Network Pharmacology to Reveal the Mechanism of Fufang Banmao Capsule for Treating Unresectable Primary Liver Cancer and Clinical Data Validation.

INTRODUCTION: Fufang Banmao capsules (FFBM), a traditional Chinese medicine, has been used to treat primary liver cancer (PLC) for several years. However, the bioactive ingredients, and mechanism of FFBM for treating PLC remains unclear. Our objective is to utilize network pharmacology to investigate these aspects and subsequently validate their effectiveness through clinical data. MATERIALS AND METHODS: The FFBM ingredients were obtained from the HERB database and screened for bioactive ingredients using the SwissTargetPrediction database. The PharmMapper and GEO database were used to acquire targets and differentially expressed genes (DEGs) for FFBM and PLC, respectively. Common targets were identified using Venn diagrams, followed by enrichment and protein-protein interaction (PPI) analysis. Furthermore, the Cytoscape software was utilized to identify Hub genes and construct the ingredienttarget- pathway network. Subsequently, patients diagnosed with unresectable PLC who underwent transcatheter arterial chemoembolization (TACE) at our hospital between January 2008 and December 2019 were retrospectively collected. Finally, Cox analysis was conducted to reveal the role of FFBM in the treatment of unresectable PLC. RESULTS: FFBM had 232 targets, and PLC had 1582 DEGs. HSP90AA1 and SRC were identified as crucial targets. Alpha-santalol, glycyrrhizin, and morroniside were identified as the top three bioactive ingredients. Enrichment analysis revealed a significant connection between FFBM utilization for treating PLC and multiple pathways, such as chemical carcinogenesis, PI3K-AKT, Rap1, FoxO, MAPK, and VEGF pathway. Clinic data revealed that consuming FFBM significantly improved the prognosis of unresectable PLC with a hazard ratio of 0.69. CONCLUSION: Our study identified the bioactive ingredients of FFBM and its potential mechanisms for treating PLC. Additionally, we validated the effectiveness through clinical data.

The immunotherapy mechanism of Hedyotis Diffusae Herba in treating liver cancer: a study based on network pharmacology, bioinformatics, and experimental validation.

Liver cancer is a malignant tumor that develops on or inside the liver. Hedyotis diffusa Willd (HDW) plays a significant role in anti-tumor activities; however, its mechanism against liver cancer remains unclear. This study aims to evaluate the immunotherapeutic mechanism of HDW in treating liver cancer through network pharmacology, bioinformatics analysis, and experimental validation. Network pharmacology was utilized to identify the active components and potential targets of HDW from the TCMSP database. A potential target protein-protein interaction (PPI) network was constructed using the STRING database, followed by function and pathway enrichment analysis of the targets using GO and KEGG methods. In addition, the key targets for HDW against liver cancer were identified using five different algorithms in Cytoscape. The TCGA and HPA databases were used to assess the mRNA and protein expression of core target genes in normal liver and liver cancer tissues and their relationship with overall survival in liver cancer, as well as their role in immune infiltration. Molecular docking between the core components of HDW and the core targets was performed using PyMOL software. The effects of HDW on the proliferation and apoptosis of liver cancer cells were examined using MTT and flow cytometry. The regulatory effects of the core component quercetin on core targets were validated using RT-qPCR and Western blot. A total of 163 potential targets were identified by searching for intersections among 7 types of active components and all potential and liver cancer targets. PPI network analysis revealed the core targets IL6 and TNF. GO enrichment analysis involved 2089 biological processes, 76 cellular components, and 196 molecular functions. KEGG enrichment analysis suggested that the anti-cancer effects of HDW might be mediated by the AGE-RAGE signaling pathway, IL-17 signaling pathway, TNF signaling pathway, PI3K-Akt signaling pathway, and NF-κB signaling pathway. Database validation of key targets showed that mRNA and protein expression results for the IL6 gene were contradictory, while those for the TNF gene were consistent, both being underexpressed in liver cancer. Importantly, the expression of IL6 and TNF was related to the infiltration of 24 types of immune cells, with the highest correlation with macrophages. Molecular docking showed that IL6 and TNF had high binding stability with quercetin, with binding energies of - 7.4 and - 6.0 kJ∙mol-1, respectively. Experimental validation showed that quercetin inhibited liver cancer cell proliferation and promoted apoptosis in a dose-dependent manner, with protein results indicating that quercetin downregulated the mRNA and protein expression of IL6 and TNF, and upregulated key proteins in the AGE-RAGE signaling pathway, AGEs, and RAGE. This study comprehensively elucidates the activity, potential targets, and molecular mechanisms of HDW against liver cancer, providing a promising strategy for the scientific basis and treatment mechanism of traditional Chinese medicine in treating liver cancer.

Imperatorin attenuates CCl4-induced cirrhosis and portal hypertension by improving vascular remodeling and profibrogenic pathways.

BACKGROUND: Cirrhosis leads to portal hypertension (PHT), affecting survival with limited treatment options. This study investigated Imperatorin (IMP), a furanocoumarin with anti-inflammatory and hypotensive properties, for its therapeutic role and mechanisms in cirrhotic PHT. METHODS: Hepatic stellate cells (HSCs) inhibition by IMP was evaluated using LX-2 cell line. Rat cirrhosis was induced via CCl4 for 16 weeks. Experimental group were orally administered IMP (15/25 mg/kg/day) for 4 weeks. We subsequently examined portal pressure (PP), cirrhosis, inflammation, angiogenesis, and vascular remodeling. Network pharmacology was employed for mechanistic insights. RESULTS: IMP significantly inhibited the fibrogenesis in HSCs and suppressed cell viability. CCl4 exposure induced cirrhosis, inflammation, angiogenesis, vascular remodeling and PHT. IMP significantly reduced PP from 22.85±3.88 mmHg to 6.67±0.6 mmHg, diminished collagen deposition and pro-fibrotic factor expression, alleviated inflammation, and improved liver function. Vessel wall thickness in superior mesenteric arteries was restored, and intra-/extrahepatic angiogenesis was inhibited via VEGF and vWF. Furthermore, IMP induced sinusoidal vasodilation by upregulating eNOS and GCH1. Enrichment analysis indicated that IMP was involved in various biological processes associated with cirrhosis, such as the regulation of blood pressure, tissue remodeling, response to inflammation, and regulation of angiogenesis, etc. Additionally, IMP suppressed hepatic expression of TGF-ß both in vitro and in vivo, which was further supported by KEGG analysis. CONCLUSION: Our research demonstrated that IMP significantly mitigated cirrhosis PHT by reducing hepatic fibrosis and inflammation, curbing angiogenesis and vascular remodeling, and promoting vasodilation. This protective mechanism appears to be facilitated through the downregulation of TGF-ß.

Vitreoretinal surgical performance after acute alcohol consumption and hangover.

AIM: Routine alcohol testing of practicing physicians remains controversial since there are no uniform guidelines or legal regulations in the medical field. Our aim was to quantitatively study the acute and next-morning effects of breath alcohol concentration (BAC)-adjusted alcohol intake on overall simulated surgical performance and microtremor among senior vitreoretinal surgeons. METHODS: This prospective cohort study included 11 vitreoretinal surgeons (>10 years practice). Surgical performance was first assessed using the Eyesi surgical simulator following same-day alcohol consumption producing a BAC reading of 0.06%-0.10% (low-dose), followed by 0.11%-0.15% (high-dose). Dexterity was then evaluated after a 'night out' producing a high-dose BAC combined with a night's sleep. Changes in the total score (0-700, worst-best) and tremor (0-100, best-worst) were measured. RESULTS: Surgeon performance declined after high-dose alcohol compared with low-dose alcohol (-8.60±10.77 vs -1.21±7.71, p=0.04, respectively). The performance during hangover was similar to low-dose alcohol (-1.76±14.47 vs -1.21±7.71, p=1.00, respectively). The performance during hangover tended to be better than after high-dose alcohol (-1.76±14.47 vs -8.60±10.77, p=0.09, respectively). Tremor increased during hangover compared with low-dose alcohol (7.33±21.65 vs -10.31±10.73, p=0.03, respectively). A trend toward greater tremor during hangover occurred compared with high-dose alcohol (7.33±21.65 vs -4.12±17.17, p=0.08, respectively). CONCLUSION: Alcohol-related decline in simulated surgical dexterity among senior vitreoretinal surgeons was dose-dependent. Dexterity improved the following morning but remained comparable to after low-dose alcohol ingestion. Tremor increased during hangover compared with same-day intoxication. Further studies are needed to investigate extrapolations of these data to a real surgical environment regarding patient safety and surgeon performance.

Application of network pharmacology in traditional Chinese medicine for the treatment of digestive system diseases.

With the general improvement in living standards in recent years, people's living habits, including their dietary habits, have changed. More people around the world do not follow a healthy diet, leading to an increase in morbidity and even mortality due to digestive system diseases, which shows an increasing trend every year. The advantage of traditional Chinese medicine (TCM) in treating digestive system diseases is evident. Consequently, the mechanisms of action of single Chinese herbs and compound Chinese medicines have become the focus of research. The research method of the network pharmacology system was highly consistent with the holistic concept of TCM, and provided a new perspective and theoretical basis for basic research on digestive system diseases. This article summarizes the common databases currently used in research on TCM. It also briefly introduces the basic methods and technologies of network pharmacology studies. It also summarizes the advancements of network pharmacology technology through a comprehensive literature search on PubMed. Based on this analysis, we further explored the role of TCM in treating digestive system diseases, including chronic gastritis, gastric cancer, ulcerative colitis, and liver cirrhosis. This study provides new ideas and references for treating digestive system diseases with TCM in the future and serves as a reference for relevant researchers.

Photo-activated microtubule targeting drugs: Advancing therapies for colorectal cancer.

Over the years immunotherapy has demonstrably improved the field of cancer treatment. However, achieving long-term survival for colorectal cancer (CRC) patients remains a significant unmet need. Combination immunotherapies incorporating targeted drugs like MEK or multi-kinase inhibitors have offered some palliative benefit. Nevertheless, substantial gaps remain in the current therapeutic armamentarium for CRC. In recent years, there has been a surge of interest in exploring novel treatment strategies, including the application of light-activated drugs in conjunction with optical devices. This approach holds promise for achieving localized and targeted delivery of cytotoxic agents, such as microtubule-targeting drugs, directly to cancerous cells within the colon.

Network pharmacology-based exploration of molecular mechanisms underlying therapeutic effects of Jianpi Huatan Quyu recipe on chronic heart failure with spleen Qi deficiency syndrome.

BACKGROUND: Chronic heart failure is a complex clinical syndrome. The Chinese herbal compound preparation Jianpi Huatan Quyu recipe has been used to treat chronic heart failure; however, the underlying molecular mechanism is still not clear. AIM: To identify the effective active ingredients of Jianpi Huatan Quyu recipe and explore its molecular mechanism in the treatment of chronic heart failure. METHODS: The effective active ingredients of eight herbs composing Jianpi Huatan Quyu recipe were identified using the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform. The target genes of chronic heart failure were searched in the Genecards database. The target proteins of active ingredients were mapped to chronic heart failure target genes to obtain the common drug-disease targets, which were then used to construct a key chemical component-target network using Cytoscape 3.7.2 software. The protein-protein interaction network was constructed using the String database. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses were performed through the Metascape database. Finally, our previously published relevant articles were searched to verify the results obtained via network pharmacology. RESULTS: A total of 227 effective active ingredients for Jianpi Huatan Quyu recipe were identified, of which quercetin, kaempferol, 7-methoxy-2-methyl isoflavone, formononetin, and isorhamnetin may be key active ingredients and involved in the therapeutic effects of TCM by acting on STAT3, MAPK3, AKT1, JUN, MAPK1, TP53, TNF, HSP90AA1, p65, MAPK8, MAPK14, IL6, EGFR, EDN1, FOS, and other proteins. The pathways identified by KEGG enrichment analysis include pathways in cancer, IL-17 signaling pathway, PI3K-Akt signaling pathway, HIF-1 signaling pathway, calcium signaling pathway, cAMP signaling pathway, NF-kappaB signaling pathway, AMPK signaling pathway, etc. Previous studies on Jianpi Huatan Quyu recipe suggested that this Chinese compound preparation can regulate the TNF-α, IL-6, MAPK, cAMP, and AMPK pathways to affect the mitochondrial structure of myocardial cells, oxidative stress, and energy metabolism, thus achieving the therapeutic effects on chronic heart failure. CONCLUSION: The Chinese medicine compound preparation Jianpi Huatan Quyu recipe exerts therapeutic effects on chronic heart failure possibly by influencing the mitochondrial structure of cardiomyocytes, oxidative stress, energy metabolism, and other processes. Future studies are warranted to investigate the role of the IL-17 signaling pathway, PI3K-Akt signaling pathway, HIF-1 signaling pathway, and other pathways in mediating the therapeutic effects of Jianpi Huatan Quyu recipe on chronic heart failure.

Unlocking the potential of edible Ulva sp. seaweeds: Metabolomic profiling, neuroprotective mechanisms, and implications for Parkinson's disease management.

Green seaweed (Ulva sp.) is frequently used as a food component and nutraceutical agent because of its high polysaccharide and natural fiber content in Asian countries. This study investigates both metabolomic profiling of Ulva sp. and the neuroprotective efficacy of its ethanol extract and its underlying mechanisms in a rotenone-induced rat model of neurodegeneration, mimicking Parkinson's disease (PD) in humans. Metabolomic profiling of Ulva sp. extract was done using liquid chromatography high resolution electrospray ionization mass spectrometry and led to the identification of 22 compounds belonging to different chemical classes.Catenin Beta Additionally, this study demonstrated the neuroprotective properties against rotenone-induced PD, which was achieved through the suppression of elevated levels of tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), and IL-6 together with the inhibition of reactive oxygen species (ROS) generation, apoptosis, inflammatory mediators, and the phosphoinositide 3-kinases/serine/threonine protein kinase (PI3K/AKT) pathway. Using a protein-protein interaction network, AKT1, GAPDH, TNF-α, IL-6, caspase 3, signal transducer and activator of transcription 3, Catenin Beta 1, epidermal growth factor receptor, B-cell lymphoma -2, and HSP90AA1 were identified as the top 10 most significant genes. Finally, molecular docking results showed that compounds 1, 3, and 7 might possess a promising anti-parkinsonism effect by binding to active sites of selected hub genes. Therefore, it is hypothesized that the Ulva sp. extract has the potential to be further developed as a potential therapeutic agent for the treatment of PD.

The protective effects of aqueous extract of Schisandra sphenanthera against alcoholic liver disease partly through the PI3K-AKT-IKK signaling pathway.

Purpose: This study aimed to investigated the key chemical components and the effect of the aqueous extract of Schisandra sphenanthera (SSAE) on alcoholic liver disease (ALD) and the related molecular mechanism. Methods: This study employed UPLC-Q-TOF-MS/MS to identify the chemical compositions in SSAE. ALD rat model was established through oral administration of white spirit. Transcriptome sequencing, weighted gene co-expression network construction analysis (WGCNA), and network pharmacology were used to predict key compositions and pathways targeted by SSAE for the treatment of ALD. Enzyme-linked immunosorbent assay (ELISA), biochemical kits, hematoxylin-eosin (HE) staining, Western blotting (WB) analysis, and immunohistochemical analysis were used to validate the mechanism of action of SSAE in treating ALD. Results: Active ingredients such as schisandrin A, schisandrol A, and schisandrol B were found to regulate the PI3K/AKT/IKK signaling pathway. Compared to the model group, the SSAE group demonstrated significant improvements in cellular solidification and tissue inflammation in the liver tissues of ALD model rats. Additionally, SSAE regulated the levels of a spartate aminotransferase (AST), alanine aminotransferase (ALT), alcohol dehydrogenase (ADH), and aldehyde Dehydrogenase (ALDH) in serum (P < 0.05); Western blotting and immunohistochemical analyses showed that the expression levels of phosphorylated PI3K, AKT, IKK, NFκB, and FOXO1 proteins were significantly reduced in liver tissues (P < 0.05), whereas the expression level of Bcl-2 proteins was significantly increased (P < 0.05). Conclusion: The active components of SSAE were schisandrin A, schisandrol A, and schisandrol B, which regulated the phosphorylation levels of PI3K, AKT, IKK, and NFκB and the expression of FOXO1 protein and upregulated the expression of Bcl-2 protein in the liver tissues of ALD rats. These findings indicate that SSAE acts against ALD partly through the PI3K-AKT-IKK signaling pathway. This study provided a reference for future research and treatment of ALD and the development of novel natural hepatoprotective drugs.

Medicinal polypharmacology-a scientific glossary of terminology and concepts.

Medicinal polypharmacology is one answer to the complex reality of multifactorial human diseases that are often unresponsive to single-targeted treatment. It is an admittance that intrinsic feedback mechanisms, crosstalk, and disease networks necessitate drugs with broad modes-of-action and multitarget affinities. Medicinal polypharmacology grew to be an independent research field within the last two decades and stretches from basic drug development to clinical research. It has developed its own terminology embedded in general terms of pharmaceutical drug discovery and development at the intersection of medicinal chemistry, chemical biology, and clinical pharmacology. A clear and precise language of critical terms and a thorough understanding of underlying concepts is imperative; however, no comprehensive work exists to this date that could support researchers in this and adjacent research fields. In order to explore novel options, establish interdisciplinary collaborations, and generate high-quality research outputs, the present work provides a first-in-field glossary to clarify the numerous terms that have originated from various individual disciplines.

Sargassum pallidum reduces inflammation to exert antidepressant effect by regulating intestinal microbiome and ERK1/2/P38 signaling pathway.

Immune inflammation is one of the main factors in the pathogenesis of depression. It is an effective and active way to find more safe and effective anti-inflammatory depressant drugs from plant drugs. The purpose of this study is to explore the potential of marine plant Sargassum pallidum (Turn).C.Ag. (Haihaozi, HHZ) in the prevention and treatment of depression and to explain the related mechanism. Phytochemical analysis showed that alkaloids, terpenes, and organic acids are the main constituents. In vitro and in vivo activity studies showed the anti-neuroinflammatory and antidepressant effect of Sargassum pallidum, furthermore, confirmed that 7-Hydroxycoumarin, Scoparone, and Kaurenoic Acid are important plant metabolites in Sargasum pallidum for anti-neuroinflammation. Mechanism exploration showed that inhibition of ERK1/2/p38 inflammatory signaling pathway contributing to the antidepressant effect of Sargassum pallidum in reducing intestinal inflammatory levels. This study confirmed the value of Sargassum pallidum and its rich plant metabolites in anti-inflammatory depression, providing a new choice for the follow-up research and development of antidepressant drugs.

Integrated network pharmacology and experimental verification to reveal the role of Shezhi Huangling Decoction against glioma by inactivating PI3K/Akt-HIF1A axis.

Shezhi Huangling Decoction (SHD) has been proven clinically effective in regulating metabolic and immune homeostasis in the treatment of glioma. The investigation aimed to deconstruct the active constituents and mechanisms of SHD. Effects of SHD on malignant characteristics of HS683 and KNS89 cells have been investigated by CCK-8, clone formation, flow cytometry, and Transwell assays. A mouse xenograft model was established to assess the effect of SHD or SHD + temozolomide (TMZ) in vivo. A total of 461 constituents were found from SHD in UPLC/Q-TOF-MS/MS analysis. Functional enrichment analysis showed that pathway in cancer, proteoglycans in cancer, regulation of epithelial cell proliferation, inflammation/immune, gliogenesis, brain development, cell adhesion, and autophagy could participate in the treatment of SHD. Additionally, 9 hub genes (AKT1, TP53, CTNNB1, STAT3, EGFR, VEGFA, PIK3CA, ERBB2, and HIF1A) were identified as hub genes. Moreover, we found that SHD may greatly reduce the migration and accelerate apoptosis of HS683 and KNS89 cells. Additionally, SHD coordinates TMZ to restrict tumor growth were found in the mice. Our results suggest that the malignant behaviors of glioma cells are suppressed by SHD and the mechanism may be closing on the inhibition of the PI3K/Akt-HIF1A axis. SHD may serve as a synergistic therapeutic choice for TMZ to suppress glioblastoma growth.

Unveiling the therapeutic potential of epigallocatechin gallate in liver cancer: insights from network pharmacology and in vitro assays.

Epigallocatechin gallate (EGCG) is a prominent catechin found in green tea polyphenols and has shown promising anti-tumor properties. However, the exact regulatory mechanism of EGCG on liver cancer is not fully revealed. In this study, we conducted integrative analyses using the SwissTargetPrediction and GeneCards repositories, which identified 98 targets. These targets were used to construct a protein-protein interaction network using STRING and visualised with Cytoscape. Central to this network are hub proteins, notably TNF and PIK3CA, suggesting pivotal roles in the therapeutic landscape. Gene Ontology (GO) enrichment analysis unveiled 1,570 biological terms with a notable preponderance within oxidative stress response processes. Complementary pathway enrichment via the Kyoto Encyclopaedia of Genes and Genomes (KEGG) highlighted 134 pathways, with the PI3K-Akt pathway emerging as prominent. In silico molecular docking supported these findings, revealing binding energies of EGCG-target complexes below -7.0 kcal/mol, indicative of robust interactions. Moreover, cellular assays including CCK-8, wound-healing, and Transwell modalities, established EGCG's inhibitory concentration-dependent effects on HepG2 cell proliferation, migration, and invasion. Apoptotic assays affirmed by FACS, evidenced enhanced apoptosis with escalating EGCG concentrations, underpinned by modulations in caspase activity and apoptotic protein levels. Notably, Western blot analysis demonstrated the attenuation of the PI3K/AKT signalling cascade by EGCG, paralleling the inhibitory profile of LY294002. These multifaceted inhibitory effects underscore EGCG's potential as an anti-tumor agent, deploying a strategic blockade of oncogenic pathways and augmenting apoptotic mechanisms, which provide a strong rationale for its application in liver cancer therapeutics.

Metabolomics and molecular dynamics unveil the therapeutic potential of epalrestat in diabetic nephropathy.

Diabetic nephropathy (DN) is one of the leading clinical causes of end-stage renal failure. The classical aldose reductase (AR) inhibitor epalrestat shows beneficial effect on renal dysfunction induced by DN, with metabolic profile and molecular mechanisms remains to be investigated further. In the current study, integrated untargeted metabolomics, network pharmacology and molecular dynamics approaches were applied to explore the therapeutic mechanisms of epalrestat against DN. Firstly, untargeted serum and urine metabolomics analysis based on UPLC-Q-TOF-MS was performed, revealed that epalrestat could regulate the metabolic disorders of amino acids metabolism, arachidonic acid metabolism, pyrimidine metabolism and citrate cycle metabolism pathways after DN. Subsequently, metabolomics-based network analysis was carried out to predict potential active targets of epalrestat, mainly involving AGE-RAGE signaling pathway, TNF signaling pathway and HIF-1 signaling pathway. Moreover, a 100 ns molecular dynamics approach was employed to validate the interactions between epalrestat and the core targets, showing that epalrestat could form remarkable tight binding with GLUT1 and NFκB than it with AR. Surface-plasmon resonance assay further verified epalrestat could bind GLUT1 and NFκB proteins specifically. Overall, integrated system network analysis not only demonstrated that epalrestat could attenuate DN induced metabolic disorders and renal injuries, but also revealed that it could interact with multi-targets to play a synergistic regulatory role in the treatment of DN.

Effect of vascular senescence on the efficacy and safety of warfarin: insights from rat models and a prospective cohort study.

Warfarin, with its narrow therapeutic range, requires the understanding of various influencing factors for personalized medication. Vascular senescence, marked by vascular stiffening and endothelial dysfunction, has an unclear effect on the efficacy and safety of warfarin. Based on previous studies, we hypothesized that vascular senescence increases the risk of bleeding during warfarin therapy. This study aimed to explore these effects using animal models and clinical cohorts. We established rat models of vascular senescence and calcification using d-galactose (D-Gal), vitamin D and nicotine (VDN). After validating the models, we examined changes in the International Normalized Ratio (INR) at fixed warfarin doses (0.20 and 0.35 mg/kg). We found that vascular senescence caused significantly elevated INR values and increasd bleeding risk. In the prospective clinical cohort study(NCT06428110), hospitalized warfarin patients with standard dose adjustments were divided into vascular senescence and control groups based on ultrasound and Computed Tomography (CT) diagnosis. Using propensity score matching (PSM) to exclude the influence of confounding factors, we found that the vascular senescence group had lower steady-state warfarin doses and larger dose adjustments, with a higher probability of INR exceeding the therapeutic range. The vascular senescence group tended to experience more bleeding or thromboembolic/ischemic events during one year of follow-up, while there was no statistical difference. In conclusion, vascular senescence leads to unstable INR values and increases higher bleeding risk during warfarin therapy, highlighting the importance of considering vascular senescence in future precision warfarin therapies. Significance Statement Many factors influence warfarin efficacy, however, the effect of vascular senescence remains unclear. This study aimed to investigate the effects of vascular senescence on the efficacy and safety of warfarin. Through both rat models and clinical cohort studies, our findings indicated that vascular senescence may compromise the stability of warfarin, presenting challenges in maintaining its efficacy and safety.

Exploring the mechanism of Lianhuaqingwen (LHQW) in treating chronic bronchitis based on network pharmacology and experimental validation.

BACKGROUND: Lianhuaqingwen (LHQW) has been used in the treatment of chronic bronchitis, but the precise mechanism through which LHQW exhibits its anti-inflammatory effects in this context is not yet fully understood. The aim of this study was to investigate the active ingredients and signaling pathways responsible for LHQW's effectiveness in managing chronic bronchitis. METHODS: The research leveraged the TCMSP database to determine the active compounds and drug targets of LHQW. In parallel, the GeneCards, DrugBank, and PharmGkb databases were used to uncover targets pertinent to chronic bronchitis. To discern the potential mechanisms by which LHQW's active ingredients might treat chronic bronchitis, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed. Network pharmacology facilitated the construction of a drug-active ingredient-disease target network, aiding in forecasting the core targets for chronic bronchitis treatment by LHQW. Subsequently, molecular docking techniques alongside in vitro experiments were applied to confirm the interactions between the active ingredients and the primary targets. RESULTS: A total of 157 active ingredients, 225 potential drug targets, and 594 bronchitis-related targets were derived from various databases. Following this, 76 potential gene targets were pinpointed by integrating drug and related targets. GO and KEGG enrichment analyses were employed to identify key pathways involved in LHQW's mechanism for treating chronic bronchitis. By constructing a protein-protein interaction (PPI) network for the 76 potential gene targets, four core targets (TNF, IL6, IFNG, and STAT3) were identified as primarily involved in responses to lipopolysaccharide, the TNF pathway, and the JAK-STAT pathway. Molecular docking results revealed a favorable affinity between multiple active ingredients of LHQW and the four core targets, suggesting that the therapeutic effects are mediated through the inhibition of inflammatory responses and signaling pathways. Interestingly, quercetin, an active ingredient of LHQW, was observed to bind to all four core targets simultaneously. Furthermore, cell experiment and western blot analysis indicated that both LHQW and quercetin exhibit anti-inflammatory effects by targeting the four core proteins and the JAK-STAT pathways. CONCLUSION: This research emphasizes the diverse active ingredients, targets, channels, and pathways of LHQW in the treatment of chronic bronchitis, providing important perspectives for the creation of novel therapeutic drugs and clinical uses.

Light in evaluation of molecular diffusion in tissues: Discrimination of pathologies.

The evaluation of the diffusion properties of different molecules in tissues is a subject of great interest in various fields, such as dermatology/cosmetology, clinical medicine, implantology and food preservation. In this review, a discussion of recent studies that used kinetic spectroscopy measurements to evaluate such diffusion properties in various tissues is made. By immersing ex vivo tissues in agents or by topical application of those agents in vivo, their diffusion properties can be evaluated by kinetic collimated transmittance or diffuse reflectance spectroscopy. Using this method, recent studies were able to discriminate the diffusion properties of agents between healthy and diseased tissues, especially in the cases of cancer and diabetes mellitus. In the case of cancer, it was also possible to evaluate an increase of 5% in the mobile water content from the healthy to the cancerous colorectal and kidney tissues. Considering the application of some agents to living organisms or food products to protect them from deterioration during low temperature preservation (cryopreservation), and knowing that such agent inclusion may be reversed, some studies in these fields are also discussed. Considering the broadband application of the optical spectroscopy evaluation of the diffusion properties of agents in tissues and the physiological diagnostic data that such method can acquire, further studies concerning the optimization of fruit sweetness or evaluation of poison diffusion in tissues or antidote application for treatment optimization purposes are indicated as future perspectives.

Surveillance of antibiotics use in inpatients at Benjamin Mkapa Zonal Referral Hospital in Dodoma, Tanzania: a point prevalence survey.

OBJECTIVE: To assess antibiotics prescribing and use patterns for inpatients at Benjamin Mkapa Zonal Referral Hospital (BMH) using the WHO-Point Prevalence Survey (WHO-PPS). DESIGN: A cross-sectional survey. SETTING: The Benjamin Mkapa Zonal Referral Hospital, Dodoma, Tanzania. PARTICIPANTS: Inpatient prescriptions, regardless of whether antibiotics were prescribed (n=286) on the day of PPS. OUTCOME MEASURES: Our study analysed the prevalence of antibiotic use at BMH for inpatients, the type of antibiotics used, the indications for use and the proportion of oral and parenteral antibiotics. We also assessed prescription-prescribed antibiotics after a positive antimicrobial susceptibility testing (AST) result. RESULTS: A survey was conducted on 286 prescriptions, which revealed that 30.07% of them included antibiotics. On average, each prescription contained at least 1.6 antibiotics. All prescriptions that included antibiotics were written in generic names, and 77.91% (67/86) of them followed the Standard Treatment Guidelines. Of the prescriptions that included antibiotics, 58.14% (50/86) had a single antibiotic, 20.93% (18/86) had parenteral antibiotics and 79.07% (68/86) had oral antibiotics. Based on AWaRe's (Access, Watch and Reserve) categorisation of antibiotics, 50% (8/16) were in the Access group, 31.25% (5/16) were in the Watch group, 12.50% (2/16) were in the Reserve group and 6.25% (1/16) were not recommended antimicrobial combinations. Out of 86 prescriptions included antibiotics, only 4.65% showed positive culture growth. However, antibiotics were still prescribed in 29.07% of prescriptions where there was no growth of bacteria, and in 66.28% of prescriptions, antibiotics were prescribed empirically without any requesting of bacteria culture and AST. CONCLUSION: BMH has reduced inpatient Antibiotic Use by half compared with the 2019 WHO-PPS. Adherence to National Treatment Guidelines is suboptimal. Clinicians should use AST results to guide antibiotic prescribing.