided breast cancer who received DIBH radiotherapy after modified radical mastectomy. CT simulation positioning was performed using 2 mm or 3 mm gated window for DIBH, followed by target delineation, treatment planning, and dose verification. During treatment, setup errors guided by cone beam CT (CBCT), intra-fraction monitoring errors, and treatment times were recorded. The coefficient of variation (CV) of treatment time was calculated for both gated window settings. Based on inter- and intra-fraction error distributions, the expansion distance of the CTV were determined using the van Herk formula. Dosimetric differences between DIBH and free-breathing (FB) plans for the left lung, heart, and left anterior descending coronary artery (LAD) were compared. Spearman correlation analysis was performed between the relative increase in left lung volume and the relative reduction in OAR dose. Paired t-tests were used for inter-group comparisons. Results:The mean CV of the 3 mm gated window group was 0.08±0.03, which was lower than that of the 2 mm group (0.10±0.04; t=-3.91, P<0.001). The setup errors of the 2 mm group in the X, Y, and Z directions were (1.27±1.03), (1.68±0.94), (1.90±1.25) mm, respectively-significantly smaller than those of the 3 mm group [(1.81±1.41), (2.07±1.69), (2.93±1.90) mm; t=-5.80, -2.33, -5.33; P<0.001,=0.014,<0.001). Setup errors for both groups were within the 25%-75% range and all below 5 mm. The intra-fraction deviations of the 2 mm group in the X, Y, and Z directions were (0.54±0.33), (0.79±0.44), (0.70±0.53) mm, respectively, significantly smaller than those of the 3 mm group [(0.62±0.43), (0.93±0.66), (0.87±0.67) mm; t=-3.87, -3.46, -2.71,all P<0.001). The mean intra-fraction errors of both groups were within 1 mm, with greater deviations in the Y and Z directions than those in the X direction. The CTV expansion margins for the 2 mm group in the X, Y, and Z directions were 4.21, 5.35, 5.99 mm, respectively, while those for the 3 mm group were 5.81, 6.89, 9.06 mm. Compared with FB, DIBH significantly reduced the doses to the left lung, heart, and LAD (all P<0.01). The increase in left lung volume was moderately negatively correlated with the reduction in left lung D mean ( r=-0.43, P=0.028), and highly negatively correlated with the dose reductions to the heart and LAD (both P<0.001). Conclusions:The variability in respiratory gated window settings can lead to differences in treatment time stability as well as inter- and intra-fraction errors, consequently affecting CTV-to-PTV margins. The DIBH technique demonstrates significant dosimetric benefits in reducing radiation exposure to the left lung, heart, and LAD. Volumetric expansion of the left lung is strongly and inversely correlated with the reduction in radiation dose to both the heart and LAD.

OBJECTIVES: Sepsis-associated acute lung injury (S-ALI) is one of the major causes of death in intensive care unit (ICU) patients, yet its mechanisms remain incompletely understood and effective therapies are lacking. Lytic cell death of macrophages is a key driver of the inflammatory cascade in S-ALI. PANoptosis, a newly recognized form of lytic cell death characterized by PANoptosome assembly and activation, involves plasma membrane rupture (PMR) mediated by ninjurin-1 (NINJ1), a recently identified pore-forming protein. Itaconic acid is known for its anti-inflammatory effects, but its role in macrophage PANoptosis during S-ALI is unclear. This study aims to investigate the protective effect of itaconic acid on macrophage PANoptosis in S-ALI to provide new therapeutic insights. METHODS: Male specific-pathogen-free C57BL/6J mice (6-8 weeks, 18-20 g) received intraperitoneal lipopolysaccharide (LPS) to establish a classical S-ALI model. Western blotting was used to assess PANoptosome-related proteins and enzymes involved in the itaconic acid metabolic pathway, while real-time reverse transcription polymerase chain reaction and metabolomics quantified itaconic acid levels. Primary peritoneal macrophages (PMs) were pretreated with the itaconate derivative 4-octyl itaconate (4-OI) and then exposed to tumor necrosis factor alpha (TNF-α) plus interferon gamma (IFN-γ) to induce PANoptosis. Cell viability was evaluated by cell counting kit-8 (CCK-8) assay. Western blotting was employed to quantify enzymes of the itaconate-metabolic pathway in PANoptotic macrophages, to evaluate the impact of 4-OI on PANoptosome-associated proteins, and to determine NINJ1 abundance in lung tissues from S-ALI mice and in PANoptotic macrophages. Fluorescent dye FM_4-64 was used to visualize 4-OI-mediated changes in PMR, whereas immunofluorescence staining mapped the effect of 4-OI on both the expression level and membrane localization of NINJ1 in PANoptotic macrophages. The effect of 4-OI on lactate dehydrogenase (LDH) release in culture supernatants and peripheal blood serum was assessed using a LDH assay kit, and non-denataring polyacylamide gel electrophoresis was used to assess the expression of NINJ1 in S-ALI mouse lung tissues and the impact of 4-OI on the expression of PANoptosis-associated NINJ1 multimeric reflected protein in macropahges. RESULTS: In S-ALI mouse lungs, PANoptosome components [NOD-like receptor thermal protein domain associated protein 3 (NLRP3), Gasdermin D (GSDMD), Caspase-1, Z-DNA binding protein (ZBP1), and Caspase-3] and phosphorylated mixed lineage kinase domain-like protein (MLKL) S345 were significantly upregulated (all P<0.05), while metabolomics showed compensatory increases in itaconic acid and its key enzymes [aconitate decarboxylase 1 (ACOD1)/immunoresponsive gene 1 (IRG1)]. In macrophages, 4-OI obviously suppressed PANoptosome protein expression, reduced LDH release, restored plasma membrane integrity, and inhibited NINJ1 expression and oligomerization at the membrane (P<0.05). CONCLUSIONS Itaconic acid may alleviate macrophage PANoptosis in S-ALI by inhibiting NINJ1-mediated plasma membrane rupture. Targeting NINJ1 or enhancing itaconate pathways may offer a novel therapeutic strategy for S-ALI.
Animals ; Acute Lung Injury/pathology* ; Succinates/pharmacology* ; Sepsis/complications* ; Mice, Inbred C57BL ; Male ; Mice ; Macrophages/pathology* ; Cell Membrane/metabolism* ; Lipopolysaccharides ; Hydro-Lyases

Sensorineural hearing loss is one of the most common sensory disorders. In recent years, auditory neuropathy spectrum disorders caused by mutations in the OTOF gene have garnered significant attention worldwide, marking it as the first deafness gene with breakthroughs in gene therapy. Most patients with OTOF gene mutations present with stable, congenital, or prelingual onset of hearing loss, which can range from severe to profound and even complete hearing loss. However, a minority of patients may exhibit mild to moderate progressive hearing loss or temperature-sensitive hearing loss. This review further explores the genotype-phenotype relationship of the OTOF gene based on reported cases in China and abroad. Additionally, we analyze the characteristics of the natural history of OTOF gene mutations within the Chinese population. This study aims to provide a reference for the clinical diagnosis, evaluation, and treatment of hearing loss associated with OTOF gene mutations.
Humans ; Mutation ; Phenotype ; Genotype ; Hearing Loss, Sensorineural/genetics* ; Membrane Proteins/genetics*