Mitochondria, functioning not only as the central hub of cellular energy metabolism but also as semi-autonomous organelles, orchestrate cellular fate decisions through their endogenous mitochondrial DNA (mtDNA), which encodes core components of the electron transport chain. Emerging research has identified microRNAs localized within mitochondria, termed mitochondria-located microRNAs (mitomiRs). Recent studies have revealed that mitomiRs are transcribed from nuclear DNA (nDNA), processed and matured in the cytoplasm, and subsequently transported into mitochondria. mitomiRs regulate mtDNA through diverse mechanisms, including modulation of mtDNA expression at the translational level and direct binding to mtDNA to influence transcription. Aberrant expression of mitomiRs leads to mitochondrial dysfunction and contributes to the pathogenesis of metabolic diseases. Restoring mitomiR expression to physiological levels using mitomiRs mimics or inhibitors has been shown to improve mitochondrial function and alleviate related diseases. Consequently, the regulatory mechanisms of mitomiRs have become a major focus in mitochondrial research. Given that mitomiRs are located in mitochondria, targeted delivery strategies designed for mtDNA can be adapted for the delivery of mitomiRs mimics or inhibitors. However, numerous intracellular and extracellular barriers remain, highlighting the need for more precise and efficient delivery systems in the future. The regulation of mtDNA expression mediated by mitomiRs not only expands our understanding of miRNA functions in post-transcriptional gene regulation but also provides promising molecular targets for the treatment of mitochondrial-related diseases. This review systematically summarizes recent research progress on mitomiRs in regulating mtDNA expression and discusses the underlying mechanisms of mitomiRs-mtDNA interactions. Additionally, it provides new perspectives on precision therapeutic strategies, with a particular emphasis on mitomiRs-based regulation of mitochondrial function in mitochondrial-related diseases.

Accurate prediction of drug-target interactions (DTIs) plays a pivotal role in drug discovery, facilitating optimization of lead compounds, drug repurposing and elucidation of drug side effects. However, traditional DTI prediction methods are often limited by incomplete biological data and insufficient representation of protein features. In this study, we proposed KG-CNNDTI, a novel knowledge graph-enhanced framework for DTI prediction, which integrates heterogeneous biological information to improve model generalizability and predictive performance. The proposed model utilized protein embeddings derived from a biomedical knowledge graph via the Node2Vec algorithm, which were further enriched with contextualized sequence representations obtained from ProteinBERT. For compound representation, multiple molecular fingerprint schemes alongside the Uni-Mol pre-trained model were evaluated. The fused representations served as inputs to both classical machine learning models and a convolutional neural network-based predictor. Experimental evaluations across benchmark datasets demonstrated that KG-CNNDTI achieved superior performance compared to state-of-the-art methods, particularly in terms of Precision, Recall, F1-Score and area under the precision-recall curve (AUPR). Ablation analysis highlighted the substantial contribution of knowledge graph-derived features. Moreover, KG-CNNDTI was employed for virtual screening of natural products against Alzheimer's disease, resulting in 40 candidate compounds. 5 were supported by literature evidence, among which 3 were further validated in vitro assays.
Alzheimer Disease/drug therapy* ; Biological Products/therapeutic use* ; Humans ; Neural Networks, Computer ; Machine Learning ; Drug Discovery/methods* ; Algorithms ; Drug Evaluation, Preclinical/methods*

OBJECTIVE: Poxviruses are zoonotic pathogens that infect humans, mammals, vertebrates, and arthropods. However, the specific role of ticks in transmission and evolution of these viruses remains unclear. METHODS: Transcriptomic and metatranscriptomic raw data from 329 sampling pools of seven tick species across five continents were mined to assess the diversity and abundance of poxviruses. Chordopoxviral sequences were assembled and subjected to phylogenetic analysis to trace the origins of the unblasted fragments within these sequences. RESULTS: Fifty-eight poxvirus species, representing two subfamilies and 20 genera, were identified, with 212 poxviral sequences assembled. A substantial proportion of AT-rich fragments were detected in the assembled poxviral genomes. These genomic sequences contained fragments originating from rodents, archaea, and arthropods. CONCLUSION Our findings indicate that ticks play a significant role in the transmission and evolution of poxviruses. These viruses demonstrate the capacity to modulate virulence and adaptability through horizontal gene transfer, gene recombination, and gene mutations, thereby promoting co-existence and co-evolution with their hosts. This study advances understanding of the ecological dynamics of poxvirus transmission and evolution and highlights the potential role of ticks as vectors and vessels in these processes.
Animals ; Poxviridae/physiology* ; Ticks/virology* ; Phylogeny ; Transcriptome ; Evolution, Molecular ; Poxviridae Infections/virology* ; Genome, Viral

ObjectiveTo investigate the role and possible mechanism of action of rhubarb decoction （RD） retention enema in improving inflammatory damage of brain tissue in a rat model of mild hepatic encephalopathy （MHE）. MethodsA total of 60 male Sprague-Dawley rats were divided into blank group （CON group with 6 rats） and chronic liver cirrhosis modeling group with 54 rats using the complete randomization method. After 12 weeks， 40 rats with successful modeling which were confirmed to meet the requirements for MHE model by the Morris water maze test were randomly divided into model group （MOD group）， lactulose group （LT group）， low-dose RD group （RD1 group）， middle-dose RD group （RD2 group）， and high-dose RD group （RD3 group）， with 8 rats in each group. The rats in the CON group and the MOD group were given retention enema with 2 mL of normal saline once a day； the rats in the LT group were given retention enema with 2 mL of lactulose at a dose of 22.5% once a day； the rats in the RD1， RD2， and RD3 groups were given retention enema with 2 mL RD at a dose of 2.5， 5.0， and 7.5 g/kg， respectively， once a day. After 10 days of treatment， the Morris water maze test was performed to analyze the spatial learning and memory abilities of rats. The rats were analyzed from the following aspects： behavioral status； the serum levels of alanine aminotransferase （ALT）， aspartate aminotransferase （AST）， interleukin-1β （IL-1β）， interleukin-6 （IL-6）， and tumor necrosis factor-α （TNF-α） and the level of blood ammonia； pathological changes of liver tissue and brain tissue； the mRNA and protein expression levels of phosphatidylinositol 3-kinase （PI3K）， protein kinase B （AKT）， and mammalian target of rapamycin （mTOR） in brain tissue. A one-way analysis of variance was used for comparison of continuous data between multiple groups， and the least significant difference t-test was used for further comparison between two groups. ResultsCompared with the MOD group， the RD1， RD2， and RD3 groups had a significantly shorter escape latency （all P<0.01）， significant reductions in the levels of ALT， AST， IL-1β， IL-6， TNF-α， and blood ammonia （all P<0.05）， significant alleviation of the degeneration， necrosis， and inflammation of hepatocytes and brain cells， and significant reductions in the mRNA and protein expression levels of PI3K， AKT， and mTOR in brain tissue （all P<0.05）， and the RD3 group had a better treatment outcome than the RD1 and RD2 groups. ConclusionRetention enema with RD can improve cognitive function and inflammatory damage of brain tissue in MHE rats， possibly by regulating the PI3K/AKT/mTOR signaling pathway.

Important forensic diagnostic indicators of sudden death in coronary atherosclerotic heart dis-ease,such as acute or chronic myocardial ischemic changes,sometimes make it difficult to locate the ischemic site due to the short death process,the lack of tissue reaction time.In some cases,the de-ceased died of sudden death on the first-episode,resulting in difficulty for medical examiners to make an accurate diagnosis.However,clinical studies on coronary instability plaque revealed the key role of coronary spasm and thrombosis caused by their lesions in sudden coronary death process.This paper mainly summarizes the pathological characteristics of unstable coronary plaque based on clinical medi-cal research,including plaque rupture,plaque erosion and calcified nodules,as well as the influencing factors leading to plaque instability,and briefly describes the research progress and technique of the atherosclerotic plaques,in order to improve the study on the mechanism of sudden coronary death and improve the accuracy of the forensic diagnosis of sudden coronary death by diagnosing different patho-logic states of coronary atherosclerotic plaques.

From the perspective of the physiological basis of liver and kidney sharing the common source in traditional Chinese medicine(TCM),and by integrating the theory of kidney dominating bone,liver dominating tendon,and meridian sinew of TCM as well as the bone resorption and collapse theory,and non-uniform settlement theory and lower-limb musculoskeletal bowstring structure theory of modern orthopedics,the pathogenesis of osteonecrosis of the femoral head(ONFH)under the system of non-uniform settlement during bone resorption and multidimensional composite bowstring working in coordination with the theory of liver-kidney and muscle-bone was explored.The key to the TCM pathogenesis of ONFH lies in the deficiency of the liver and kidney,and then the imbalance of kidney yin-yang leads to the disruption of the dynamic balance of bone formation and bone resorption mediated by osteoblasts-osteoclasts,which manifests as the elevated level of bone metabolism and the enhancement of focal bone resorption in the femoral head,and then leads to the necrosis and collapse of the femoral head.It is considered that the kidney dominates bone,liver dominates tendon,and the tendon and bone together constitute the muscle-bone-joint dynamic and static system of the hip joint.The appearance of collapse destroys the originally balanced muscle-bone-joint system.Moreover,the failure of liver blood in the nourishment of muscles and tendons further exacerbates the imbalance of the soft tissues around the hip joint,accelerates the collapse of the muscle-bone-joint dynamic and static system,speeds up the process of femoral head collapse,and ultimately results in irreversible outcomes.Based on the above pathogenesis,the systematic integrative treatment of ONFH should be based on the TCM holistic concept,focuses on the focal improvement of internal and external blood circulation of the femoral head by various approaches,so as to rebuild the coordination of joint function.Moreover,attention should be paid to the physical constitution of the patients,and therapy of tonifying the kidney and regulating the liver can be used to restore the balance between osteogenesis and osteoblastogenesis,and to reconstruct the muscle-bone-joint system,so as to effectively delay or even prevent the occurrence of ONFH.

AIM To compare the components difference between Lonicera fragrantissima Lindl.et Paxt.(LFL)and Lonicerae japonicae Flos(LJF),and to evaluate the medicinal value of LFL,so as to provide reference for the development and utilization of LFL and LJF.METHODS With 70%methanol as extraction solvent,the components were analyzed by UPLC-TOF-MS,and the contents of 20 components were determined by HPLC-QQQ-MS.The components difference was determined by multivariate statistical analysis.RESULTS A total of 52 components were identified in the buds of LFL and LJF.There were 4 different components in LJF,and the contents of 20 quantitative components were significantly different.The contents of isochlorogenic acid C,ferulic acid,luteolin and rutin in the buds of LFL were more than 2 times that of LJF,and the contents of marchanic acid and marchanin were 11.96 times and 37.23 times that of LJF respectively.Maganin,isochlorogenic acid A,maganic acid,rutin and dicomachanic acid are the key differentiating components of LFL and LJF.CONCLUSION The buds of LFL and LJF have similar species,but the content difference is obvious.The buds of LFL have important medicinal value,which need further development and utilization.

Physiologically based pharmacokinetic (PBPK) models have been widely used to predict various stages of drug absorption, distribution, metabolism and excretion. Models based on machine learning (ML) and artificial intelligence (AI) can provide better ideas for the construction of PBPK models, which can accelerate the prediction speed and improve the prediction quality of PBPK. ML and AL can complement the advantages of PBPK model to accelerate the progress of drug research and development. This review introduces the application of machine learning and artificial intelligence in pharmacokinetics, summarizes the research progress of physiological pharmacokinetic models based on machine learning and artificial intelligence, and analyzes the limitations of machine learning and artificial intelligence applications and their application prospects and prospects.

Nitazoxanide is an FDA-approved antiprotozoal drug. Our previous study found that oral administration of nitazoxanide inhibited Western diet (WD)-induced hepatic steatosis in ApoE^-/- mice. However, the specific mechanism remains to be elucidated. In the present study, we performed an untargeted metabolomics approach to reveal the effect of nitazoxanide on the liver metabolic profiles in WD-fed ApoE^-/- mice, and carried out the cellular experiments to elucidate the underlying mechanisms. UPLC-MS-based untargeted metabolomics analysis was used to investigate the effect of nitazoxanide on global metabolite changes in liver tissues. The differential metabolites were screened for enrichment analysis and pathway analysis. Hepatocytes were treated with tizoxanide, the metabolite of nitazoxanide, to investigate the underlying mechanism based on the findings in metabolomics study. The improvement of liver lipid metabolism disorders by nitazoxanide treatment in WD-fed ApoE^-/- mice was mainly through regulating glycerophospholipid metabolism, D-glutamine and glutamate metabolism, glutathione metabolism, and arginine biosynthesis metabolism. Tizoxanide, the active metabolite of nitazoxanide, increased glutathione (GSH) contents and glutamate-cysteine ligase catalytic subunit (Gcl-c) and glutathione reductase (Gsr) mRNA expressions in HepG2 cells. Tizoxanide increased cystathionine β-synthase (CBS) and phosphatidylethanolamine N-methyltransferase (PEMT) protein levels, inhibited lipid accumulation in hepatocytes induced by free fatty acid (FFA). Tizoxanide increased S-adenosyl-L-homocysteine hydrolase (SAHH) protein levels in HepG2 cells and mouse primary liver cells stimulated with free fatty acid (FFA). Tizoxanide increased N-acetyl glutamate synthase (Nags) and carbamoylphosphate synthetase 1 (Cps1) mRNA expressions in HepG2 cells. In conclusion, nitazoxanide improves WD-induced hepatic steatosis in ApoE^-/- mice and the underlying mechanisms include increasing CBS expression, GSH content, PEMT protein expression, Nags and Cps1 mRNA expression in hepatocytes.

Objective: To investigate the cause of a foodborne outbreak that occurred in Dong Nai province, Viet Nam, in 2024, and implement control measures. Methods: An initial investigation was conducted to confirm the outbreak, which was followed by epidemiological and environmental investigations to find the plausible causative food item. Clinical specimens and food samples were tested to identify the pathogen. Results: A total of 547 symptomatic cases were recorded, of whom two were in severe condition requiring extracorporeal membrane oxygenation and ventilation, one of whom died. Among 99 interviewed cases, the mean incubation time was 9 hours (range 2–24 hours), with the main symptoms being fever, abdominal pain, diarrhoea and vomiting. All patients had eaten banh mi from a local bakery. Salmonella spp. were identified in food samples and clinical specimens. The bakery halted production, and the outbreak ended after 1 week. Discussion: All the patients were exposed to only one food in common, which facilitated the investigation process. This outbreak is a reminder to small retailers and take-away shops of the importance of food safety management in preventing similar future outbreaks. All food handlers must comply with food hygiene principles, especially in hot temperatures, which boosts bacterial growth.