Integration of network pharmacology, UHPLC-Q exactive orbitrap HRMS technique and metabolomics to elucidate the active ingredients and mechanisms of compound danshen pills in treating hypercholesterolemic rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Hypercholesterolemia (HLC) was a key risk factor for cardiovascular disease (CVD) characterized by elevated cholesterol levels, particularly LDL. While traditional Chinese medicine preparations Compound Danshen Pills(CDP) has been clinically used for hypercholesterolemia and coronary heart disease, its specific therapeutic effect on HLC remains understudied, necessitating further investigation into its mechanisms. AIM OF THE STUDY: The aim of this study was to explore the potential of CDP in treating HLC and elucidate its underlying mechanisms and active components. MATERIALS AND METHODS: A hypercholesterolemic lipemia rat model induced by a high-fat diet was employed. Network pharmacology combined with UHPLC-Q exactive orbitrap HRMS technique was used to predict the active components, targets and mechanisms of CDP for HLC. Histological analysis and serum biochemical assays were used to assess the therapeutic effect of CDP and its main active ingredient Sa B on hypercholesterolemic lipemia rat model. Immunofluorescence assays and western blotting were used to verify the mechanism of CDP and Sa B in the treatment of HLC. Metabolomics approach was used to demonstrate that CDP and Sa B affected the metabolic profile of HLC. RESULTS: Our findings demonstrated that both CDP and its main active ingredient Sa B significantly ameliorated hypercholesterolemic lipemic lesions, reducing levels of TC, LDL, AST, ALT, and ALP. Histological analysis revealed a decrease in lipid droplet accumulation and collagen fiber deposition in the liver, as well as reduced collagen fiber deposition in the aorta. Network pharmacology predicted potential targets such as PPARα and CYP27A1. Immunofluorescence assays and western blotting confirmed that CDP and Sa B upregulated the expression of Adipor1, PPARα and CYP27A1. Metabolomics analyses further indicated improvements in ABC transporters metabolic pathways, with differential metabolites such as riboflavin, taurine, and choline showed regression in levels after CDP treatment and riboflavin, L-Threonine, Thiamine, L-Leucine, and Adenosine showed improved expression after Sa B treatment. CONCLUSION: CDP and Sa B have been shown to alleviate high-fat diet-induced hypercholesterolemia by activating the PPAR pathway and improving hepatic lipid metabolism. Our study demonstrated, for the first time, the complex mechanism of CDP, Sa B in the treatment of hypercholesterolemia at the protein and metabolic levels and provided a new reference that could elucidate the pharmacological effects of traditional Chinese medicine on hypercholesterolemia from multiple perspectives.

Profiling of antioxidant properties and identification of potential analgesic inhibitory activities of Allophylus villosus and Mycetia sinensis employing in vivo, in vitro, and computational techniques.

ETHNOPHARMACOLOGICAL RELEVANCE: The traditional use of plants for medicinal purposes, called phytomedicine, has been known to provide relief from pain. In Bangladesh, the Chakma indigenous community has been using Allophylus villosus and Mycetia sinensis to treat various types of pain and inflammation. AIM OF THE STUDY: The object of this research is to evaluate the effectiveness of these plants in relieving pain and their antioxidant properties using various approaches such as in vitro, in vivo, and computational techniques. Additionally, the investigation will also analyse the phytochemicals present in these plants. MATERIALS AND METHODS: We conducted in vivo analgesic experiment on Swiss albino mice and in-silico inhibitory activities on COX-2 & 15-LOX-2 enzymes. Assessment of DPPH, Anti Radical Activities (ARA), FRAP, H2O2 Free Radical Scavenging, Reducing the power of both plants performed significant % inhibition with tolerable IC50. Qualitative screening of functional groups of phytochemicals was précised by FTIR and GC-MS analysis demonstrated phytochemical investigations. RESULTS: The ethyl acetate (EtOAc) fractioned Mycetia sinensis extract as well as the ethanoic extract and all fractioned extracts of Allophylus villosus have reported a significant percentage (%) of writhing inhibition (p < 0.05) with the concentrated doses 250 mg as well as 500 mg among the Swiss albino mice for writhing observation of analgesic effect. In the silico observation, a molecular-docking investigation has performed according to GC-MS generated 43 phyto-compounds of both plants to screen their binding affinity by targeting COX-2 and 15-LOX-2 enzymes. Consequently, in order to assess and ascertain the effectiveness of the sorted phytocompounds, ADMET (Absorption, Distribution, Metabolism, Excretion, and Toxicity) investigation, DFT (Density-functional theory) by QM (Quantum mechanics), and MDS (Molecular dynamics simulation) were carried out. As the outcome, compounds like 5-(2,4-ditert-butylphenoxy)-5-oxopentanoic acid; 2,4-ditert-butylphenyl 5-hydroxypentanoate; 3,3-diphenyl-5-methyl-3H-pyrazole; 2-O-(6-methylheptan-2-yl) 1-O-octyl benzene-1,2-dicarboxylate and dioctan-3-yl benzene-1,2-dicarboxylate derived from the ethnic plant A. villosus and another ethnic plant M. sinensis extracts enchants magnificent analgesic inhibitions and performed more significant drug like activities with the targeted enzymes. CONCLUSIONS: Phytocompounds from A. villosus & M. sinensis exhibited potential antagonist activity against human 15-lipoxygenase-2 and cyclooxygenase-2 proteins. The effective ester compounds from these plants performed more potential anti-nociceptive activity which could be used as a drug in future.

Taurolidine-containing solution for reducing cardiac implantable electronic device infection-early report from the European TauroPace™ registry.

INTRODUCTION: Infection is a significant complication of cardiac implantable electronic device (CIED) therapy. The European TauroPace™ Registry investigates the safety and efficacy of TauroPace™ (TP), an antimicrobial solution containing taurolidine, designed to prevent CIED infections. METHODS: This multicenter study included patients undergoing CIED procedures at participating centers where TP was used as a disinfectant for external hardware surfaces and an antiseptic for irrigating surgical sites. All patients eligible for CIED placement with adjunctive TP as the standard of care were included. Other aspects of CIED procedures adhered to current guidelines. Data on CIED-related infective endocarditis, CIED pocket infection, device and procedure-related complications, adverse events, and all-cause mortality were prospectively collected for 12 months. In cases of revision, the previous procedure was censored, and a new procedure was created. Binomial and Kaplan-Meier statistics were employed to analyze event rates. RESULTS: From January 2020 to November 2022, TP was used in 822 out of 1170 CIED procedures. Among patients who completed the 3-month follow-up, no CIED pocket infections were observed, and one case of CIED-related infective endocarditis was reported. In the 12-month follow-up cohort, two additional local pocket CIED infections were observed, resulting in a total of three major CIED infections within 1 year after the CIED placement procedure. The 3-month and 12-month major CIED infection rates were 0.125% and 0.51%, respectively. During the observation a complication rate of 4.4% was reported. No adverse events related to TP were observed. CONCLUSIONS: TP appears to be effective and safe in preventing CIED infections. CLINICALTRIALS: gov Identifier: NCT04735666.

Urolithin A promotes the degradation of TMSB10 to deformation F-actin in non-small-cell lung cancer.

BACKGROUND: Lung cancer is one of the most frequently diagnosed cancers and non-small-cell lung cancer (NSCLC) poses major diagnoses. Urolithin A (UA) is a natural compound produced by the gut microbiota through the metabolism of polyphenol ellagitannins (ETs) and ellagic acid (EA), which has been found to inhibit epithelial-mesenchymal transition (EMT) in lung cancer cell lines. However, the mechanism of UA function in NSCLC remains elusive. PROPOSE: This study aimed to investigate the potential effectiveness of UA in NSCLC therapeutic and uncovering its underlying mechanisms. METHODS: Effects of UA treatment, TMSB10 gene knockdown or overexpression on NSCLC cell phenotype were evaluated by availability, transwell assays. The downstream factors and pathways of UA were investigated by proteomics. TMSB10 expression in NSCLC tissues was detected by bioinformatics analysis as well as immunohistochemistry. Confocal imaging, GST pull-down and western blotting investigated the mechanism of UA induced TMSB10 degradation. RESULTS: In the present study, we demonstrated that UA shows an inhibitory role in NSCLC cell proliferation, migration, and invasion. This inhibition is attributed to the accelerated degradation of TMSB10, a biomarker among various cancers, via the autophagy-lysosome pathway. Additionally, knocked down of TMSB10 showed a similar phenotype with UA treatment. The reduction of TMSB10 protein level following decreased ATP level inhibits the F-actin formation for cell migration, thereby disrupting the equilibrium between G-actin-TMSB10 and G-actin-ATP interactions in A549 cells. CONCLUSION: Our results reveal that UA is potential for NSCLC therapeutics through reducing the protein level of TMSB10 to deformation the F-actin.

Impact of compound warm and wet events on dengue fever infection in South and Southeast Asian countries.

BACKGROUND: Multiple studies have reported the profound influence of various climate factors on dengue fever infection, while the effects of joint exposure to warm and wet environment, a condition favouring dengue vectors, on disease transmission were less evaluated. This study aims to investigate the impact of various compound temperature, rainfall, and relative humidity exposures on dengue fever infection in the South and Southeast Asia regions. METHODS: Weekly dengue fever surveillance data from 2012 to 2020 were collected from 48 locations in four countries named Singapore (1 location), Sri Lanka (15 locations), Malaysia (9 locations), and Thailand (23 locations, with 11 locations having different study periods). The distributed lag non-linear models were built to assess the impacts of compound temperature, rainfall, and relative humidity on dengue fever infection risks. RESULTS: A total of 1,359,993 dengue fever cases were reported with 9.33%, 24.02%, 48.73, and 17.91% cases were contributed by Singapore, Sri Lanka, Malyaia, and Thailand, respectively. Compared to non-warm-non-wet, compound warm-wet was associated with an increased dengue risk (RR:1.36, 95% CI:1.24-1.44). Compared to moderate temperature-humidity, warm-wet environment was also associated with an increase in dengue risk (RR:1.37, 95% CI:1.22-1.55). In comparison to weeks with moderate temperature-rainfall, warm-wet weeks was linked to an elevated dengue risk (RR:1.39, 95% CI:1.27-1.52), whereas cold-dry weather would significantly reduce the infection risk (RR:0.62, 95% CI:0.62-0.80). Modification effects showed that the hot effect on dengue infection was more pronounced under higher humidity, while the impact of rainfall increased with warmer temperature. CONCLUSION: Warm-wet events were associated with increased dengue fever risk, while the infection risk would decline in cold-dry environment, and modification effects exist among exposures . Findings from this study highlight the importance of considering joint temperature, humidity, and rainfall dependency of dengue fever infection in disease prevention and control.

A comprehensive review on the potential of coumarin and related derivatives as multi-target therapeutic agents in the management of gynecological cancers.

Current treatments for gynecological cancers include surgery, radiotherapy, and chemotherapy. However, these treatments often have significant side effects. Phytochemicals, natural compounds derived from plants, offer promising anticancer properties. Coumarins, a class of benzopyrone compounds found in various plants like tonka beans, exhibit notable antitumor effects. These compounds induce cell apoptosis, target PI3K/Akt/mTOR signaling pathways, inhibit carbonic anhydrase, and disrupt microtubules. Additionally, they inhibit tumor multidrug resistance and angiogenesis and regulate reactive oxygen species. Specific coumarin derivatives, such as auraptene, praeruptorin, osthole, and scopoletin, show anti-invasive, anti-migratory, and antiproliferative activities by arresting the cell cycle and inducing apoptosis. They also inhibit metalloproteinases-2 and -9, reducing tumor cell migration, invasion, and metastasis. These compounds can sensitize tumor cells to radiotherapy and chemotherapy. Synthetic coumarin derivatives also demonstrate potent antitumor and anticancer activities with minimal side effects. Given their diverse mechanisms of action and minimal side effects, coumarin-class phytochemicals hold significant potential as therapeutic agents in gynecological cancers, potentially improving treatment outcomes and reducing side effects. This review will aid in the synthesis and development of novel coumarin-based drugs for these cancers.

Interaction and dynamic changes of microbial communities and volatile flavor compounds during the fermentation process of coffee flower rice wine.

To develop a unique flavor of rice wine, coffee flowers (by-products of the coffee industry) were added because of their biologically active compounds that are conducive to health, and the fermentation parameters were optimized. In addition, the dynamic changes of microbial communities and volatile flavor compounds (VFCs) during the different fermentation stages were investigated. After the optimization of the fermentation parameters, a novel product, i.e., the coffee flower rice wine (CFRW), was obtained with a bright yellow transparent, fragrant, and harmonious aroma and mellow and refreshing taste by sensory evaluation, when 4.62% of the coffee flowers and 1.93% koji were added and fermented at 24.10°C for 3.88 days. The results showed that Lactococcus was the dominant bacteria, accounting for 87.0-95.7%, while Rhizopus and Cladosporium were the main fungi, accounting for 68.2% and 11.3% on average, respectively, in the fermentation process of the CFRW. Meanwhile, twenty-three VFCs were detected in the CFRW, which included three alcohols, six terpenes, ten esters, three aromatics, and one furan. The correlation analysis revealed that there were 16 significant positive correlations and 23 significant negative correlations between the bacterium and VFCs (|ρ| > 0.6, p < 0.05), while there were 12 significant positive correlations and one significant negative correlation between the fungi and VFCs (|ρ| > 0.6, p < 0.05). Furthermore, five VFCs, including linalool, geraniol, ethyl acetate, 1-hexanol, and 3-methyl-1-butanol, contributed vital flavors to the CFRW, and they were all significantly negatively correlated with the changes of Massilia and Acinetobacter (|ρ| > 0.6, p < 0.05). Moreover a significant positive correlation was found between the relative abundance of Lactococcus and the contents of 3-methyl-1-butanol and ethyl acetate (|ρ| > 0.6, p < 0.05). Therefore, this study provides a valuable theoretical basis for further improving the quality and production technology of CFRW.

Cloning, characterization of ß-glucosidase from Furfurilactobacillus rossiae in bioconversion and its efficacy.

Minor ginsenosides produced by ß-glucosidase are interesting biologically and pharmacologically. In this study, new ginsenoside-hydrolyzing glycosidase from Furfurilactobacillus rossiae DCYL3 was cloned and expressed in Escherichia coli strain BL21. The enzyme converted Rb1 and Gyp XVII into Rd and compound K following the pathways: Rb1→Rd and Gyp XVII→F2→CK, respectively at optimal condition: 40 °C, 15 min, and pH 6.0. Furthermore, we examined the cytotoxicity, NO production, ROS generation, and gene expression of Gynostemma extract (GE) and bioconverted Gynostemma extract (BGE) in vitro against A549 cell lines for human lung cancer and macrophage RAW 264.7 cells for antiinflammation, respectively. As a result, BGE demonstrated significantly greater toxicity than GE against lung cancer at a dose of 500 µg/mL but in normal cells showed lower toxicity. Then, we indicated an enhanced generation of ROS, which may be boosting cancer cell toxicity. By blocking the intrinsic way, BGE increased p53, Bax, Caspase 3, 9, and while Bcl2 is decreased. At 500 µg/mL, the BGE sample was less toxic in normal cells and decreased the LPS-treated NO and ROS level to reduce inflammation. In addition, BGE inhibited the expression of pro-inflammatory genes COX-2, iNOS, IL-6, and IL-8 in RAW 264.7 cells than the sample of GE. In conclusion, FrBGL3 has considerable downstream applications for high-yield, low-cost, effective manufacture of minor ginsenosides. Moreover, the study's findings imply that BGE would be potential materials for anti-cancer and anti-inflammatory agent after consideration of future studies.

•The first time ß-glucosidase (FrBGL3) from Furfurilactobacillus rossiae was identified and characterized.•FrBGL3 activity in ginsenoside and gypenoside bioconversion were found and confirmed.•Application in Gynostemma extract bioconversion by FrBGL3 boosts anti-inflammatory and anti-cancer activities.

Sea cucumber-derived extract can protect skin cells from oxidative DNA damage and mitochondrial degradation, and promote wound healing.

Our skin serves as the primary barrier against external environmental insults, the latter of which can cause oxidative stress within cells, while various bioactive peptides sourced from natural resources hold promise in protecting cells against such oxidative stress. In this study, we investigate the efficacy of a low molecular weight extract from the sea cucumber Apostichopus japonicus, denoted as Sample-P, in facilitating cell migration and wound healing under oxidative stress conditions in skin cells. The naturally derived compound is a highly complex mix of peptides exhibiting antioxidative properties, as highlighted through liquid chromatography-mass spectrometry peptide screening and an in vitro antioxidant assay. Our results demonstrate that Sample-P is capable of promoting cell migration while preventing severe stress responses such as visible through mTOR expression. To further identify the molecular pathways underpinning the overall protective mechanism of Sample-P, we have utilised a proteomics approach. Our data reveal that Sample-P regulates protein expression associated with ribosomal pathways, glycolysis/gluconeogenesis and protein processing in the endoplasmic reticulum (ER), which help in preserving DNA integrity and safeguarding cellular organelles, such as mitochondria and the ER, under oxidative stress conditions in skin cells. In summary, in the presence of H2O2, Sample-P exhibits antioxidative properties at both molecular and cellular levels, rendering it a promising candidate for topical skin treatment to wound healing and to address age-related skin conditions.

An Updated Review Summarizing the Pharmaceutical Efficacy of Genistein and its Nanoformulations in Ovarian Carcinoma.

Implementing lifestyle interventions as a primary prevention strategy is a cost-effective approach to reducing the occurrence of cancer, which is a significant contributor to illness and death globally. Recent advanced studies have uncovered the crucial role of nutrients in safeguarding women's health and preventing disorders. Genistein is an abundant isoflavonoid found in soybeans. Genistein functions as a chemotherapeutic drug against various forms of cancer, primarily by modifying apoptosis, the cell cycle, and angiogenesis and suppressing metastasis. Furthermore, Genistein has demonstrated diverse outcomes in women, contingent upon their physiological characteristics, such as being in the early or postmenopausal stages. The primary categories of gynecologic cancers are cervical, ovarian, uterine, vaginal, and vulvar cancers. Understanding the precise mechanism by which Genistein acts on ovarian cancer could contribute to the advancement of anti-breast cancer treatments, particularly in situations where no specific targeted therapies are currently known or accessible. Additional investigation into the molecular action of Genistein has the potential to facilitate the development of a plant-derived cancer medication that has fewer harmful effects. This research could also help overcome drug resistance and prevent the occurrence of ovarian cancers.

Transcription factor NtMYB59 targets NtMYB12 to negatively regulate the biosynthesis of polyphenols in Nicotiana tabacum.

MYB12 is a key regulator that has been shown to promote the accumulation of various phenylpropanoid compounds in plants. However, the regulation of MYB12 gene is largely unknown. In this study, we found that overexpression of the NtMYB59 gene significantly inhibited the accumulation of chlorogenic acid (CGA), flavonols, and anthocyanins in tobacco, while knock-down and knock-out of NtMYB59 significantly increased the contents of these polyphenol compounds. Transcriptome analysis between WT and NtMYB59-OE plants revealed several differentially expressed genes (DEGs) encoding crucial enzymes in the phenylpropanoid pathway and the transcription factor NtMYB12. ChIP-seq assay further indicated that NtMYB12 might be a direct target of NtMYB59. Subsequent yeast one-hybrid, electrophoretic mobility shift assay, and Dual-Luciferase assays confirmed that NtMYB59 directly binds to the promoter of NtMYB12 to inhibit its expression. Moreover, loss-function of NtMYB59 significantly promoted the accumulation of flavonols and anthocyanins in ntmyb59, but their contents in ntmyb59/ntmyb12 double mutants were significantly lower than that of WT and ntmyb59 plants, indicating that the regulation of NtMYB59 on flavonoids biosynthesis depends on the activity of NtMYB12. Our study revealed that NtMYB59 regulates the expression of NtMYB12, and provided new potential strategies for modulating phenylpropanoids biosynthesis in tobacco.

Oral exposure to benzalkonium chlorides in male and female mice reveals alteration of the gut microbiome and bile acid profile.

Benzalkonium chlorides (BACs) are commonly used disinfectants in a variety of consumer and food-processing settings, and the COVID-19 pandemic has led to increased usage of BACs. The prevalence of BACs raises the concern that BAC exposure could disrupt the gastrointestinal microbiota, thus interfering with the beneficial functions of the microbes. We hypothesize that BAC exposure can alter the gut microbiome diversity and composition, which will disrupt bile acid homeostasis along the gut-liver axis. In this study, male and female mice were exposed orally to d7-C12- and d7-C16-BACs at 120 µg/g/day for one week. UPLC-MS/MS analysis of liver, blood, and fecal samples of BAC-treated mice demonstrated the absorption and metabolism of BACs. Both parent BACs and their metabolites were detected in all exposed samples. Additionally, 16S rRNA sequencing was carried out on the bacterial DNA isolated from the cecum intestinal content. For female mice, and to a lesser extent in males, we found that treatment with either d7-C12- or d7-C16-BAC led to decreased alpha diversity and differential composition of gut bacteria with notably decreased actinobacteria phylum. Lastly, through a targeted bile acid quantitation analysis, we observed decreases in secondary bile acids in BAC-treated mice, which was more pronounced in the female mice. This finding is supported by decreases in bacteria known to metabolize primary bile acids into secondary bile acids, such as the families of Ruminococcaceae and Lachnospiraceae. Together, these data signify the potential impact of BACs on human health through disturbance of the gut microbiome and gut-liver interactions.

Compound Sophorae Decoction mitigates DSS-induced ulcerative colitis by activating autophagy through PI3K-AKT pathway：a integrative research combining network pharmacology and in vivo animal model validation.

ETHNOPHARMACOLOGICAL RELEVANCE: Compound sophora decoction (CSD), a widely used Chinese herbal formula, has been shown to effectively alleviate symptoms ulcerative colitis (UC), including of bloody diarrhea, tenesmus, abdominal pain, and fever. Despite its clinical use, the precise pharmacological mechanisms of CSD remain enigmatic. AIM OF THE STUDY: This study aims to investigate the potential efficacy and underlying mechanisms of CSD in the treatment of UC by employing an integrative pharmacology-based approach, molecular docking analysis and experimental validation. MATERIALS AND METHODS: In this study, an integrative pharmacology-based approach was employed to predict the primary pathway through which CSD treats UC. The mechanism of CSD was further validated using a DSS-induced UC mouse model. Disease severity was assessed by monitoring stool property, body weight, colon length, and colon histopathology. Colonic pathological changes were examined using hematoxylin and eosin (H&E) staining. The concentration of cytokines was measured via ELISA, while key molecules in the PI3K/AKT pathway and autophagy-related markers were evaluated using Western blotting. Autophagy in intestinal epithelial cells was observed using electron microscopy. RESULTS: The results demonstrated that CSD alleviated DSS-induced UC by inhibiting the activation of PI3K/AKT pathway, reducing the release of inflammatory cytokines, down-regulating oxidative mediators, and enhancing autophagy. Moreover, the protective effects of CSD were diminished by bpV, a PTEN inhibitor, further supporting the involvement of the PI3K/AKT pathway. CONCLUSIONS: The underlying mechanism of CSD's therapeutic effect on UC may involve significant attenuation of DSS-induced intestinal inflammation by promoting autophagy through the inhibition of PI3K-AKT pathway activation.

High-Dose Compound Betamethasone Used in Local Infiltration Analgesia Does Not Increase Reinfection Rates Following Periprosthetic Joint Infection Treatment.

BACKGROUND: The administration of cocktails that contain glucocorticoids for local infiltration analgesia (LIA) is highly advocated and has been shown to be effective in managing pain in total joint arthroplasty (TJA). However, it remains ambiguous whether this protocol maintains its safety and efficacy in the treatment of periprosthetic joint infection (PJI), a devastating complication of TJA. METHODS: A comprehensive retrospective study was carried out on 299 single-stage revision cases for PJI spanning the years 2010 to 2021. Of these, 127 received LIAs containing high-dose compound betamethasone (CB) were termed the CB group, and the other 172 were termed the non-CB group. The rates of reinfection and other postoperative complications, along with postoperative visual analog scale (VAS) scores, and opioid consumption were compared. RESULTS: During minimum 2-year follow-up, there was no significant difference in the reinfection rate between the non-CB and CB groups (9.3 versus 8.7%; P = 0.85), consistent within the subsets of hip (8.4 versus 4.5%; P = 0.51) and knee (10.4 versus 13.3%; P = 0.60) PJIs individually. The administration of high-dose CB was neither an independent risk factor for reinfection (P > 0.05; 95% CI [confidence interval] including 1) nor was it associated with the occurrence of reinfection (P > 0.05). The incidence of postoperative nausea and vomiting (PONV) was significantly lower in the CB group (P < 0.05). In the initial 48-hour postoperative period, the CB group exhibited lower mean scores in both resting and movement VAS evaluations (P < 0.05). Notably, the movement VAS scores of the CB group remained lower even at 72 hours post-surgery for knee PJIs (P < 0.001). Furthermore, within the first 72 hours post-surgery, the necessity for additional opioid analgesics in the CB group was significantly reduced compared to the non-CB group (P < 0.05). CONCLUSION: A LIA with a high-dose compound betamethasone reduces postoperative pain, opioid consumption, and the incidence of PONV following a single-stage revision without affecting reinfection and other complication rates.

Bis[2-(isoquinolin-1-yl)phenyl-κ2 N,C 1](2-phenyl-1H-imidazo[4,5-f][1,10]phenanthroline-κ2 N,N')iridium(III) hexa-fluorido-phosphate methanol monosolvate.

The title compound, [Ir(C15H10N)2(C19H12N4)]PF6·CH3OH, crystallizes in the C2/c space group with one monocationic iridium complex, one hexa-fluorido-phosphate anion, and one methanol solvent mol-ecule of crystallization in the asymmetric unit, all in general positions. The anion and solvent are linked to the iridium complex cation via hydrogen bonding. All bond lengths and angles fall into expected ranges compared to similar compounds.

[Potential pathways for traditional Chinese medicine intervention in diabetic kidney disease: macrophage polarization].

Diabetic kidney disease(DKD) is a prevalent and severe microvascular complication of type 2 diabetes mellitus(T2DM). Chronic microinflammation is an important factor exacerbating renal tissue damage in DKD individuals. Macrophages play a crucial role in immune-inflammatory responses, and they can transiently and reversibly polarize into the pro-inflammatory M1 phenotype and anti-inflammatory M2 phenotype based on microenvironmental differences. The imbalance in M1/M2 macrophage polarization can exacerbate DKD progression by fostering inflammatory cytokine aggregation in the glomeruli and renal interstitium. Therefore, restoring the balance of macrophage is a pivotal avenue to ameliorate the chronic microinflammation state in DKD. Macrophage polarization is a complex and dynamic process. Various information molecules and cytokines involved in the polarization process play important roles in regulating phenotypes during the progression of DKD. They are closely related to various mechanisms such as metabolism, inflammation, fibrosis, and mitochondrial autophagy in DKD. By coordinating the inflammatory responses through polarization, they play a key role in regulating inflammation in metabolic-related diseases. The complex network of pathways involved in macrophage polarization corresponds well with the multi-pathway, multi-target treatment model of traditional Chinese medicine(TCM). Active ingredients and formulas of TCM can intervene in DKD by regulating macrophage polarization. Studies on relieving renal inflammation, repairing renal tissues, and promoting renal function recovery through macrophage polarization modulation are not uncommon. Therefore, based on exis-ting evidence, this study reviews TCM in targeting M1/M2 macrophage polarization balance to improve DKD, aiming to explore the potential of macrophage polarization in regulating DKD, which is expected to provide evidence support for the clinical diagnosis and treatment of DKD with TCM as well as the exploration of its biological mechanisms.

ATH434, a promising iron-targeting compound for treating iron regulation disorders.

Cytotoxic accumulation of loosely bound mitochondrial Fe2+ is a hallmark of Friedreich's Ataxia (FA), a rare and fatal neuromuscular disorder with limited therapeutic options. There are no clinically approved medications targeting excess Fe2+ associated with FA or the neurological disorders Parkinson's disease and Multiple System Atrophy. Traditional iron-chelating drugs clinically approved for systemic iron overload that target ferritin-stored Fe3+ for urinary excretion demonstrated limited efficacy in FA and exacerbated ataxia. Poor treatment outcomes reflect inadequate binding to excess toxic Fe2+ or exceptionally high affinities (i.e. ≤10-31) for non-pathologic Fe3+ that disrupts intrinsic iron homeostasis. To understand previous treatment failures and identify beneficial factors for Fe2+-targeted therapeutics, we compared traditional Fe3+ chelators deferiprone (DFP) and deferasirox (DFX) with additional iron-binding compounds including ATH434, DMOG, and IOX3. ATH434 and DFX had moderate Fe2+ binding affinities (Kd's of 1-4 µM), similar to endogenous iron chaperones, while the remaining had weaker divalent metal interactions. These compounds had low/moderate affinities for Fe3+(0.46-9.59 µM) relative to DFX and DFP. While all compounds coordinated iron using molecular oxygen and/or nitrogen ligands, thermodynamic analyses suggest ATH434 completes Fe2+ coordination using H2O. ATH434 significantly stabilized bound Fe2+ from ligand-induced autooxidation, reducing reactive oxygen species (ROS) production, whereas DFP and DFX promoted production. The comparable affinity of ATH434 for Fe2+ and Fe3+ position it to sequester excess Fe2+ and facilitate drug-to-protein iron metal exchange, mimicking natural endogenous iron binding proteins, at a reduced risk of autooxidation-induced ROS generation or perturbation of cellular iron stores.

Advances in Protein-Ligand Binding Affinity Prediction via Deep Learning: A Comprehensive Study of Datasets, Data Preprocessing Techniques, and Model Architectures.

BACKGROUND: Drug discovery is a complex and expensive procedure involving several timely and costly phases through which new potential pharmaceutical compounds must pass to get approved. One of these critical steps is the identification and optimization of lead compounds, which has been made more accessible by the introduction of computational methods, including deep learning (DL) techniques. Diverse DL model architectures have been put forward to learn the vast landscape of interaction between proteins and ligands and predict their affinity, helping in the identification of lead compounds. OBJECTIVE: This survey fills a gap in previous research by comprehensively analyzing the most commonly used datasets and discussing their quality and limitations. It also offers a comprehensive classification of the most recent DL methods in the context of protein-ligand binding affinity prediction, providing a fresh perspective on this evolving field. METHODS: We thoroughly examine commonly used datasets for BAP and their inherent characteristics. Our exploration extends to various preprocessing steps and DL techniques, including graph neural networks, convolutional neural networks, and transformers, which are found in the literature. We conducted extensive literature research to ensure that the most recent deep learning approaches for BAP were included by the time of writing this manuscript. RESULTS: The systematic approach used for the present study highlighted inherent challenges to BAP via DL, such as data quality, model interpretability, and explainability, and proposed considerations for future research directions. We present valuable insights to accelerate the development of more effective and reliable DL models for BAP within the research community. CONCLUSION: The present study can considerably enhance future research on predicting affinity between protein and ligand molecules, hence further improving the overall drug development process.

Application of compound poisson model to estimate underreported risk of non-communicable diseases in underdeveloped areas.

Background: Hypertension and diabetes are major components of non-communicable diseases (NCDs), with a substantial number of patients residing in underdeveloped areas. Limited medical resources in these areas often results in underreporting of disease prevalence, masking the true extent of diseases. Taking the underdeveloped Liangshan Yi Autonomous Prefecture in China as an example, this study aimed to correct the underreported prevalence of hypertension and type 2 diabetes so as to provide inspiration for the allocation of medical resources in such areas. Methods: Assuming the true number of patients in each area follows a Poisson distribution, we applied a Compound Poisson Model based on Clustering of Data Quality (CPM-CDQ) to estimate the potential true prevalence of hypertension and diabetes, as well as the registration rate of existing patients. Specifically, a hierarchical clustering approach was utilized to group the counties based on the data quality, and then the registration rate of the cluster with the best data quality was used as a priori information for the model. The model parameters were estimated by the maximum likelihood method. Sensitivity analyses were performed to test the robustness of the model. Results: The estimated prevalence of hypertension in the entire Liangshan Prefecture from 2018 to 2020 ranged from 24.59 % to 25.28 %, and for diabetes, it ranged from 4.95 % to 8.42 %. The registration rates for hypertension and diabetes were 14.10 % to 24.59 % and 15.98 % to 29.12 %, respectively. Additionally, the accuracy of clustering the counties with the best data quality had a significant impact on the performance of the model. Conclusion: Liangshan Prefecture is experiencing a significant high prevalence of hypertension and diabetes, accompanied by a concerningly low registration rate. The CPM-CDQ proved useful for assessing underreporting risks and facilitating targeted interventions for NCDs control and prevention, particularly in underdeveloped areas.

Quantitive variation of male and female-specific compounds in 99 drosophilid flies.

Variation in sex pheromones is regarded as one of the causes of reproductive isolation and speciation. We recently identified 51 male- and female-specific compounds - many of which function as sex pheromones - in 99 drosophilid species [1]. Here, we report that despite many of these compounds being shared between species, their quantities differ significantly. For example, although 34 drosophilid species share the male-specific compound cis-vaccenyl acetate (cVA), which plays a critical role in regulating various social and sexual behaviors, the amount of cVA can differ by up to 600-fold between different species. Additionally, we found 7-tricosene, the cuticular hydrocarbon pheromone, present in 35 Drosophila species. Our findings indicate that 7-tricosene is equally present in both sexes of 14 species, more abundant in males of 14 species, and more abundant in females of 7 species. We provide raw data on the concentration of potential pheromone components in the 99 drosophilids, which can provide important insights for further research on the behavior and evolution of these species. Quantitative variations highlight species-specific patterns, suggesting an additional mechanism for reproductive isolation built on specific combinations of compounds at set concentrations.