Tribuloside: Mechanisms and Efficacy in Treating Acute Lung Injury Revealed by Network Pharmacology and Experimental Validation.

Background: Acute lung injury (ALI) is a serious illness that has few treatment options available. Tribuloside, a natural flavonoid extracted from the Tribulus Terrestris plant in China, is potent in addressing many health issues such as headaches, dizziness, itching, and vitiligo. Objective: This study intends to explore the mechanisms of action of Tribuloside in treating ALI through a combination of network pharmacology and experimental validation. Methods: We obtained the 2D structure and SMILES number of Tribuloside from the PubChem database. We used the SwissTargetPrediction database to identify pharmacological targets. We found 1215 targets linked to ALI by examining the GeneCards database. We used the String database and Cytoscape software to create the "drug or disease-target" network as well as the protein-protein interactions (PPI). Key targets were identified by evaluating associated biological processes and pathway enrichment. A Venny Diagram showed 49 intersection points between Tribuloside and ALI. Molecular docking with AutoDockTools found that Tribuloside had a high affinity for IL6, BCL2, TNF, STAT3, IL1B, and MAPK3, the top 6 targets in the PPI network by Degree values. To test Tribuloside's therapeutic efficacy in ALI, an acute lung damage model in mice was constructed using lipopolysaccharide. Tribuloside treatment reduced inflammatory cell infiltration, decreased fibrotic area, repaired damaged alveoli, and suppressed inflammatory factors IL-6, TNF-α, and IL-1ß in the lungs through many pathways and targets. Conclusion: This study reveals that Tribuloside has the potential to treat ALI by targeting various pathways and targets, according to network pharmacology predictions and experimental confirmation.

Landolphia (P. Beauv.) genus: Ethnobotanical, phytochemical and pharmacological studies.

The genus Landolphia (P. Beauv.) belongs to the Apocynaceae family with over 65 species distributed all over the tropical regions. This genus has a considerable number of documented medicinal, industrial, and ecologically beneficial effects. Therefore, this review is tailored towards the appraisal of the traditional significance, phytochemistry, and pharmacological activities of the genus Landolphia. This will help researchers understand future research trends by bridging the gaps between documented literature and contemporary uses. Relevant information was obtained from selection of scientific databases such as Web of Science, PubMed, Scopus, Google Scholar, ScienceDirect and Wiley. From documented literature, different parts of Landolphia have been used to improve fertility, lessen menstrual pain, boost sex libido, cure malaria and typhoid. Several classes of bioactive constituents such as terpenoids, phenolics, flavonoids, steroids, fatty acids, saponins, phytosterol and phenylpropanoid, volatile compounds, lignans and coumarins have been isolated from this genus. These secondary metabolites could be responsible for the reported antimicrobial, antimalarial, aphrodisiac, antioxidant, anti-inflammatory, antidiabetic and anticancer activities exhibited by this genus. The leaves, flower, bark and root of this genus have a wide range of essential nutrients and antinutrients which are essential for normal growth and development in living organisms. Despite all findings indicating the economical, industrial and pharmacological activities of Landolphia species, secondary metabolites and pharmacological potency of Landolphia of this genus are not adequately documented. Therefore, bioassay-guided isolation on the Landolphia extracts with proven biological activities should be prioritised in order to isolate pharmacophores with unique structural frameworks.

Network pharmacology and in vivo experiment-based strategy for investigating the mechanism of chronic prostatitis/chronic pelvic pain syndrome in QianLieJinDan tablets.

Background: Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is a common urinary system disease that is prone to recurrence. It typically leads to varying degrees of pelvic pain and discomfort, as well as symptoms related to the urinary system in affected patients. QianLieJinDan tablets (QLJD), a traditional Chinese medicine, have shown promising therapeutic effects on CP/CPPS in clinical practice, but the underlying mechanisms of QLJD in treating CP/CPPS have not been determined. Objective: To reveal the phytochemical characterization and multitarget mechanism of QLJD on CP/CPPS. Methods: The concentrations of the components of QLJD were determined using UHPLC-Q Exactive Orbitrap-MS. Utilizing network pharmacology approaches, the potential components, targets, and pathways involved in the treatment of CP/CPPS caused by QLJD were screened. Molecular docking calculations were employed to assess the affinity between the components of the QLJD and potential targets, revealing the optimal molecular conformation and binding site. Finally, the therapeutic efficacy and potential underlying mechanisms of QLJD were investigated through pharmacological experiments. Results: In this study, a total of 35 components targeting 29 CP-related genes were identified, among which quercetin, baicalin, icariin, luteolin, and gallic acid were the major constituents. Enrichment analysis revealed that the potential targets were involved mainly in the regulation of cytokines, cell proliferation and apoptosis, and the oxidative stress response and were primarily associated with the cytokine‒cytokine receptor interaction pathway, the IL-17 signaling pathway, the Th17 cell differentiation pathway, and the JAK-STAT signaling pathway. In vivo experiments demonstrated that QLJD effectively attenuated the infiltration of CD3+ T cells and the expression of ROS in a CP/CPPS model rat prostate tissue. Furthermore, through the inhibition of IL-6 and STAT3 expression, QLJD reduced the differentiation of Th17 cells, thereby ameliorating pathological injury and prostatic index in prostate tissue. Conclusion: The potential of QLJD as an anti-CP/CPPS agent lies in its ability to interfere with the expression of IL-6 and STAT3, inhibit Th17 cell differentiation, reduce inflammatory cell infiltration in rat prostate tissue, and alleviate oxidative stress damage through its multi-component, multi-target, and multi-pathway effects.

Globospiramine from Voacanga globosa Exerts Robust Cytotoxic and Antiproliferative Activities on Cancer Cells by Inducing Caspase-Dependent Apoptosis in A549 Cells and Inhibiting MAPK14 (p38α): In Vitro and Computational Investigations.

Bisindole alkaloids are a source of inspiration for the design and discovery of new-generation anticancer agents. In this study, we investigated the cytotoxic and antiproliferative activities of three spirobisindole alkaloids from the traditional anticancer Philippine medicinal plant Voacanga globosa, along with their mechanisms of action. Thus, the alkaloids globospiramine (1), deoxyvobtusine (2), and vobtusine lactone (3) showed in vitro cytotoxicity and antiproliferative activities against the tested cell lines (L929, KB3.1, A431, MCF-7, A549, PC-3, and SKOV-3) using MTT and CellTiter-Blue assays. Globospiramine (1) was also screened against a panel of breast cancer cell lines using the sulforhodamine B (SRB) assay and showed moderate cytotoxicity. It also promoted the activation of apoptotic effector caspases 3 and 7 using Caspase-Glo 3/7 and CellEvent-3/7 apoptosis assays. Increased expressions of cleaved caspase 3 and PARP in A549 cells treated with 1 were also observed. Apoptotic activity was also confirmed when globospiramine (1) failed to promote the rapid loss of membrane integrity according to the HeLa cell membrane permeability assay. Network pharmacology analysis, molecular docking, and molecular dynamics simulations identified MAPK14 (p38α), a pharmacological target leading to cancer cell apoptosis, as a putative target. Low toxicity risks and favorable drug-likeness were also predicted for 1. Overall, our study demonstrated the anticancer potentials and apoptotic mechanisms of globospiramine (1), validating the traditional medicinal use of Voacanga globosa.

Xiaoer-Feire-Qing granules alleviate pyretic pulmonary syndrome induced by Streptococcus pneumoniae in young rats by affecting the lungs and intestines: An in vivo study based on network pharmacology.

ETHNOPHARMACOLOGICAL RELEVANCE: The traditional Chinese medicine (TCM) Xiaoer-Feire-Qing granules (XEFRQ) has been used to treat pyretic pulmonary syndrome (PPS) in children for many years. The function of the lungs is considered to be closely related to the large intestine in TCM. PURPOSE: We aimed to investigate the effects of XEFRQ on PPS and the underlying mechanisms via network pharmacology and animal experiments. METHODS: The TCMSP platform was used to identify the ingredients and potential targets of XEFRQ. The GeneCards, OMIM, and TTD databases were used to predict PPS-associated targets. Cytoscape 3.9.1 was employed to construct the protein-protein interaction network, and target prediction was performed by GO and KEGG analyses. For the animal experiment, a PPS model was constructed by three cycles of nasal drip of Streptococcus pneumoniae (STP; 0.5 mL/kg). The animals were randomly divided into the following four groups according to their weight (n = 10 rats per group): the blank group, the model group, the XEFRQ-L (16.3 g/kg) group, and the XEFRQ-H (56.6 g/kg) group. Rats in the blank group and the model group were given 0.5% CMC-Na by gavage. The general conditions of the rats were observed, and their food-intake, body weight, and body temperature were recorded for 14 days. After the intervention of 14 days, serum was collected to detect inflammatory cytokines (TNF-α, IL-1ß, and PGE2) and neurotransmitters (5-HT, SP, and VIP). H&E staining was used to observe the pathological morphology of lung and colon tissue. AQP3 expression was detected by Western blot. In addition, the gut microbiota in cecal content samples were analyzed by 16S rDNA high-throughput sequencing. RESULTS: Our network analysis revealed that XEFRQ may alleviate PPS injury by affecting the levels of inflammatory cytokines and neurotransmitters and mitigating STP-induced PPS.In vivo validation experiments revealed that XEFRQ improved STP-induced PPS and reduced the expression of inflammatory cytokines and neurotransmitters. Notably, XEFRQ significantly decreased the protein expression levels of AQP3, which was associated with dry stool. Our gut microbiota analysis revealed that the relative abundance of [Eubacterium]_ruminantium_group, Colidextribacter, Romboutsia, and Oscillibacter was decreased, which means XEFRQ exerts therapeutic effects against PPS associated with these bacteria. CONCLUSION: Our results demonstrate that XEFRQ alleviates PPS by affecting the lungs and intestines, further guiding its clinical application.

A quantitative systems pharmacology model of plasma kallikrein-kinin system dysregulation in hereditary angioedema.

Hereditary angioedema (HAE) due to C1-inhibitor deficiency is a rare, debilitating, genetic disorder characterized by recurrent, unpredictable, attacks of edema. The clinical symptoms of HAE arise from excess bradykinin generation due to dysregulation of the plasma kallikrein-kinin system (KKS). A quantitative systems pharmacology (QSP) model that mechanistically describes the KKS and its role in HAE pathophysiology was developed based on HAE attacks being triggered by autoactivation of factor XII (FXII) to activated FXII (FXIIa), resulting in kallikrein production from prekallikrein. A base pharmacodynamic model was constructed and parameterized from literature data and ex vivo assays measuring inhibition of kallikrein activity in plasma of HAE patients or healthy volunteers who received lanadelumab. HAE attacks were simulated using a virtual patient population, with attacks recorded when systemic bradykinin levels exceeded 20 pM. The model was validated by comparing the simulations to observations from lanadelumab and plasma-derived C1-inhibitor clinical trials. The model was then applied to analyze the impact of nonadherence to a daily oral preventive therapy; simulations showed a correlation between the number of missed doses per month and reduced drug effectiveness. The impact of reducing lanadelumab dosing frequency from 300 mg every 2 weeks (Q2W) to every 4 weeks (Q4W) was also examined and showed that while attack rates with Q4W dosing were substantially reduced, the extent of reduction was greater with Q2W dosing. Overall, the QSP model showed good agreement with clinical data and could be used for hypothesis testing and outcome predictions.

Urinary proteomic signature of mineralocorticoid receptor antagonism by spironolactone: evidence from the HOMAGE trial.

OBJECTIVE: Heart failure (HF) is characterised by collagen deposition. Urinary proteomic profiling (UPP) followed by peptide sequencing identifies parental proteins, for over 70% derived from collagens. This study aimed to refine understanding of the antifibrotic action of spironolactone. METHODS: In this substudy (n=290) to the Heart 'Omics' in Ageing Study trial, patients were randomised to usual therapy combined or not with spironolactone 25-50 mg/day and followed for 9 months. The analysis included 1498 sequenced urinary peptides detectable in ≥30% of patients and carboxyterminal propeptide of procollagen I (PICP) and PICP/carboxyterminal telopeptide of collagen I (CITP) as serum biomarkers of COL1A1 synthesis. After rank normalisation of biomarker distributions, between-group differences in their changes were assessed by multivariable-adjusted mixed model analysis of variance. Correlations between the changes in urinary peptides and in serum PICP and PICP/CITP were compared between groups using Fisher's Z transform. RESULTS: Multivariable-adjusted between-group differences in the urinary peptides with error 1 rate correction were limited to 27 collagen fragments, of which 16 were upregulated (7 COL1A1 fragments) on spironolactone and 11 downregulated (4 COL1A1 fragments). Over 9 months of follow-up, spironolactone decreased serum PICP from 81 (IQR 66-95) to 75 (61-90) µg/L and PICP/CITP from 22 (17-28) to 18 (13-26), whereas no changes occurred in the control group, resulting in a difference (spironolactone minus control) expressed in standardised units of -0.321 (95% CI 0.0007). Spironolactone did not affect the correlations between changes in urinary COL1A1 fragments and in PICP or the PICP/CITP ratio. CONCLUSIONS: Spironolactone decreased serum markers of collagen synthesis and predominantly downregulated urinary collagen-derived peptides, but upregulated others. The interpretation of these opposite UPP trends might be due to shrinking the body-wide pool of collagens, explaining downregulation, while some degree of collagen synthesis must be maintained to sustain vital organ functions, explaining upregulation. Combining urinary and serum fibrosis markers opens new avenues for the understanding of the action of antifibrotic drugs. TRIAL REGISTRATION NUMBER: NCT02556450.

Pharmacologic Venous Thromboembolism Prophylaxis in Patients with Nontraumatic Subarachnoid Hemorrhage Requiring an External Ventricular Drain.

BACKGROUND: Optimal pharmacologic thromboprophylaxis dosing is not well described in patients with subarachnoid hemorrhage (SAH) with an external ventricular drain (EVD). Our patients with SAH with an EVD who receive prophylactic enoxaparin are routinely monitored using timed anti-Xa levels. Our primary study goal was to determine the frequency of venous thromboembolism (VTE) and secondary intracranial hemorrhage (ICH) for this population of patients who received pharmacologic prophylaxis with enoxaparin or unfractionated heparin (UFH). METHODS: A retrospective chart review was performed for all patients with SAH admitted to the neurocritical care unit at Emory University Hospital between 2012 and 2017. All patients with SAH who required an EVD were included. RESULTS: Of 1,351 patients screened, 868 required an EVD. Of these 868 patients, 627 received enoxaparin, 114 received UFH, and 127 did not receive pharmacologic prophylaxis. VTE occurred in 7.5% of patients in the enoxaparin group, 4.4% in the UFH group (p = 0.32), and 3.2% in the no VTE prophylaxis group (p = 0.08). Secondary ICH occurred in 3.83% of patients in the enoxaparin group, 3.51% in the UFH group (p = 1), and 3.94% in the no VTE prophylaxis group (p = 0.53). As steady-state anti-Xa levels increased from 0.1 units/mL to > 0.3 units/mL, there was a trend toward a lower incidence of VTE. However, no correlation was noted between rising anti-Xa levels and an increased incidence of secondary ICH. When compared, neither enoxaparin nor UFH use was associated with a significantly reduced incidence of VTE or an increased incidence of ICH. CONCLUSIONS: In this retrospective study of patients with nontraumatic SAH with an EVD who received enoxaparin or UFH VTE prophylaxis or no VTE prophylaxis, there was no statistically significant difference in the incidence of VTE or secondary ICH. For patients receiving prophylactic enoxaparin, achieving higher steady-state target anti-Xa levels may be associated with a lower incidence of VTE without increasing the risk of secondary ICH.

Coordination of oral anticoagulant care at hospital discharge (COACHeD): pilot randomised controlled trial.

OBJECTIVES: To evaluate whether a focused, expert medication management intervention is feasible and potentially effective in preventing anticoagulation-related adverse events for patients transitioning from hospital to home. DESIGN: Randomised, parallel design. SETTING: Medical wards at six hospital sites in southern Ontario, Canada. PARTICIPANTS: Adults 18 years of age or older being discharged to home on an oral anticoagulant (OAC) to be taken for at least 4 weeks. INTERVENTIONS: Clinical pharmacologist-led intervention, including a detailed discharge medication management plan, a circle of care handover and early postdischarge virtual check-up visits to 1 month with 3-month follow-up. The control group received the usual care. OUTCOMES MEASURES: Primary outcomes were study feasibility outcomes (recruitment, retention and cost per patient). Secondary outcomes included adverse anticoagulant safety events composite, quality of transitional care, quality of life, anticoagulant knowledge, satisfaction with care, problems with medications and health resource utilisation. RESULTS: Extensive periods of restriction of recruitment plus difficulties accessing patients at the time of discharge negatively impacted feasibility, especially cost per patient recruited. Of 845 patients screened, 167 were eligible and 56 were randomised. The mean age (±SD) was 71.2±12.5 years, 42.9% females, with two lost to follow-up. Intervention patients were more likely to rate their ability to manage their OAC as improved (17/27 (63.0%) vs 7/22 (31.8%), OR 3.6 (95% CI 1.1 to 12.0)) and their continuity of care as improved (21/27 (77.8%) vs 2/22 (9.1%), OR 35.0 (95% CI 6.3 to 194.2)). Fewer intervention patients were taking one or more inappropriate medications (7 (22.5%) vs 15 (60%), OR 0.19 (95% CI 0.06 to 0.62)). CONCLUSION: This pilot randomised controlled trial suggests that a transitional care intervention at hospital discharge for older adults taking OACs was well received and potentially effective for some surrogate outcomes, but overly costly to proceed to a definitive large trial. TRIAL REGISTRATION NUMBER: NCT02777047.

Retrospective study investigating naloxone prescribing and cost in US Medicaid and Medicare patients.

BACKGROUND: Opioid overdoses in the USA have increased to unprecedented levels. Administration of the opioid antagonist naloxone can prevent overdoses. OBJECTIVE: This study was conducted to reveal the pharmacoepidemiologic patterns in naloxone prescribing to Medicaid patients from 2018 to 2021 as well as Medicare in 2019. DESIGN: Observational pharmacoepidemiologic study SETTING: US Medicare and Medicaid naloxone claims INTERVENTION: The Medicaid State Drug Utilisation Data File was utilised to extract information on the number of prescriptions and the amount prescribed of naloxone at a national and state level. The Medicare Provider Utilisation and Payment was also utilised to analyse prescription data from 2019. OUTCOME MEASURES: States with naloxone prescription rates that were outliers of quartile analysis were noted. RESULTS: The number of generic naloxone prescriptions per 100 000 Medicaid enrollees decreased by 5.3%, whereas brand naloxone prescriptions increased by 245.1% from 2018 to 2021. There was a 33.1-fold difference in prescriptions between the highest (New Mexico=1809.5) and lowest (South Dakota=54.6) states in 2019. Medicare saw a 30.4-fold difference in prescriptions between the highest (New Mexico) and lowest states (also South Dakota) after correcting per 100 000 enrollees. CONCLUSIONS: This pronounced increase in the number of naloxone prescriptions to Medicaid patients from 2018 to 2021 indicates a national response to this widespread public health emergency. Further research into the origins of the pronounced state-level disparities is warranted.

In silico modelling of stroke volume, cardiac output and systemic vascular resistance in cardiovascular safety pharmacology studies by telemetry.

The principle of proportionality of the systolic area of the central aortic pressure to stroke volume (SV) has been long known. The aim of the present work was to evaluate an in silico solution derived from this principle for modelling SV (iSV model) in cardiovascular safety pharmacology studies by telemetry. Blood pressure was measured in the abdominal aorta in accordance with standard practice. Central aortic pressure was modelled from the abdominal aortic pressure waveform using the N-point moving average (NPMA) method for beat-to-beat estimation of SV. First, the iSV was compared to the SV measured by ultrasonic flowmetry in the ascending aorta (uSV) after various pharmacological challenges in beagle dogs anaesthetised with etomidate/fentanyl. The iSV showed minimal bias (0.2 mL i.e. 2%) and excellent agreement with uSV. Then, previous telemetry studies including reference vasoactive and inotropic compounds were retrospectively reanalysed to model drug effects on stroke volume (iSV), cardiac output (iCO) and systemic vascular resistance (iSVR). Among them, the examples of nicardipine and isoprenaline highlight risks of erroneous or biased estimation of drug effects from the abdominal aortic pressure due to pulse pressure amplification. Furthermore, the examples of verapamil, quinidine and moxifloxacin show that iSV, iCO and iSVR are earlier biomarkers than blood pressure itself for predicting drug effect on blood pressure. This in silico modelling approach included in vivo telemetry safety pharmacology studies can be considered as a New Approach Methodology (NAM) that provides valuable additional information and contribute to improving non-clinical translational research to the clinic.

Erjingwan and Alzheimer's disease: research based on network pharmacology and experimental confirmation.

Background: Alzheimer's disease (AD), a challenging neurodegenerative condition, has emerged as a significant global public health concern. The Chinese medicine decoction Erjingwan (EJW) has shown promising efficacy in AD treatment, though its mechanism remains unclear. Objective: This study aims to elucidate the mechanism by which EJW treats AD through network pharmacology analysis and in vivo experiments. Methods: We identified EJW's components using the Traditional Chinese Medicine Systems Pharmacology (TCMSP) database and determined AD-related targets from various databases. A network comprising herbs-compounds-targets was established, and EJW's core targets were ascertained through protein-protein interaction (PPI) analysis. This study assessed the cognitive abilities of APP/PS1 mice using Morris water mazes and Y mazes, in addition to analyzing blood samples for triglyceride (TG), total cholesterol (TC), low-density lipoprotein (LDL), and high-density lipoprotein (HDL) levels. Brain tissues were examined histologically with HE staining, Nissl staining, and immunohistochemistry (IHC) for amyloid ß-protein (Aß) detection. Superoxide dismutase (SOD), reactive oxygen species (ROS), Interleukin-1ß (IL-1ß), and Interleukin-6 (IL-6) levels in the hippocampal region were measured by ELISA. mRNA expression of apolipoprotein A-I (APOA-I), apolipoprotein B (APOB), apolipoprotein E4 (APOE4), advanced glycation end products (AGE), the receptor for AGE (RAGE), and nuclear factor kappa-B (NF-κB) was evaluated by quantitative PCR (q-PCR). Western blotting was used to detect the expression of AGE, RAGE, NF-κB, and Tau protein. Results: Screening identified 57 chemical components and 222 potential targets of EJW. Ten core targets for AD treatment were identified, with enrichment analysis suggesting EJW's effects are related to lipid metabolism and AGEs/RAGE pathways. EJW enhanced learning and memory in APP/PS1 mice, protected neuronal structure in the hippocampal region, reduced Aß deposition, and altered levels of TG, TC, LDL, IL-1ß, and IL-6, and the expression of APOE4, AGEs, RAGE, NF-κB, and Tau protein, while increasing SOD, APOA-I, and APOB mRNA expression. Conclusion: The study identified four core components of EJW-iosgenin, baicalein, beta-sitosterol, quercetin-and ten core targets including AKT1, IL6, VEGFA, TP53, CASP3, for treating AD. Experimental results demonstrate EJW's capacity to modulate lipid profiles, reduce pathological markers such as Aß1-42, Tau, IL-6, IL-1ß, reactive oxygen species, SOD, and enhance cognitive functions in APP/PS1 mice, potentially through inhibiting the AGEs/RAGE/NF-κB pathway.

ALK inhibitors suppress HCC and synergize with anti-PD-1 therapy and ABT-263 in preclinical models.

Hepatocellular carcinoma (HCC) currently lacks effective therapies, leaving a critical need for new treatment options. A previous study identified the anaplastic lymphoma kinase (ALK) amplification in HCC patients, raising the question of whether ALK inhibitors could be a viable treatment. Here, we showed that both ALK inhibitors and ALK knockout effectively halted HCC growth in cell cultures. Lorlatinib, a potent ALK inhibitor, suppressed HCC tumor growth and metastasis across various mouse models. Additionally, in an advanced immunocompetent humanized mouse model, when combined with an anti-PD-1 antibody, lorlatinib more potently suppressed HCC tumor growth, surpassing individual drug efficacy. Lorlatinib induced apoptosis and senescence in HCC cells, and the senolytic agent ABT-263 enhanced the efficacy of lorlatinib. Additional studies identified that the apoptosis-inducing effect of lorlatinib was mediated via GGN and NRG4. These findings establish ALK inhibitors as promising HCC treatments, either alone or in combination with immunotherapies or senolytic agents.

Network pharmacology combined with an experimental validation study to reveal the effect and mechanism of Lonicera japonica Thunb. extracts against immunomodulation.

Lonicera japonica Thunb. (LJT) is known for its valuable medicinal properties that highlight its potential application in the pharmaceutical and health food industry. We predict that LJT polyphenols by network pharmacology may be involved in immunomodulation, and the study of LJT polyphenols regulating immunity is still insufficient; therefore, we experimentally found that LJT enhances immunity by promoting the proliferation and phagocytic activity of RAW246.7 cells. A model of an immunosuppressed mouse was constructed using cyclophosphamide-induced, and LJT was extracted for the intervention. We found that LJT restored immune homeostasis in immune deficiency mice by inhibiting the abnormal apoptosis in lymphocytes, enhancing natural killer cell cytotoxicity, promoting T lymphocyte proliferation, and increasing the CD4+ and CD8+ T lymphocytes in quantity. Moreover, LJT treatment modulates immunity by significantly downregulating lipopolysaccharide-induced inflammation and oxidative stress levels. We verified the immunomodulatory function of LJT through both cell and animal experiments. The combination of potential-protein interactions and molecular docking later revealed that LJT polyphenols were associated with immunomodulatory effects on MAPK1; together, LJT intervention significantly modulates the immune, with the activation of MAPK1 as the underlying mechanism of action, which provided evidence for the utilization of LJT as a nutraceutical in immune function.

A review on the pharmacology of cariprazine and its role in the treatment of negative symptoms of schizophrenia.

Management of negative symptoms is one of the most challenging and important unmet needs of schizophrenia treatment. Negative symptoms together with positive symptoms result in significant psychosocial impairment and poor quality of life. Existing studies on atypical antipsychotics reported limited treatment adherence due to higher prevalence of treatment-emergent adverse events, such as diabetes, weight gain, hyperlipidemia, hyperprolactinemia and hypertension. A compound with greater affinity for dopamine D2/D3 receptors may improve negative symptoms, mood, and cognitive impairment associated with schizophrenia. In 2015, the US FDA has approved cariprazine, a partial D2/D3 agonist for treatment of schizophrenia, mania or mixed episodes. Midlands and Lancashire Commissioning Support Unit, UK (2019) has particularly suggested cariprazine for the treatment of predominant negative symptoms of schizophrenia. India's Central Drugs Standard Control Organization (CDSCO) has approved cariprazine in 2021 for the treatment of schizophrenia, manic or mixed episodes associated with bipolar I disorder. A ten-fold greater affinity for D3 receptors and partial agonism to serotonin receptors, along with longer half-life make cariprazine distinct when compared with other atypical antipsychotics. Cariprazine is also reported to have fewer incidents of metabolic and hormonal adverse events, and has been shown to provide better relapse prevention. Recent evidence indicates promising effect of cariprazine in ameliorating negative symptoms as well as psychotic symptoms in patients with schizophrenia. In addition, improved adherence to treatment (adjunctive/monotherapy) with cariprazine in patients having inadequate response to an ongoing antipsychotic treatment has also been clinically established. This review presents the evidence-based safety and efficacy of cariprazine for treatment of predominant negative symptoms of schizophrenia.

Kokusaginine attenuates renal fibrosis by inhibiting the PI3K/AKT signaling pathway.

Kokusaginine is an active ingredient alkaloid that has been isolated and extracted from Ruta graveolens L. Some researches have indicated that alkaloids possess anti-inflammatory and antioxidant effects. Nevertheless, the potential nephroprotective effects of kokusaginine on renal fibrosis remain undetermined. This study was conducted to examine the protective effect of kokusaginine on renal fibrosis and to explore the underlying mechanisms using both in vivo and in vitro models. Renal fibrosis was induced in male C57BL/6 J mice by feeding with 0.2% adenine-containing food and UUO surgery. Kokusaginine was administered orally simultaneously after the establishment of renal fibrosis. Renal function was measured by serum levels of creatinine and urea nitrogen. Renal pathological changes were assessed by HE staining and Masson staining. Western blotting was employed to detect the expression levels of fibrosis-related proteins in mice and cells. Additionally, network pharmacology analysis and RNA-seq were utilized to predict the pathways through which kokusaginine could exert its anti-fibrotic effects. The treatment with kokusaginine enhanced renal function, alleviated renal histoarchitectural lesions, and mitigated renal fibrosis in the renal fibrosis models. The network pharmacology and RNA-seq enrichment analysis of the KEGG pathway demonstrated that kokusaginine could exert anti-renal fibrosis activity via the PI3K/AKT signaling pathway. And the results were verified in both in vitro and in vivo experiments. In conclusion, our data implied that kokusaginine inhibited the activation of the PI3K/AKT signaling pathway both in vitro and in vivo, and suppressed the formation of renal fibrosis. Thus, the kokusaginine-mediated PI3K/AKT signaling pathway may represent a novel approach for the treatment of renal fibrosis.

Exploring Ciprofol Alternatives: A Comprehensive Review of Intravenous Anesthesia Options.

Ciprofol is a recently developed, short-acting γ-aminobutyric acid receptor agonist sedative that is more potent than propofol. Still, there have been few clinical studies of this agent to date. This review explores alternative intravenous anesthesia options to ciprofol, considering their pharmacology, clinical efficacy, safety profile, and practical considerations. While ciprofol offers advantages such as rapid onset and predictable offset, concerns regarding its safety profile and individual variability in response have prompted the search for alternatives. Propofol, etomidate, ketamine, and dexmedetomidine are discussed as established options, each with unique characteristics and potential benefits. Emerging agents, including remimazolam, sufentanil, alfaxalone, and brexanolone, are examined for their potential role in anesthesia management. Recommendations for future research include large-scale comparative studies, optimization of dosing strategies, and personalized approaches guided by pharmacogenomic insights. Ultimately, the future of intravenous anesthesia lies in a multifaceted approach that integrates evidence-based practices, technological innovations, and individualized patient care to enhance safety, efficacy, and patient satisfaction across the perioperative continuum. Collaboration among stakeholders will be crucial in advancing the field and shaping the future landscape of intravenous anesthesia options.

Danlou tablet alleviates sepsis-induced acute lung and kidney injury by inhibiting the PARP1/HMGB1 pathway.

Background: Sepsis-associated acute lung injury (ALI) and acute kidney injury (AKI) are common complications that significantly impact patient prognosis. Danlou tablet (DLT) is a traditional herbal preparation with anti-inflammatory and antioxidant properties. However, its therapeutic potential in sepsis remains unknown. Methods: The impact of DLT on ALI and AKI was evaluated using the cecal ligation and puncture (CLP) experimental sepsis animal model. The effects of DLT on macrophages were observed through LPS-stimulated RAW264.7 cell line. Inflammatory cytokines, oxidative stress indicators, HE, PAS, and DHE staining, lung wet-to-dry weight ratio, and serum creatinine and urea nitrogen levels were used to assess tissue injury. Network pharmacology, molecular docking, and molecular dynamics simulations were used to explore the potential regulatory mechanisms of DLT in sepsis. Western blot and immunohistochemical staining were used to validate the expression of mechanism-related proteins. Results: DLT inhibited the inflammatory response and oxidative stress, improved structural and functional abnormalities in lung and kidney tissues in CLP mice, and alleviated pro-inflammatory responses of LPS-stimulated macrophages. PARP1 and HMGB1 were identified as key regulatory targets. The results of in vitro and in vivo experiments suggest that DLT can effectively inhibit PARP1/HMGB1 and improve sepsis-associated ALI and AKI. Conclusion: The present study demonstrated that DLT suppressed pro-inflammatory responses of macrophage and alleviated ALI and AKI in the CLP mice by inhibiting the transition activation of PARP1/HMGB1. These findings partially elucidate the mechanism of DLT in sepsis-associated ALI and AKI and further clarify the active components of DLT, thereby providing a scientific theoretical basis for treating sepsis with DLT.

Network and Experimental Pharmacology on Mechanism of Yixintai Regulates the TMAO/PKC/NF-κB Signaling Pathway in Treating Heart Failure.

Objective: This study aims to explore the mechanism of action of Yixintai in treating chronic ischemic heart failure by combining bioinformatics and experimental validation. Materials and Methods: Five potential drugs for treating heart failure were obtained from Yixintai (YXT) through early mass spectrometry detection. The targets of YXT for treating heart failure were obtained by a search of online databases. Gene ontology (GO) functional enrichment analysis and Kyoto encyclopedia of genes and genomes (KEGG) pathway enrichment analyses were conducted on the common targets using the DAVID database. A rat heart failure model was established by ligating the anterior descending branch of the left coronary artery. A small animal color Doppler ultrasound imaging system detected cardiac function indicators. Hematoxylin-eosin (HE), Masson's, and electron microscopy were used to observe the pathological morphology of the myocardium in rats with heart failure. The network pharmacology analysis results were validated by ELISA, qPCR, and Western blotting. Results: A total of 107 effective targets were obtained by combining compound targets and eliminating duplicate values. PPI analysis showed that inflammation-related proteins (TNF and IL1B) were key targets for treating heart failure, and KEGG enrichment suggested that NF-κB signaling pathway was a key pathway for YXT treatment of heart failure. Animal model validation results indicated the following: YXT can significantly reduce the content of intestinal microbiota metabolites such as trimethylamine oxide (TMAO) and improve heart failure by improving the EF and FS values of heart ultrasound in rats and reducing the levels of serum NT-proBNP, ANP, and BNP to improve heart failure. Together, YXT can inhibit cardiac muscle hypertrophy and fibrosis in rats and improve myocardial ultrastructure and serum IL-1ß, IL-6, and TNF-α levels. These effects are achieved by inhibiting the expressions of NF-κB and PKC. Conclusion: YXT regulates the TMAO/PKC/NF-κB signaling pathway in heart failure.

Integrated Network Pharmacology Analysis and Experimental Validation to Elucidate the Mechanism of Acteoside in Treating Diabetic Kidney Disease.

Background: Acteoside, an active ingredient found in various medicinal herbs, is effective in the treatment of diabetic kidney disease (DKD); however, the intrinsic pharmacological mechanism of action of acteoside in the treatment of DKD remains unclear. This study utilizes a combined approach of network pharmacology and experimental validation to investigate the potential molecular mechanism systematically. Methods: First, acteoside potential targets and DKD-associated targets were aggregated from public databases. Subsequently, utilizing protein-protein interaction (PPI) networks, alongside GO and KEGG pathway enrichment analyses, we established target-pathway networks to identify core potential therapeutic targets and pathways. Further, molecular docking facilitated the confirmation of interactions between acteoside and central targets. Finally, the conjectured molecular mechanisms of acteoside against DKD were verified through experimentation on unilateral nephrectomy combined with streptozotocin (STZ) rat model. The underlying downstream mechanisms were further investigated. Results: Network pharmacology identified 129 potential intersected targets of acteoside for DKD treatment, including targets such as AKT1, TNF, Casp3, MMP9, SRC, IGF1, EGFR, HRAS, CASP8, and MAPK8. Enrichment analyses indicated the PI3K-Akt, MAPK, Metabolic, and Relaxin signaling pathways could be involved in this therapeutic context. Molecular docking revealed high-affinity binding of acteoside to PIK3R1, AKT1, and NF-κB1. In vivo studies validated the therapeutic efficacy of acteoside, demonstrating reduced blood glucose levels, improved serum Scr and BUN levels, decreased 24-hour urinary total protein (P<0.05), alongside mitigated podocyte injury (P<0.05) and ameliorated renal pathological lesions. Furthermore, this finding indicates that acteoside inhibits the expression of pyroptosis markers NLRP3, Caspase-1, IL-1ß, and IL-18 through the modulation of the PI3K/AKT/NF-κB pathway. Conclusion: Acteoside demonstrates renoprotective effects in DKD by regulating the PI3K/AKT/NF-κB signaling pathway and alleviating pyroptosis. This study explores the pharmacological mechanism underlying acteoside's efficacy in DKD treatment, providing a foundation for further basic and clinical research.