Colorectal cancer （CRC） is one of the most common cancers， with its incidence ranking high among cancers. It stands as the second leading cause of cancer-related death worldwide. In the early stages， CRC lacks specific symptoms， and most patients are diagnosed at advanced stages， making it a major research focus in the field of gastrointestinal tumors. Currently， clinical CRC treatments face several common challenges， including high surgical risks， frequent metastasis and recurrence， drug resistance， and significant side effects from chemotherapy and radiation therapy. With the development and application of traditional Chinese medicine （TCM）， it has been found that TCM and its active ingredients can effectively inhibit CRC cell proliferation， invasion， migration， and angiogenesis， and promote apoptosis and autophagy， thereby slowing the progression of CRC. This has become a key focus of CRC treatment research. Salvia Miltiorrhiza has multiple pharmacological effects， including activating blood circulation to dispel blood stasis， unlocking meridians to relieve pain， clearing heat to calm irritability， and cooling blood to reduce abscesses. It contains a variety of chemical components， including diterpenoids， phenolic acids， flavonoids， polysaccharides， nitrogen-containing compounds， steroids， and lactone compounds. This review summarized the molecular mechanisms of Salvia miltiorrhiza and its active ingredients in the treatment of CRC. It is found that these ingredients exert anti-CRC effects through various molecular mechanisms， including cell cycle arrest， promotion of apoptosis， inhibition of cell invasion and migration， induction of autophagy， suppression of tumor angiogenesis， and remodeling of the tumor microenvironment. The review aims to provide new insights for the drug development and clinical application of Salvia miltiorrhiza in CRC treatment.

To the present study aimed to investigate the protective effects of Erlong Zuoci Pills on oxidative stress induced by hydrogen peroxide (H2O2) in House Ear Institute-Organ of Corti 1 (HEI-OC1) and to explore the mechanism by cellular metabolomics. There were 6 groups in the experiment: the control group, model group, three dose groups of ELZC (low, medium, and high), and positive control ascorbic acid group. The oxidative stress injury model was established in the HEI-OC1 by inducing 0.9 mmol/L H2O2 for 12 h. The proliferation of HEI-OC1 cells was observed by CCK-8 assay; the contents and activity of lactate hydrogenase (LDH), reactive oxygen species (ROS), and superoxide dismutase (SOD) in HEI-OC1 cells were detected by corresponding kits. Finally, the endogenous substances of cells were analyzed from the perspective of metabolomics. Compared with the model group, ELZC groups could significantly increase the cell proliferation rate after administration. Moreover, they could also ameliorate the increase of ROS and LDH content and the decrease of antioxidant enzyme SOD caused by H2O2. Metabolomic results revealed significant differences among multiple groups in the scores of partial least squares discriminant analysis. The ELZC group could relocate the model group back to the control group. The metabolic regulation of ELZC on oxidative stress in HEI-OC1 cells mainly affects nucleotide metabolism and amino acid metabolism. In summary, the results indicate that ELZC exhibits protective effects on H2O2-induced oxidative stress in HEI-OC1 cells. Additionally, this protective effect may be produced by increasing the content of amino acids such as uridine and phenylalanine, thereby regulating pathways such as pyrimidine metabolism, phenylalanine metabolism, biosynthesis of phenylalanine, tyrosine, and tryptophan, and histidine metabolism.

Stria vascularis（SV）, located in the lateral wall of the cochlea, is a highly vascularized tissue that plays a crucial role in maintaining the homeostasis of endolymph and normal auditory function, with its core function relying on the transporter system distributed within it. These transporters in the SV precisely mediate the transport of ions, nutrients, and metabolites, constituting the cornerstone of the homeostasis of endolymph. Abnormal expression or dysfunction of transporters in the SV can lead to an imbalance in the inner ear microenvironment, which can lead to hearing loss. However, the effects of transporters in SV on hearing loss have not been fully clarified. In this paper, the function and distribution of different types of transporters in SV and their relationship with hearing loss are reviewed, providing a new perspective and prospect for exploring the molecular basis of hearing loss and targeted therapies of transporters in the future.

BACKGROUND: While emotional distress, encompassing anxiety and depression, has been associated with negative clinical outcomes, its impact across various clinical departments and general hospitals has been less explored. Previous studies with limited sample sizes have examined the effectiveness of specific treatments (e.g., antidepressants) rather than a systemic management strategy for outcome improvement in non-psychiatric inpatients. To enhance the understanding of the importance of addressing mental health care needs among non-psychiatric patients in general hospitals, this study retrospectively investigated the impacts of emotional distress and the effects of early detection and management of depression and anxiety on hospital length of stay (LOS) and rate of long LOS (LLOS, i.e., LOS >30 days) in a large sample of non-psychiatric inpatients. METHODS: This retrospective cohort study included 487,871 inpatients from 20 non-psychiatric departments of a general hospital. They were divided, according to whether they underwent a novel strategy to manage emotional distress which deployed the Huaxi Emotional Distress Index (HEI) for brief screening with grading psychological services (BS-GPS), into BS-GPS ( n = 178,883) and non-BS-GPS ( n = 308,988) cohorts. The LOS and rate of LLOS between the BS-GPS and non-BS-GPS cohorts and between subcohorts with and without clinically significant anxiety and/or depression (CSAD, i.e., HEI score ≥11 on admission to the hospital) in the BS-GPS cohort were compared using univariable analyses, multilevel analyses, and/or propensity score-matched analyses, respectively. RESULTS: The detection rate of CSAD in the BS-GPS cohort varied from 2.64% (95% confidence interval [CI]: 2.49%-2.81%) to 20.50% (95% CI: 19.43%-21.62%) across the 20 departments, with a average rate of 5.36%. Significant differences were observed in both the LOS and LLOS rates between the subcohorts with CSAD (12.7 days, 535/9590) and without CSAD (9.5 days, 3800/169,293) and between the BS-GPS (9.6 days, 4335/178,883) and non-BS-GPS (10.8 days, 11,483/308,988) cohorts. These differences remained significant after controlling for confounders using propensity score-matched comparisons. A multilevel analysis indicated that BS-GPS was negatively associated with both LOS and LLOS after controlling for sociodemographics and the departments of patient discharge and remained negatively associated with LLOS after controlling additionally for the year of patient discharge. CONCLUSION Emotional distress significantly prolonged the LOS and increased the LLOS of non-psychiatric inpatients across most departments and general hospitals. These impacts were moderated by the implementation of BS-GPS. Thus, BS-GPS has the potential as an effective, resource-saving strategy for enhancing mental health care and optimizing medical resources in general hospitals.
Humans ; Retrospective Studies ; Male ; Length of Stay/statistics & numerical data* ; Female ; Middle Aged ; Adult ; Psychological Distress ; Inpatients/psychology* ; Aged ; Anxiety/diagnosis* ; Depression/diagnosis*

Increasing evidence has underscored the significance of post-stroke alterations along gut-brain axis, while its role in pathogenesis and treatment of ischemic stroke (IS) remains largely unexplored. This study aimed to elucidate the therapeutic effects and action targets of Panax notoginseng saponins (PNS) on IS and explore a novel pathogenesis and treatment strategy of IS via profiling the microbial community and metabolic characteristics along gut-brain axis. Our findings revealed for the first time that the therapeutic effect of PNS on IS was microbiota-dependent. Ischemia/reperfusion (I/R) modeling significantly down-regulated Lactobacilli in rats, and PNS markedly recovered Lactobacilli, particularly Lactobacillus reuteri (L.Reu). Metabolomics showed a significant reduction in serum histidine (HIS) in clinical obsolete IS patients and rehabilitation period I/R rats. Meanwhile, the L.Reu colonization in I/R rats exhibited significant neuroprotective activity and greatly increased HIS in serum, gut microbiota, and brain. Moreover, exogenous HIS demonstrated indirect neuroprotective effects through metabolizing to histamine. Notably, vagus nerve severance in I/R rats was performed to investigate HIS's neuroprotective mechanism. The results innovatively revealed that PNS could promote HIS synthesis in gut by enhancing L.Reu proportion, thereby increasing intracerebral HIS through peripheral pathway. Consequently, our data provided novel insights into HIS metabolism mediated by L.Reu in the pathogenesis and treatment of IS.

Tumors exhibit abnormal glucose metabolism, consuming excessive glucose and excreting lactate, which constructs a tumor microenvironment that facilitates cancer progression and disrupts immunotherapeutic efficacy. Currently, tumor glucose metabolic dysregulation to reshape the immunosuppressive microenvironment and enhance immunotherapy efficacy is emerging as an innovative therapeutic strategy. However, glucose metabolism modulators lack specificity and still face significant challenges in overcoming tumor delivery barriers, microenvironmental complexity, and metabolic heterogeneity, resulting in poor clinical benefit. Nanomedicines, with their ability to selectively target tumors or immune cells, respond to the tumor microenvironment, co-deliver multiple drugs, and facilitate combinatorial therapies, hold significant promise for enhancing immunotherapy through tumor glucose metabolic reprogramming. This review explores the complex interactions between tumor glucose metabolism-specifically metabolite transport, glycolysis processes, and lactate-and the immune microenvironment. We summarize how nanomedicine-mediated reprogramming of tumor glucose metabolism can enhance immunotherapy efficacy and outline the prospects and challenges in this field.

Traditional Chinese medicine,as a treasure of the Chinese nation,has a long history and rich cultural connotations.O-ver the past few hundred years,a large number of active compounds with clear structure,significant activity and elucidated mechanism have been discovered.Their research constitutes the material basis for traditional Chinese medicine research.However,the natural components of traditional Chinese medicine have diverse skeletons and complex structures.In addition to small molecule monomer com-pounds,more and more recent studies have found that there are new forms of material basis for traditional Chinese medicines to exert their pharmacological effects,such as supramolecules formed by active monomer compounds,and bio-macromolecules with pharmaco-logical activity.This article focuses on new forms of the material basis of traditional Chinese medicine,and through analysis of new technologies,mechanisms,and applications,it aims to provide new ideas for research on the material basis of efficacy in traditional Chinese medicine and its pharmacokinetic/pharmacodynamic correlation.

AIM:To study the effect of hepatitis B combined with hepatic fibrosis on endogenous and exogenous metabolism of liver and the effect of glycyrrhizic acid combined with tenofovir(TFV)es-ter on anti-HBV efficacy.METHODS:Hepatitis B mouse was induced by chronic CCI4 to form a mod-el of hepatitis B with hepatic fibrosis.H&E staining,Sirius Red Staining,α-SMA immunohistochemistry were used to detect pathological changes in liver tissue.The changes of liver endogenous metabo-lism in mice with hepatitis B and hepatic fibrosis were detected by metabolomics.LC-MS/MS was used to investigate the plasma and liver concentra-tions of TFV and its active metabolite(TFV-DP),for investigating the changes of exogenous metabo-lism.RESULTS:HBV+CCl4 mice showed fibrosis symptoms such as liver injury and collagen deposi-tion.Hepatitis B combined with hepatic fibrosis af-fected nucleotide metabolism,amino acid metabo-lism,tricarboxylic acid cycle,pentose phosphate pathway and other endogenous metabolism,low-ered the hepatic level of TFV-DP,and decreased the antiviral efficacy.By combining with glycyrrhizic acid or forming a self-assembled preparation,the hepatic level of TFV-DP was improved,and the anti-viral efficacy was enhanced.CONCLUSIONS:Hepati-tis B combined with hepatic fibrosis affected both endogenous and exogenous metabolism of liver.Different forms of combination of glycyrrhizic acid and TFV could elevate the level of TFV-DP in liver and improve the antiviral efficacy in HBV+CCI4 mice.

Metabolic dysfunction-associated steatotic liver disease(MASLD)is the most prevalent chronic liver disease globally,with only one Food and Drug Administration(FDA)-approved drug for its treatment.Given MASLD's complex pathophysiology,ther-apies that simultaneously target multiple pathways are highly desirable.One promising approach is dual-modulation of the famesoid X receptor(FXR),which regulates lipid and bile acid metabolism.However,FXR agonists alone are insufficient due to their limited anti-inflammatory effects.This study aimed to dto identify natural products capable of both FXR activation and inflammation inhibition to provide a comprehensive therapeutic approach for MASLD.Potential FXR ligands from the Natural Product Library were predicted via virtual screening using the Protein Preparation Wizard module in Schrodinger(2018)for molecular docking.Direct binding and regulation of candidate compounds on FXR were analyzed using surface plasmon resonance(SPR)binding assay,reporter gene ana-lysis,and reverse transcription-polymerase chain reaction(RT-PCR).The anti-inflammatory properties of these compounds were eval-uated in AML12 cells treated with tumor necrosis factor-alpha(TNF-α).Dual-function compounds with FXR agonism and inflamma-tion inhibition were further identified in cells transfected with Fxr siRNA and treated with TNF-α.The effects of these dual-function compounds on lipid accumulation and inflammation were evaluated in cells treated with palmitic acid.Results revealed that 17 natural products were predicted via computational molecular docking as potential FXR agonists,with 15 exhibiting a strong affinity for FXR recombinant protein.Nine isoflavone compounds significantly enhanced FXR reporter luciferase activity and the mRNA expressions of Shp and Ostb.Structure-activity relationship analysis indicated that introducing isopropyl or methoxy groups at the C7 position or a methoxy group at the C6 position could enhance the agonistic efficacy of isoflavones.Three compounds(2,6,and 8)were identified as dual-function natural products functioning as FXR agonists and inflammatory inhibitors,while one compound(12)acted as an FXR agonist to inhibit inflammation.These natural products protected hepatocytes against palmitic acid-induced lipid accumulation and in-flammation.In conclusion,compounds 2,6,and 8(genistein,biochanin A,and 7-methoxyisoflavone,respectively)were identified as dual-function bioactive products that transactivate FXR and inhibit inflammation,serving as potential candidates or lead compounds for MASLD therapy.

Hydrogen sulfide (H₂S) is a gas signaling molecule with versatile bioactivities; however, its exploitation for disease treatment appears challenging. This study describes the design and characterization of a novel type of H₂S donor-drug conjugate (DDC) based on the thio-ProTide scaffold, an evolution of the ProTide strategy successfully used in drug discovery. The new H₂S DDCs achieved hepatic co-delivery of H₂S and an anti-fibrotic drug candidate named hydronidone, which synergistically attenuated liver injury and resulted in more sufficient intracellular drug exposure. The potent hepatoprotective effects were also attributed to the H₂S-mediated multipronged intervention in lipid peroxidation both at the whole cellular and lysosomal levels. Lysosomal H₂S accumulation and H₂S DDC activation were facilitated by the hydrolysis through the specific lysosomal hydrolase, representing a distinct mechanism for lysosomal targeting independent of the classical basic moieties. These findings provided a novel pattern for the design of optimally therapeutic H₂S DDC and organelle-targeting functional molecules.