Geographically and Temporally Weighted Regression in Assessing Dengue Fever Spread Factors in YunnanBorder Regions.

Objective: This study employs the Geographically and Temporally Weighted Regression (GTWR) model to assess the impact of meteorological elements and imported cases on dengue fever outbreaks, emphasizing the spatial-temporal variability of these factors in border regions. Methods: We conducted a descriptive analysis of dengue fever's temporal-spatial distribution in Yunnan border areas. Utilizing annual data from 2013 to 2019, with each county in the Yunnan border serving as a spatial unit, we constructed a GTWR model to investigate the determinants of dengue fever and their spatio-temporal heterogeneity in this region. Results: The GTWR model, proving more effective than Ordinary Least Squares (OLS) analysis, identified significant spatial and temporal heterogeneity in factors influencing dengue fever's spread along the Yunnan border. Notably, the GTWR model revealed a substantial variation in the relationship between indigenous dengue fever incidence, meteorological variables, and imported cases across different counties. Conclusion: In the Yunnan border areas, local dengue incidence is affected by temperature, humidity, precipitation, wind speed, and imported cases, with these factors' influence exhibiting notable spatial and temporal variation.

Investigation of the differential susceptibility of extraocular muscles in patients diagnosed with ocular myasthenia gravis based on the computerized diplopia test and the Ocular Motor Nerve Palsy Scale.

Introduction: The pattern of extraocular muscle involvement in ocular myasthenia gravis varies across different reports, diverging from our own observations. Thus, we employed two novel tools to discern this pattern. Methods: A retrospective analysis was conducted to collect and organize clinical data from 43 patients diagnosed with ocular myasthenia gravis. Each patient underwent both the computerized diplopia test and the Ocular Motor Nerve Palsy Scale assessment to evaluate the involvement of extraocular muscles. Results: Among the patients, there were 30 male and 13 female individuals, with a total of 113 affected extraocular muscles identified. Among all the affected extraocular muscles, the involvement of the levator palpebrae superioris muscle accounted for 35.40%, medial rectus muscle 7.7%, lateral rectus muscle 16.81%, superior rectus muscle 13.27%, inferior rectus muscle 12.39%, superior oblique muscle 1.77%, and inferior oblique muscle 2.65% of the total affected extraocular muscles. The positivity rates of the Neostigmine test were 89.19%, AChR antibody detection was 59.38%, and repetitive nerve stimulation was 34.38%. The AChR antibody positive rate among patients with only diplopia was 100%; among those with only ptosis, it was 80%; and among those with both diplopia and ptosis, it was 86.67%. Conclusion: The involvement of the extraocular muscles is not uniform. The levator palpebrae superioris exhibits the highest incidence rate, followed by the four rectus muscles and two oblique muscles. The inferior oblique involvement typically occurs when four or more EOMs are affected. Moreover, the levator palpebrae superioris and medial rectus show a higher tendency for bilateral involvement compared with other extraocular muscles.

Integrated mRNA-miRNA transcriptome profiling of blood immune responses potentially related to pulmonary fibrosis in forest musk deer.

Background: Forest musk deer (FMD, Moschus Berezovskii) is a critically endangered species world-widely, the death of which can be caused by pulmonary disease in the farm. Pulmonary fibrosis (PF) was a huge threat to the health and survival of captive FMD. MicroRNAs (miRNAs) and messenger RNAs (mRNAs) have been involved in the regulation of immune genes and disease development. However, the regulatory profiles of mRNAs and miRNAs involved in immune regulation of FMD are unclear. Methods: In this study, mRNA-seq and miRNA-seq in blood were performed to constructed coexpression regulatory networks between PF and healthy groups of FMD. The hub immune- and apoptosis-related genes in the PF blood of FMD were explored through Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. Further, protein-protein interaction (PPI) network of immune-associated and apoptosis-associated key signaling pathways were constructed based on mRNA-miRNA in the PF blood of the FMD. Immune hub DEGs and immune hub DEmiRNAs were selected for experimental verification using RT-qPCR. Results: A total of 2744 differentially expressed genes (DEGs) and 356 differentially expressed miRNAs (DEmiRNAs) were identified in the PF blood group compared to the healthy blood group. Among them, 42 DEmiRNAs were negatively correlated with 20 immune DEGs from a total of 57 correlations. The DEGs were significantly associated with pathways related to CD molecules, immune disease, immune system, cytokine receptors, T cell receptor signaling pathway, Th1 and Th2 cell differentiation, cytokine-cytokine receptor interaction, intestinal immune network for IgA production, and NOD-like receptor signaling pathway. There were 240 immune-related DEGs, in which 186 immune-related DEGs were up-regulated and 54 immune-related DEGs were down-regulated. In the protein-protein interaction (PPI) analysis of immune-related signaling pathway, TYK2, TLR2, TLR4, IL18, CSF1, CXCL13, LCK, ITGB2, PIK3CB, HCK, CD40, CD86, CCL3, CCR7, IL2RA, TLR3, and IL4R were identified as the hub immune genes. The mRNA-miRNA coregulation analysis showed that let-7d, miR-324-3p, miR-760, miR-185, miR-149, miR-149-5p, and miR-1842-5p are key miRNAs that target DEGs involved in immune disease, immune system and immunoregulation. Conclusion: The development and occurrence of PF were significantly influenced by the immune-related and apoptosis-related genes present in PF blood. mRNAs and miRNAs associated with the development and occurrence of PF in the FMD.

SPAG5 and ASPM play important roles in gastric cancer: An observational study.

Gastric cancer typically originates from the abnormal proliferation of normal cells within the gastric mucosa, eventually forming tumors. The roles of sperm-associated antigen 5 (SPAG5) and abnormal spindle-like microcephaly (ASPM) associated genes in gastric cancer are not yet clear. Gastric cancer datasets GSE51575 and GSE36076 profiles were downloaded from the GPL13607 and GPL570-generated gene expression omnibus database. The analysis included filtering for differentially expressed genes, weighted gene co-expression network analysis, functional enrichment analysis, gene set enrichment analysis, immune infiltration analysis, construction and analysis of the protein-protein interaction network, survival analysis, and Comparative Toxicogenomics Database analysis. Heatmaps of gene expression were also created. A total of 1457 differentially expressed genes were identified. According to gene ontology analysis, they are primarily enriched in the metabolic processes of organic acids, condensed chromosome centromere regions, and oxidoreductase activity. Kyoto Encyclopedia of Gene and Genome analysis showed they are mainly involved in metabolic pathways, P53 signaling pathway, and PPAR signaling pathway. The soft threshold power for weighted gene co-expression network analysis was set to 8. Three core genes (CENPE, SPAG5, and ASPM) were identified. Heatmaps of core gene expression revealed that SPAG5 and ASPM are highly expressed in gastric cancer samples and low in normal samples. Comparative Toxicogenomics Database analysis indicated that the core genes (CENPE, SPAG5, and ASPM) are associated with gastric tumors, gastric diseases, gastritis, gastric ulcers, tumors, inflammation, and necrosis. The SPAG5 and ASPM genes are overexpressed in gastric cancer tissues, and higher expression levels are associated with worse prognosis, may serve as potential prognostic markers.

The optimal atropine concentration for myopia control in Chinese children: a systematic review and network Meta-analysis.

AIM: To figure out whether various atropine dosages may slow the progression of myopia in Chinese kids and teenagers and to determine the optimal atropine concentration for effectively slowing the progression of myopia. METHODS: A systematic search was conducted across the Cochrane Library, PubMed, Web of Science, EMBASE, CNKI, CBM, VIP, and Wanfang database, encompassing literature on slowing progression of myopia with varying atropine concentrations from database inception to January 17, 2024. Data extraction and quality assessment were performed, and a network Meta-analysis was executed using Stata version 14.0 Software. Results were visually represented through graphs. RESULTS: Fourteen papers comprising 2475 cases were included; five different concentrations of atropine solution were used. The network Meta-analysis, along with the surface under the cumulative ranking curve (SUCRA), showed that 1% atropine (100%)>0.05% atropine (74.9%) >0.025% atropine (51.6%)>0.02% atropine (47.9%)>0.01% atropine (25.6%)>control in refraction change and 1% atropine (98.7%)>0.05% atropine (70.4%)>0.02% atropine (61.4%)>0.025% atropine (42%)>0.01% atropine (27.4%)>control in axial length (AL) change. CONCLUSION: In Chinese children and teenagers, the five various concentrations of atropine can reduce the progression of myopia. Although the network Meta-analysis showed that 1% atropine is the best one for controlling refraction and AL change, there is a high incidence of adverse effects with the use of 1% atropine. Therefore, we suggest that 0.05% atropine is optimal for Chinese children to slow myopia progression.

Ocular rosacea without facial erythema involvement manifesting as bilateral multiple recurrent chalazions: A case report.

BACKGROUND: In addition to the non-specific symptomatology of ocular rosacea, currently, there are no reliable diagnostic tests for the disease, which may lead to its misdiagnosis. Here, we report a case of ocular rosacea presenting with multiple recurrent chalazion on both eyelids. CASE SUMMARY: A 63-year-old female patient presented with multiple chalazion and dry eyes in both eyes, with no facial erythema. Initial management done were application of steroid eye ointment on both eyelids, hot compresses, and eyelid margin cleaning; noting that there was no relief of symptoms. Surgical excision of the chalazion was done on both eyes, however, bilateral recurrence occurred post-operatively. The pathological studies showed infiltration of a small amount of fibrous tissue with many chronic inflammatory cells. Immunohistochemistry studies were positive for LL-37. Resolution of the chalazion occurred after oral administration of doxycycline and azithromycin. CONCLUSION: Our findings show that ophthalmologists should recognize the ocular manifestations of skin diseases.

Fatigue crack-based strain sensors achieving flow detection and motion monitoring for reconnaissance robot applications.

Crack-based flexible strain sensors with ultra-high sensitivity under tiny strain are highly desired for environmental perception and motion detection of novel flexible and miniature robots. However, previously reported methods for fabricating crack patterns have often sacrificed the cyclic stability of the sensor, leading to a trade-off relationship between the sensitivity and the cyclic stability. Here, a universal and simple strategy based on fatigue loading with an ultra-large cumulative strain of up to ∼1.2 × 107%, rather than the traditionally quasi-static pre-overloading methods, is proposed to introduce channel cracks in the sensing layer without sacrificing the cyclic stability. The developed flexible strain sensors exhibit high strain-sensitivity (gauge factor = 5798) under tiny strain (< 3%), high cyclic stability (15 000 cycles) and a low strain detecting limit (0.02%). Furthermore, a leaf-like mechanosensor is developed using the fatigue crack-based strain sensor for the realization of multifunctional applications in environment perception and micro-motion detection. Brilliant airflow sensing performance with a wide sensing range (0.93-11.93 m s-1) and a fast response time (0.28 s) for amphibious applications is demonstrated. This work provides a new strategy for overcoming limits of crack-based flexible strain sensors and the developed leaf-like mechanosensor shows great application potential in miniature and flexible reconnaissance robots.

Nephrotic Syndrome Complicated with Familial Hypocalciuric Hypercalcemia in an Infant: A Case Report and Comprehensive Literature Review.

Background: Nephrotic syndrome, a prevalent childhood glomerular disorder, manifests with proteinuria, hypoalbuminemia, edema, and hypercholesteremia. Hypercalcemia, though rare, occasionally complicates these cases. Familial hypocalciuric hypercalcemia, an autosomal dominant disorder, is characterized by lifelong hypercalcemia, hypocalciuria, and normal or elevated parathyroid hormone levels due to loss-of-function mutations. Case Presentation: We detail a 2-year-old girl with nephrotic syndrome whose proteinuria responded effectively to steroid therapy without side effects. Hypercalcemia emerged after one month, prompting a familial history investigation, revealing a predisposition to hypercalcemia. Genetic analysis identified a heterozygous mutation c.1394G>A (p.R465Q) in the calcium-sensing receptor gene, shared among the patient, her grandmother, her father, and one sister. Notably, hypercalcemia required no intervention. Conclusions: This case report is the first documenting familial hypocalciuric hypercalcemia in a child with primary nephrotic syndrome and delineates the familial pedigree. While familial hypocalciuric hypercalcemia is infrequent, our findings affirm its generally benign nature. A critical aspect of patient care involves monitoring for potential complications, including acute pancreatitis or chondrocalcinosis. The indispensability of genetic studies in both diagnosis and the differentiation of related conditions is underscored, emphasizing their pivotal role in enhancing our understanding of this rare yet clinically significant disease. Continued research is imperative for advancing knowledge and improving clinical management.

Exploring lipid digestion discrepancies between preterm formula and human milk: Insights from in vitro gastrointestinal digestion and the impact of added milk fat.

Lipids play a pivotal role in the nutrition of preterm infants, acting as a primary energy source. Due to their underdeveloped gastrointestinal systems, lipid malabsorption is common, leading to insufficient energy intake and slowed growth. Therefore, it is critical to explore the reasons behind the low lipid absorption rate in formulas for preterm infants. This study utilized a simulated in intro gastrointestinal digestion model to assess the differences in lipid digestion between preterm human milk and various infant formulas. Results showed that the fatty acid release rates for formulas IF3, IF5, and IF7 were 58.90 %, 56.58 %, and 66.71 %, respectively, lower than human milk's 72.31 %. The primary free fatty acids (FFA) and 2-monoacylglycerol (2-MAG) released during digestion were C14:0, C16:0, C18:0, C18:1n-9, and C18:2n-6, in both human milk and formulas. Notably, the higher release of C16:0 in formulas may disrupt fatty acid balance, impacting lipid absorption. Further investigations are necessary to elucidate lipid absorption differences, which will inform the optimization of lipid content in preterm infant formulas.

JinLiDa granules alleviates cardiac hypertrophy and inflammation in diabetic cardiomyopathy by regulating TP53.

BACKGROUND: JinLiDa granules (JLD) is a traditional Chinese medicine (TCM) used to treat type 2 diabetes mellitus with Qi and Yin deficiency. Clinical evidence has shown that JLD can alleviate diabetic cardiomyopathy, but the exact mechanism is not yet clear. PURPOSE: The purpose of this study was to examine the potential role and mechanism of JLD in the treatment of diabetic cardiomyopathy through network pharmacological analysis and basic experiments. METHODS: The targets of JLD associated with diabetic cardiomyopathy were examined by network pharmacology. Protein interaction analysis was performed on the targets, and the associated pathways were searched by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. Diabetic mice were treated with low or high doses of JLD by gavage, and AC16 and H9C2 cardiomyocytes exposed to high-glucose conditions were treated with JLD. The analysis results were verified by various experimental techniques to examine molecular mechanisms. RESULTS: Network pharmacological analysis revealed that JLD acted on the tumor suppressor p53 (TP53) during inflammation and fibrosis associated with diabetic cardiomyopathy. The results of basic experiments showed that after JLD treatment, ventricular wall thickening in diabetic mouse hearts was attenuated, cardiac hypertrophy and myocardial inflammation were alleviated, and the expression of cardiac hypertrophy- and inflammation-related factors in cardiomyocytes exposed to a high-glucose environment was decreased. Cardiomyocyte morphology also improved after JLD treatment. TP53 expression and the tumor necrosis factor (TNF) and transforming growth factor beta-1 (TGFß1) signaling pathways were significantly altered, and inhibiting TP53 expression effectively alleviated the activation of the TNF and TGFß1 signaling pathways under high glucose conditions. Overexpression of TP53 activated these signaling pathways. CONCLUSIONS: JLD acted on TP53 to regulate the TNF and TGFß1 signaling pathways, effectively alleviating cardiomyocyte hypertrophy and inflammation in high glucose and diabetic conditions. Our study provides a solid foundation for the future treatment of diabetic cardiomyopathy with JLD.

[Research progress on mechanisms of ligustilide in treatment of nervous system diseases].

Ligustilide is the main active component of the volatile oil from Angelica sinensis and Ligusticum chuanxiong in the Umbelliferae family. It is a phthalein compound with anti-inflammatory, analgesic, antioxidant, anti-tumor, anti-atherosclerosis, neuroprotective, and other pharmacological effects. It can improve the permeability of the blood-brain barrier and has important potential in the treatment of neurodegenerative diseases and other nervous system diseases, such as Alzheimer's disease, ischemic stroke, Parkinson's disease, vascular dementia, and depression. Therefore, the mechanism of ligustilide in the treatment of nervous system diseases was summarized to provide a reference for drug development and clinical application.

The dual effects of dexmedetomidine on intestinal barrier and intestinal motility during sepsis.

BACKGROUND: Sepsis, characterized by dysregulated host responses to infection, remains a critical global health concern, with high morbidity and mortality rates. The gastrointestinal tract assumes a pivotal role in sepsis due to its dual functionality as a protective barrier against injurious agents and as a regulator of motility. Dexmedetomidine, an α2-adrenergic agonist commonly employed in critical care settings, exhibits promise in influencing the maintenance of intestinal barrier integrity during sepsis. However, its impact on intestinal motility, a crucial component of intestinal function, remains incompletely understood. METHODS: In this study, we investigated dexmedetomidine's multifaceted effects on intestinal barrier function and motility during sepsis using both in vitro and in vivo models. Sepsis was induced in Sprague-Dawley rats via cecal ligation and puncture. Rats were treated with dexmedetomidine post-cecal ligation and puncture, and various parameters were assessed to elucidate dexmedetomidine's impact. RESULTS: Our findings revealed a dichotomous influence of dexmedetomidine on intestinal physiology. In septic rats, dexmedetomidine administration resulted in improved intestinal barrier integrity, as evidenced by reduced mucosal hyper-permeability and morphological alterations. However, a contrasting effect was observed on intestinal motility, as dexmedetomidine treatment inhibited both the frequency and amplitude of contractions in isolated intestinal strips and decreased the distance of ink migration in vivo. Additionally, dexmedetomidine suppressed the secretion of pro-motility hormones while having no influence on hormones that inhibit intestinal peristalsis. CONCLUSION: The study revealed that during sepsis, dexmedetomidine exhibited protective effects on barrier integrity, although concurrently it hindered intestinal motility, partly attributed to its modulation of pro-motility hormone secretion. These findings underscore the necessity of a comprehensive understanding of dexmedetomidine's impact on multiple facets of gastrointestinal physiology in sepsis management, offering potential implications for therapeutic strategies and patient care.

The association between neuropsychological impairment, self-perceived cognitive deficit, symptoms, and health related quality of life in newly diagnosed ovarian cancer patients.

Objective: To assess cognitive function in patients newly diagnosed with ovarian cancer (OC) before treatment and explore the relationship between neuropsychological impairment, self-perceived cognitive deficit, symptoms, and health-related quality of life in them. Methods: From May 2021 to February 2022, 105 women newly diagnosed with OC were enrolled in the Cancer Center of Fudan University, Shanghai, China. Objective and subjective cognitive functions were assessed using the Montreal Cognitive Assessment (MoCA) scale and Perceptual Deficits Questionnaire (PDQ). Symptoms and quality of life were evaluated using the Memorial Symptom Assessment Scale (MSAS) and Functional Assessment of Cancer Therapy-Ovarian Cancer (FACT-O), respectively. Results: This study included 105 newly diagnosed OC patients, with an average age of 49.73 (±8.48) years. Of these, 72.38% had impaired neuropsychological test scores, especially in delayed recall, abstraction, and visuospatial/executive function. Retrospective, and prospective memory were the most serious perceived deficits. The results of the MoCA test were not associated with PDQ (Rs = -0.180, P = 0.067) and significantly correlated with the distress index, physiological and total scores of the MSAS, and emotional well- being of the FACT-O. The PDQ positively correlated with all MSAS dimensions but not with the FACT-O. Conclusion: The incidence of neuropsychological impairment in patients newly diagnosed with OC was high, with no association with self-perceived cognitive deficits. It is recommended that healthcare providers include cognitive impairment in symptom management in this population, who may benefit from early assessment, prevention, and intervention.

Direct targeting of S100A9 with Icariin counteracted acetaminophen­induced hepatotoxicity.

Acetaminophen (APAP) is a widely used antipyretic and analgesic medication, but its overdose can induce acute liver failure with lack of effective therapies. Icariin is a bioactive compound derived from the herb Epimedium that displays hepatoprotective activities. Here, we explored the protective effects and mechanism of icariin on APAP-induced hepatotoxicity. Icariin (25/50 mg/kg) or N-Acetylcysteine (NAC, 300 mg/kg) were orally administered in wild-type C57BL/6 mice for 7 consecutive days before the APAP administration. Icariin attenuated APAP-induced acute liver injury in mice, as measured by alleviated serum enzymes activities and hepatic apoptosis. In vitro, icariin pretreatment significantly inhibited hepatocellular damage and apoptosis by reducing the BAX/Bcl-2 ratio as well as the expression of cleaved-caspase 3 and cleaved-PARP depended on the p53 pathway. Moreover, icariin attenuated APAP-mediated inflammatory response and oxidative stress via the Nrf2 and NF-κB pathways. Importantly, icariin reduced the expression of S100A9, icariin interacts with S100A9 as a direct cellular target, which was supported by molecular dynamics simulation and surface plasmon resonance assay (equilibrium dissociation constant, KD = 1.14 µM). In addition, the genetic deletion and inhibition of S100A9 not only alleviated APAP-induced injury but also reduced the icariin's protective activity in APAP-mediated liver injury. These data indicated that icariin targeted S100A9 to alleviate APAP-induced liver damage via the following signaling pathways NF-κB, p53, and Nrf2.

Self-evolving persistent luminescence nanoprobes for autofluorescence-free ratiometric imaging and on-demand enhanced chemodynamic therapy of pulmonary metastatic tumors.

Precise imaging-guided therapy of a pulmonary metastasis tumor is of great significance for tumor management and prognosis. Persistent luminescence nanoparticles (PLNPs) are promising probes due to their in situ excitation-free and low-background imaging characteristics. However, most of the PLNP-based probes cannot intelligently distinguish between normal and tumor tissues or balance the needs of targeted accumulation and rapid metabolism, resulting in false positive signals and potential side effects. Besides, the luminescence intensity of single-emissive PLNPs is affected by external factors. Herein, we report a self-evolving double-emissive PLNP-based nanoprobe ZGMC@ZGC-TAT for pulmonary metastatic tumor imaging and therapy. Acid-degradable green-emitting PLNPs (ZGMC) with good afterglow performance and therapeutic potential are synthesized by systematic optimization of dopants. Ultra-small red-emitting PLNPs (ZGC) are then prepared as imaging and reference probes. The two PLNPs are finally covalently coupled and further modified with a cell-penetrating peptide (TAT) to obtain ZGMC@ZGC-TAT. Dual emission ensures a stable luminescence ratio (I700/I537) independent of probe concentration, test voltage and time gate. ZGMC degrades and phosphorescence disappears in a tumor microenvironment (TME), resulting in an increase in I700/I537, thus enabling tumor-specific ratiometric imaging. Cu2+ and Mn2+ released by ZGMC degradation achieve GSH depletion and enhance CDT, effectively inhibiting tumor cell proliferation. Meanwhile, the size of ZGMC@ZGC-TAT decreases sharply, and the resulting ZGC-TAT further causes nuclear pyknosis and quickly clear metabolism. The developed ZGMC@ZGC-TAT turns non-targeted lung aggregation of nanomaterials into a unique advantage, and integrates TME-triggered phosphorescence and size self-evolution, and on-demand therapeutic functions, showing outstanding prospects in precise imaging and efficient treatment of pulmonary metastatic tumors.

Efficacy and Safety of Semaglutide in Weight Loss of Non-diabetic People.

OBJECTIVE: The study aimed to investigate the efficacy and safety of semaglutide in weight loss in non-diabetic people. METHODS: In this study, 84 non-diabetic people who used semaglutide to lose weight in the outpatient department of our hospital from January 1, 2022, to June 30, 2022, were enrolled and compared for changes in body weight, waist circumference, Body Mass Index (BMI), fasting blood glucose, blood pressure, pulse, and body composition (body fat ratio, visceral fat area, and skeletal muscle) before treatment and 12 weeks after the treatment to analyze the weight loss efficacy and safety. RESULTS: After administering semaglutide 0.25 mg, 0.5 mg, 0.75 mg, or 1 mg subcutaneously once a week for 12 weeks, 84 participants in this study obtained an average weight loss of 5.91 ± 3.37 kg, equivalent to 6.15 ± 4.28% of baseline body weight, and there was also a significant reduction in visceral fat area and a slight reduction in blood pressure. The most common adverse reactions included gastrointestinal reactions (nausea, vomiting, and diarrhea), which were mild and subsided within 1-2 days. No severe adverse reaction, such as hypoglycemia and hypotension, was observed. CONCLUSION: Low-dose semaglutide has been found to be effective and safe for short-term weight loss in non-diabetic people.

MiRNA-145-5p inhibits gastric cancer progression via the serpin family E member 1- extracellular signal-regulated kinase-1/2 axis.

BACKGROUND: MicroRNAs (miRNAs) regulate gene expression and play a critical role in cancer physiology. However, there is still a limited understanding of the function and regulatory mechanism of miRNAs in gastric cancer (GC). AIM: To investigate the role and molecular mechanism of miRNA-145-5p (miR145-5p) in the progression of GC. METHODS: Real-time polymerase chain reaction (RT-PCR) was used to detect miRNA expression in human GC tissues and cells. The ability of cancer cells to migrate and invade was assessed using wound-healing and transwell assays, respectively. Cell proliferation was measured using cell counting kit-8 and colony formation assays, and apoptosis was evaluated using flow cytometry. Expression of the epithelial-mesenchymal transition (EMT)-associated protein was determined by Western blot. Targets of miR-145-5p were predicated using bioinformatics analysis and verified using a dual-luciferase reporter system. Serpin family E member 1 (SERPINE1) expression in GC tissues and cells was evaluated using RT-PCR and immunohistochemical staining. The correlation between SERPINE1 expression and overall patient survival was determined using Kaplan-Meier plot analysis. The association between SERPINE1 and GC progression was also tested. A rescue experiment of SERPINE1 overexpression was conducted to verify the relationship between this protein and miR-145-5p. The mechanism by which miR-145-5p influences GC progression was further explored by assessing tumor formation in nude mice. RESULTS: GC tissues and cells had reduced miR-145-5p expression and SERPINE1 was identified as a direct target of this miRNA. Overexpression of miR-145-5p was associated with decreased GC cell proliferation, invasion, migration, and EMT, and these effects were reversed by forcing SERPINE1 expression. Kaplan-Meier plot analysis revealed that patients with higher SERPINE1 expression had a shorter survival rate than those with lower SERPINE1 expression. Nude mouse tumorigenesis experiments confirmed that miR-145-5p targets SERPINE1 to regulate extracellular signal-regulated kinase-1/2 (ERK1/2). CONCLUSION: This study found that miR-145-5p inhibits tumor progression and is expressed in lower amounts in patients with GC. MiR-145-5p was found to affect GC cell proliferation, migration, and invasion by negatively regulating SERPINE1 levels and controlling the ERK1/2 pathway.

Targeting OXCT1-mediated ketone metabolism reprograms macrophages to promote antitumor immunity via CD8+ T cells in hepatocellular carcinoma.

BACKGROUND & AIMS: The liver is the main organ of ketogenesis, while ketones are mainly metabolized in peripheral tissues via the critical enzyme OXCT1. We previously found that ketolysis is reactivated in hepatocellular carcinoma (HCC) cells through OXCT1 expression to promote tumor progression; however, whether OXCT1 regulates antitumor immunity remains unclear. METHODS: To investigate the expression pattern of OXCT1 in hepatocellular carcinoma in vivo, we conducted multiplex immunohistochemistry (mIHC) experiments on human HCC specimens. To explore the role of OXCT1 in mouse hepatocellular carcinoma tumor-associated macrophages (TAMs), we generated LysMcreOXCT1f/f (OXCT1 conditional knockout in macrophages) mice. RESULTS: Here, we found that inhibiting OXCT1 expression in tumor-associated macrophages reduced CD8+ T-cell exhaustion through the succinate-H3K4me3-Arg1 axis. Initially, we found that OXCT1 was highly expressed in liver macrophages under steady state and that OXCT expression was further increased in TAMs. OXCT1 deficiency in macrophages suppressed tumor growth by reprogramming TAMs toward an antitumor phenotype, reducing CD8+ T-cell exhaustion and increasing CD8+ T-cell cytotoxicity. Mechanistically, high OXCT1 expression induced the accumulation of succinate, a byproduct of ketolysis, in TAMs, which promoted Arg1 transcription by increasing the H3K4 trimethylation (H3K4me3) level in the Arg1 promoter. In addition, Pimozide, an inhibitor of OXCT1, suppressed Arg1 expression as well as TAM polarization toward the protumor phenotype, leading to decreasing CD8+ T-cell exhaustion and deceleration of tumor growth. Finally, high expression of OXCT1 in macrophages was positively associated with poor survival in HCC patients. CONCLUSIONS: In conclusion, our results demonstrate that OXCT1 epigenetically suppresses antitumor immunity, suggesting that suppressing OXCT1 activity in TAMs is an effective approach for treating liver cancer. IMPACT AND IMPLICATIONS: The intricate metabolism of liver macrophages plays a critical role in shaping HCC progression and immune modulation. Targeting macrophage metabolism to counteract immune suppression presents a promising avenue for HCC. Here, we found that ketogenesis gene OXCT1 was highly expressed in tumor-associated macrophages and promoted tumor growth by reprogramming TAMs toward a protumor phenotype. And the strategic pharmacological intervention or genetic downregulation of OXCT1 in TAMs enhances the antitumor immunity and decelerated tumor growth. Our results suggest that suppressing OXCT1 activity in TAMs is an effective approach for treating liver cancer.