Unveiling the Mechanism of Compound Ku-Shen Injection in Liver Cancer Treatment through an Ingredient-Target Network Analysis.

BACKGROUND: Compound Ku-Shen Injection (CKI) is a traditional Chinese medicine preparation derived from Ku-Shen and Bai-Tu-Ling, commonly used in the adjunctive treatment of advanced cancers, including liver cancer. However, the underlying mechanisms of CKI's effectiveness in cancer treatment are not well defined. METHODS: This study employs network pharmacology to investigate the traditional Chinese medicine (TCM) compatibility theory underlying CKI's action in treating liver cancer, with findings substantiated by molecular docking and in vitro experiments. Sixteen active components were identified from CKI, along with 193 potential targets for treating liver cancer. Key therapeutic target proteins, including EGFR and ESR1, were also identified. KEGG enrichment results showed that the neuroactive ligand-receptor interaction, cAMP signaling pathway, and serotonergic synapses make up the key pathway of CKI in the treatment of liver cancer. Molecular docking results confirmed that the key active ingredients effectively bind to the core targets. CCK-8 cytotoxic experiment results show that the CKI key components of oxymatrine and matrine can inhibit the growth of HepG2 liver cancer cell proliferation. A Western blot analysis revealed that oxymatrine suppresses the expression of EGFR, contributing to its therapeutic efficacy against liver cancer. CONCLUSION: our study elucidated the therapeutic mechanism of CKI in treating liver cancer and unveiled the underlying principles of its TCM compatibility through its mode of action.

Matrine alkaloids modulating DNA damage repair in chemoresistant non-small cell lung cancer cells.

BACKGROUND: Non-small cell lung cancer (NSCLC) presents a significant challenge in the medical field due to its high incidence and resistance to chemotherapy. Chemoresistance in NSCLC diminishes treatment efficacy and contributes to poor patient outcomes. Matrine alkaloids have shown promise in reversing chemotherapy resistance in NSCLC by targeting DNA repair mechanisms. METHODS: Utilizing molecular dynamics simulations, we explored the interactions between Matrine alkaloids and DNA repair-related proteins to elucidate their impact on NSCLC cells. In vitro experiments involved treating A549/DDP cells with Matrine alkaloids to evaluate their sensitizing effects on lung cancer cells. Additionally, animal model experiments were conducted to validate the therapeutic potential of Matrine alkaloids in NSCLC treatment. RESULTS: Our findings demonstrate that Matrine alkaloids disrupt DNA damage repair processes in NSCLC cells, leading to increased sensitivity to chemotherapy. Molecular docking studies revealed the intricate mechanisms by which Matrine alkaloids interact with DNA repair proteins, impacting cell survival and proliferation. Both cell experiments and animal models confirmed the chemosensitizing effects of Matrine alkaloids in NSCLC treatment. CONCLUSION: Matrine alkaloids offer a promising avenue for overcoming chemotherapy resistance in NSCLC by interfering with DNA repair pathways. This study lays a solid foundation for future clinical investigations into the potential of Matrine alkaloids as effective therapeutic agents for enhancing NSCLC treatment outcomes.

Safety and efficacy of CyTisine for smoking cessation in a hOSPital context (CITOSP): study protocol for a prospective observational study.

Tobacco addiction is the primary preventable factor contributing to global mortality, and nicotine is one of the substances with the greatest potential for addiction. With a strong affinity for the α4ß2 subtype receptor, cytisine (CYT) functions as a partial agonist of the acetylcholine nicotinic cholinergic receptor. It counteracts the effects of nicotine without causing any withdrawal symptoms. These features, combined with its limited mild adverse effects and minimal drug-drug interactions, make cytisine a cost-effective treatment for smoking cessation. The current protocol describes a prospective observational study on the safety and efficacy of CYT administered to inpatient smokers of the Integrated University Hospital of Verona (IUHVR), Veneto (Italy). This is a monocentric, observational, and prospective study on both sex smokers over the age of 18 years admitted to the IUHVR who meet the criteria for recruitment and have given their consent. Eligible participants will be assigned to the CYT intervention based on the West dosing schedule and will be followed up for 12 months from treatment initiation. Evaluation of safety, efficacy, and compliance will be assessed at 7 and 25 days, with follow-up at 3, 6, and 12 months from the start of the treatment (quit day). During each visit, any adverse events or adverse reactions reported by patients following the intake of CYT will be evaluated. This study will contribute, for the first time, to the knowledge about the use of CYT for smoking cessation in a hospital setting.

CARDIORESPIRATORY EFFECTS OF VATINOXAN IN BLESBOK (DAMALISCUS PYGARGUS PHILLIPSI) IMMOBILIZED WITH THIAFENTANIL-MEDETOMIDINE.

Combinations of a low dose of opioid, such as thiafentanil, and a high dose of medetomidine, are increasingly being used for immobilization of African ungulates. Both drugs can have undesirable cardiorespiratory effects. In this study we assessed whether vatinoxan, a peripherally acting alpha2-adrenergic receptor antagonist, can be used to alleviate some of these effects without affecting the immobilization quality. Eight healthy, female, boma-confined blesbok (Damaliscus pygargus phillipsi), weighing a mean (SDtion) of 56.8 (4.4) kg, were immobilized twice in a randomized cross-over study with a 2-wk washout period using (1) 0.5 mg thiafentanil + 1.5 mg medetomidine (TM), (2) TM + vatinoxan: 0.5 mg thiafentanil + 1.5 mg medetomidine + 15 mg vatinoxan per milligram medetomidine (total of 22.5 mg, administered intramuscularly at 10 min post recumbency). Heart rate, respiratory rate, rectal temperature, oxygen saturation (SpO2), arterial blood pressure, and sedation scores from 1 to 5 (1 = limited effect; 5 = excessively deep) were measured every 5 min. Arterial blood gases (PaO2 and PaCO2) were measured at 10, 15, 25, and 35 min postrecumbency and the alveolar--arterial oxygen gradient (P[A-a]O2) was calculated. Induction times and immobilization quality did not differ between groups. The heart rate was significantly higher and the mean arterial pressure significantly lower in blesbok after receiving vatinoxan. All animals were hypoxemic and there were no significant differences in the respiratory rates, PaO2, PaCO2, SpO2, or P(A-a)O2 gradients at any time point. Although vatinoxan did not improve respiratory variables and blood oxygenation in these animals, the change in cardiovascular variables may suggest that it improves tissue perfusion, a positive outcome that requires further investigation.

Modified oxymatrine as novel therapeutic inhibitors against Monkeypox and Marburg virus through computational drug design approaches.

Global impact of viral diseases specially Monkeypox (mpox) and Marburg virus, emphasizing the urgent need for effective drug interventions. Oxymatrine is an alkaloid which has been selected and modified using various functional groups to enhance its efficacy. The modifications were evaluated using various computatioanal analysis such as pass prediction, molecular docking, ADMET, and molecular dynamic simulation. Mpox and Marburg virus were chosen as target diseases based on their maximum pass prediction spectrum against viral disease. After that, molecular docking, dynamic simulation, DFT, calculation and ADMET prediction were determined. The main objective of this study was to enhance the efficacy of oxymatrine derivatives through functional group modifications and computational analyses to develop effective drug candidates against mpox and Marburg viruses. The calculated binding affinities indicated strong interactions against both mpox virus and Marburg virus. After that, the molecular dynamic simulation was conducted at 100 ns, which confirmed the stability of the binding interactions between the modified oxymatrine derivatives and target proteins. Then, the modified oxymatrine derivatives conducted theoretical ADMET profiling, which demonstrated their potential for effective drug development. Moreover, HOMO-LUMO calculation was performed to understand the chemical reactivity and physicochemical properties of compounds. This computational analysis indicated that modified oxymatrine derivatives for the treatment of mpox and Marburg virus suggested effective drug candidates based on their binding affinity, drug-like properties, stability and chemical reactivity. However, further experimental validation is necessary to confirm their clinical value and efficacy as therapeutic candidates.

Oxymatrine alleviates NSAID-associated small bowel mucosal injury by regulating MIP-1/CCR1 signalling and gut microbiota.

Oxymatrine (OMT) as a quinazine alkaloid extracted from matrine has been shown to exhibit anti-inflammatory and anti-tumour effects. However, the protective mechanism of OMT on NSAID-associated small bowel mucosal injury remains unreported. We found that OMT could improve the clinical symptoms and pathological inflammation scoring, reduce the secretion of proinflammatory cytokines IL-1ß, IL-6 and TNF-α and cell apoptosis, promote cell proliferation and protect intestinal mucosal barrier as compared with the Diclofenac Sodium (DS) group. Further RNA-seq and KEGG analysis uncovered that the differentially expressed genes between DS and control groups were mainly enriched in immune regulation, of which MIP-1γ and its receptor CCR1 expression were validated to be repressed by OMTH. MAPK/NF-κB as the MIP-1 upstream signalling was also inactivated by OMT treatment. In this study, OMT regulated gut microbiota. Venn diagrams visualized and identified 1163 shared OTUs between DS group and OMTH group. The results showed that the α diversity index in the DS group was lower than that in the OMTH group, indicating that the complexity of the flora was reduced in the intestinal inflammatory state. ß diversity mainly includes Principal Component Analysis (PCA) and Principal Co-ordinates Analysis (PCoA). The differences between groups can be observed through PCA. The more similar the composition of the flora, the closer the samples are. We found that the difference was smaller in the DS group than in the OMTH group. The results of PcoA showed that the sample similarity between OMTH groups was the highest. Moreover, gut microbiota analysis unveiled that the abundances of Ruminococcus 1, Oscillibacter and Prevotellaceae at the genus level as well as Lactobacillus SP-L-Yj at the species level were increased in OMTH group as compared with the DS group but the abundance of Allobaculum, Ruminococceos-UCG-005, Ruminococceos-NK4A214 and Clostridium associated with DS-induced small bowel mucosal injury could be decreased by OMTH. MIP-1α and CCR1 were upregulated in human small bowel injury samples as compared with the normal ileal mucosa tissues. In conclusion, our findings demonstrated that OMT could alleviate NSAID-associated small bowel mucosal injury by inhibiting MIP-1γ/CCR1 signalling and regulating gut microbiota.

Assessing the inhibitory effects of some secondary amines, thioureas and 1,3-dimethyluracil conjugates of (-)-cytisine and thermopsine on the RNA-dependent RNA polymerase of SARS-CoV-1 and SARS-CoV-2.

SARS-CoV-2 causes COVID-19, with symptoms ranging from mild to severe, including pneumonia and death. This beta coronavirus has a 30-kilobase RNA genome and shares about 80 % of its nucleotide sequence with SARS-CoV-1. The replication/transcription complex, essential for viral RNA synthesis, includes RNA-dependent RNA polymerase (RdRp, nsp12) enhanced by nsp7 and nsp8. Antivirals like molnupiravir and remdesivir, which are RdRp inhibitors, treat severe COVID-19 but have limitations, highlighting the need for new therapies. This study assessed (-)-cytisine, methylcytisine, and thermopsine derivatives against SARS-CoV-1 and SARS-CoV-2 in vitro, focusing on their RdRp inhibition. Selected compounds from a previous study were evaluated using a SARS-CoV-2 RNA polymerase assay kit to investigate their structure-activity relationships. Compound 17 (1,3-dimethyluracil conjugate with (-)-cytisine and thermopsine) emerged as a potent inhibitor of SARS-CoV-1 and SARS-CoV-2 RdRp, with an IC50 value of 7.8 µM against SARS-CoV-2 RdRp. It showed a dose-dependent reduction in cytopathic effects in cells infected with SARS-CoV-1 and SARS-CoV-2 replicon-based single-round infectious particles (SRIPs) and significantly inhibited SARS-CoV N protein expression, with EC50 values of 0.12 µM for SARS-CoV-1 and 1.47 µM for SARS-CoV-2 SRIPs. Additionally, compound 17 reduced viral subgenomic RNA levels in a concentration-dependent manner in SRIP-infected cells. The structure-activity relationships of compound 17 with SARS-CoV-1 and SARS-CoV-2 RdRp were also investigated, highlighting it as a promising lead for developing antiviral agents against SARS and COVID-19.

Effectiveness and safety of upadacitinib in acute severe ulcerative colitis patients from single Chinese IBD Center: a monocentric study.

Upadacitinib is an oral new selective JAK1 inhibitor that has been approved for treating adult patients with moderately to severely active ulcerative colitis. However, a growing number of studies are needed on the effectiveness of upadacitinib in the treatment of acute severe ulcerative colitis. This study was mainly aimed to describe the clinical and endoscopic effectiveness of upadacitinib 45 mg in Chinese acute severe ulcerative colitis patients following eight weeks of treatment. In this study, we examined all patients with acute severe ulcerative colitis from Xijing IBD Center, Xi'an, China, with acute severe ulcerative colitis. All patients were initially given oral upadacitinib 45 mg. Clinical indicators, C-reactive protein, and erythrocyte sedimentation rates were collected. Clinical response and clinical remission were assessed using modified Mayo. Endoscopic evaluation was performed carried out using the Mayo Endoscopic Score and Ulcerative colitis endoscopic index of severity score. A total of 14 patients who received upadacitinib were included in the study period. All patients exhibited a clinical response to 45 mg upadacitinib initially. All patients completed the 8-week induction. The clinical remission rate was 28.6% after eight weeks. Two patients revealed endoscopic remission at 14.3%. The pathology improved in 50.0% of patients. The 8-week surgical resection rate was 7.1%, with the 16-week surgical resection rate being 14.3%. Adverse events included herpes simplex virus infection and increased thrombin time. The results of our study support the short-term effectiveness and safety of upadacitinib in acute severe ulcerative colitis, providing new choices for patients' treatment. However, more extended investigation needs to be performed on the long-term effectiveness and safety.

Effect of oxymatrine on neutrophil function based on zebrafish inflammation model and primary neutrophil inflammatory responses.

Sophora flavescens Ait. (SFA), an extensively utilized herb for the treatment of fevers, inflammatory disorders, ulcers and skin diseases related to bur, contains oxymatrine (OMT) as its principal active constituent. OMT exerts regulatory effects over inflammation, oxidative stress and apoptosis. Neutrophils, critical regulators of the inflammation response, have not been thoroughly elucidated regarding the protective properties and underlying mechanisms of OMT-mediated anti-inflammation. This study was aim to explore the protective effect of OMT on neutrophils under inflammatory conditions and delve into its potential mechanism. Leveraging the advantages of zebrafish, an animal model with a real-time dynamic observation system, we established an in vivo caudal fin wound model and a copper sulfate induced-inflammation model in zebrafish line Tg (mpx:GFP). The result revealed that OMT significantly attenuated neutrophil migration, upregulated the mRNA expression levels of JNK, casp3, mapk14a, mapkapk2a and map2k1 damaged by zebrafish caudal fin wound model, and downregulated mRNA expression levels of JNK, casp3, mapk14a, mapkapk2a and map2k1 in the copper sulfate injury model. In vitro experiments demonstrated that OMT modulated the chemotaxis response of primary neutrophils from mice, enhanced phagocytosis, reduced oxidative stress and alleviated inflammation level. We hypothesize that the OMT may exert its anti-inflammatory effects by regulating primary neutrophils through the MAPK signaling pathway.

Characterization of Acid-Responsive-Release Matrine/ZIF-8@Sodium Alginate Microcapsules Prepared by Electrostatic Spray and Their Application in the Control of Soybean Cyst Nematode.

Matrine (MT) is a kind of alkaloid extracted from Sophora and is a promising substitute for chemical nematicides and botanical pesticides. The present study utilized sodium alginate (SA), zeolite imidazole salt skeleton (ZIF), and MT as raw materials to prepare a pH-response-release nematicide through the electrostatic spray technique. Zinc metal-organic framework (ZIF-8) was initially synthesized, followed by the successful loading of MT. Subsequently, the electrostatic spray process was employed to encapsulate it in SA, resulting in the formation of MT/ZIF-8@SA microcapsules. The efficiency of encapsulation and drug loadings can reach 79.93 and 26.83%, respectively. Soybean cyst nematode (SCN) is one of the important pests that harm crops; acetic acid produced by plant roots and CO2 produced by root respiration causing a decrease in the pH of the surrounding environment, which is most attractive to the SCN when the pH is between 4.5 and 5.4. MT/ZIF-8@SA releases the loaded MT in response to acetic acid produced by roots and acidic oxides produced by root respiration. The rate of release was 37.67% higher at pH 5.25 compared with pH 8.60. The control efficiency can reach 89.08% under greenhouse conditions. The above results demonstrate that the prepared MT/ZIF-8@SA not only exhibited excellent efficacy but also demonstrated a pH-responsive release of the nematicide.

Effect of nine pesticides against the date palm mite, Oligonychus afrasiaticus (Acari: Tetranychidae) and the predatory mite, Amblyseius swirskii (Acari: Phytoseiidae) under laboratory and field conditions.

Date palm trees, their cultivation and harvesting have become challenging due to infestations caused by some specific mites including Oligonychus afrasiaticus (McGregor) (Tetranychidae). Current research has been carried out to investigate the efficiency of nine pesticides against eggs and date palm mite, Oligonychus afrasiaticus against nine pesticides. Side effects of the nine pesticides were also examined on predatory mite, Amblyseius swirskii Athias-Henriot (Phytoseiidae). Mites and their eggs were treated with the recommended dosage of nine pesticides namely, Bifenazate 24%, Bifenthrin 10%, Matrine 0.6%, Imidacloprid 37% + Abamectin 3%, Sulphur 99.5%, Micronized Sulphur 80%, Mineral oil 95%, Pyrethrin 1.5% and Hexythiazox 10%, while they were present in their natural environment on the date palm trees in the experimental fields. Highest mortality of 91.16% was observed when O. afrasiaticus was treated with Bifenazate (24%) followed by 87.31%, 85.20%, 72.06%, 71.34%, 65.35%, 64.14%, 61.06% and 24.25% in case of Bifenthrin 10%, Matrine 0.6%, Imidacloprid 37% + Abamectin 3%, Sulphur 99.5%, Micronized Sulphur 80%, Mineral oil 95%, Pyrethrin 1.5%, and Hexythiazox 10%, respectively. A minimum hatching of 25.74% was observed when eggs of O. afrasiaticus were treated with Hexythiazox 10% and the highest success of hatching (99.07%) was seen when treatment was given with Imidacloprid 37% + Abamectin 3%. When same trials with same nine pesticides were performed on predatory mite; Amblyseius swirskii, the highest mortality in terms of percentage reduction (75.63%) was observed with Bifenthrin and the lowest (14.69%) with Matrine. Nine pesticides used in this study have distinct toxicity against targeted mite, their eggs and the predatory mite. A two steps control strategy is recommended for this treatment. First spray Hexythiazox at the egg laying stage and then at the moving stage of mites by using Matrine which is toxic to mites but negligibly toxic to predatory mites. Further studies are recommended to evaluate varied actions of the pesticide against eggs, phytophagous mites, and predatory mites.

The effects of intra-accumbal administration of the nicotinic acetylcholine receptor agonist cytisine on the operant oral self-administration of ethanol were prevented by the GABAB receptor agonist baclofen in rats.

RATIONALE: Although the mesocorticolimbic dopamine (DA) system is the main neurochemical substrate that regulates the addictive and reinforcing effects of ethanol (EtOH), other neurotransmitter systems, such as the acetylcholine (Ach) system, modulate DAergic function in the nucleus accumbens (nAcc). Previously, we reported that intra-nAcc administration of the nicotinic Ach receptor agonist cytisine increased oral EtOH self-administration. GABAB receptors in the nAcc are expressed in DAergic terminals, inhibit the regulation of DA release into the nAcc, and could modulate the effects of cytisine on oral EtOH self-administration. The present study assessed the effects of intra-nAcc administration of the GABAB receptor agonist baclofen (BCF) on the impacts of cytisine on oral EtOH self-administration. METHODS: Male Wistar rats were deprived of water for 23.30 h and then trained to press a lever to receive EtOH on an FR3 schedule until a stable response rate of 80 % was achieved. After this training, the rats received an intra-nAcc injection of the nAch receptor agonist cytisine, BCF, and cytisine or 2-hydroxysaclofen, BCF, and cytisine before they were given access to EtOH on an FR3 schedule. RESULTS: Intra-nAcc injections of cytisine increased oral EtOH self-administration; this effect was reduced by BCF, and 2-hydroxysaclofen blocked the effects of BCF. CONCLUSIONS: These findings suggest that the reinforcing effects of EtOH are modulated not only by the DA system but also by other neurotransmitter systems involved in regulating DA release from DAergic terminals.

Medetomidine-vatinoxan-midazolam provides similar sedation depth with reduced bradycardia compared to dexmedetomidine-midazolam in pigeons (Columba livia domestica).

OBJECTIVE: To determine if sedation with medetomidine-vatinoxan (Zenalpha; Dechra Veterinary Products) and midazolam (Alvogen) (ZM) would cause less cardiovascular depression and maintain similar depth and duration of sedation in pigeons (Columba livia domestica) compared to dexmedetomidine and midazolam (DM). METHODS: In a blinded crossover study, 15 healthy adult domestic pigeons were sedated IM with either dexmedetomidine (0.08 mg/kg) and midazolam (2 mg/kg) or medetomidine (0.16 mg/kg), vatinoxan (3.2 mg/kg), and midazolam (2 mg/kg) from November through December 2023. Each subject was monitored for 60 minutes, then the sedation was reversed with atipamezole (0.8 mg/kg) and flumazenil (0.1 mg/kg) as needed. Sedation scores, heart rates, and respiratory rates were compared. RESULTS: There was no significant difference in the peak sedation score between DM and ZM groups, with both exhibiting median scores of 4 (heavy sedation). Mean heart rate was significantly higher for ZM than DM at 5, 10, 20, 30, 45, 60, and 65 minutes postinjection. Bradycardia occurred in both groups at 5 and 10 minutes postinjection and persisted for DM until reversal with atipamezole. Arrhythmias were auscultated in both groups. Bradypnea was not observed in either group, and all birds resumed normal behavior following recovery and the following day. CONCLUSIONS: Medetomidine-vatinoxan-midazolam provides a similar depth of sedation to DM but with less incidence of bradycardia. Further study is needed to determine the clinical applicability of this sedative in birds. CLINICAL RELEVANCE: Medetomidine-vatinoxan may be considered for short-term sedation and restraint in cardiovascularly stable pigeons.

Co-amorphous systems of sulfasalazine with matrine-type alkaloids: Enhanced solubility behaviors and synergistic therapeutic potential.

Sulfasalazine (SULF), a sulfonamide antibiotic, has been utilized in the treatment of rheumatoid arthritis (RA) and inflammatory bowel disease (IBD) since its discovery. However, its poor water solubility causes the high daily doses (1---3 g) for patients, which may lead to the intolerable toxic and side effects for their lifelong treatment for RA and IBD. In this work, two water-soluble natural anti-inflammatory alkaloids, matrine (MAR) and sophoridine (SPD), were employed to construct the co-amorphous systems of SULF for addressing its solubility issue. These newly obtained co-amorphous forms of SULF were comprehensively characterized by powder X-ray diffraction (PXRD), temperature-modulated differential scanning calorimetry (mDSC), Fourier-transform infrared spectroscopy (FTIR), and X-ray photoelectron spectroscopy (XPS). We also investigated their dissolution behavior, including powder dissolution, in vitro release, and intrinsic dissolution rate. Both co-amorphous systems exhibited superior dissolution performance compared to crystalline SULF. The underlying mechanism responsible for the enhanced dissolution behaviors in co-amorphous systems were also elucidated. These mechanisms include the inhibition of nucleation, complexation, increased hydrophilicity, and robust intermolecular interactions in aqueous solutions. Importantly, these co-amorphous systems demonstrated satisfactory physical stability under various storage conditions. Network pharmacological analysis was utilized to investigate the potential therapeutic targets of both co-amorphous systems against RA, revealing similar yet distinct multi-target synergistic therapeutic mechanisms in the treatment of this condition. Our study suggests these drug-drug co-amorphous systems hold promise for optimizing SULF dosage in the future and providing a potential drug combination strategy.

Oral matrine alleviates CCl4-induced liver fibrosis via preserved HSP72 from modulated gut microbiota.

Hepatic fibrosis is intricately associated with dysregulation of gut microbiota and host metabolomes. Our previous studies have demonstrated that matrine can effectively reduce hepatosteatosis and associated disorders. However, it is poorly understood whether the gut microbiota involved in the attenuation of liver fibrosis by matrine. Herein we explored a novel mechanism of how oral administration of matrine alleviates liver fibrosis by modulating gut microbiota. Administration of matrine not only potently ameliorated liver fibrosis in carbon tetrachloride (CCl4)-induced mice, but also significantly preserved hepatic heat shock protein 72 (HSP72) in vivo and in vitro. Matrine was failed to reduce liver fibrosis when HSP72 upregulation was blocked by the HSP72 antagonist VER-155008. Also, consumption of matrine significantly alleviated gut dysbiosis and fecal metabonomic changes in CCl4-treated mice. Transplanted the faces of matrine-treated mice induced a remarkable upregulation of HSP72 and remission of fibrosis in liver in CCl4-exposed mice and inhibition of TGF-ß1-induced inflammatory response and epithelial-mesenchymal transition (EMT) in AML-12 cells. Furthermore, deficiency of HSP72 partly reversed the intestinal microbial composition that prevented matrine from reducing CCl4-induced liver fibrosis in mice. This study reveals the "gut microbiota-hepatic HSP72" axis as a key mechanism of matrine in reducing liver fibrosis and suggest that this axis may be targeted for developing other new therapies for liver fibrosis.

Mental health related adverse events of cytisine and varenicline in smokers with and without mental health disorders: Secondary analysis of a randomized controlled trial.

INTRODUCTION: Little is known about the adverse events (AEs) of cytisine versus varenicline among individuals with mental health disorders (MHDs), highlighting the necessity for further exploration to inform clinical practice. This secondary analysis of clinical trial data aimed to investigate the effect of varenicline vs. cytisine regarding mental-health-related AEs (MH-related AEs) on smokers with and without MHDs. METHODS: Australian daily smokers interested in quitting were randomised to varenicline (84 days) or cytisine (25 days) and categorised by self-reported MHD diagnosis or treatment in the past year (MHD or non-MHD groups). Treatment adherence was assessed by self-reported number of doses taken during the active treatment phase via two check-in calls (at one month), while AEs were evaluated through four phone interviews: two check-in calls (one month) and follow-up calls at four and seven months. Logistic regression analysis compared MH-related AEs between groups, including only participants taking at least one dose. RESULTS: Of 1452 smokers 246 reported MHDs, 725 received cytisine and 727 received varenicline. Median number of doses taken was comparable between MHD (34 cytisine and 12 varenicline) and non-MHD (33 cytisine and 13 varenicline) groups. MH-related AEs were: 14.1 % (n = 30) in MHD (12.5 % in cytisine and 15.4 % in varenicline), and 11.8 % (n = 126) in non-MHD group (10.9 % in cytisine and 13.7 % in varenicline). No significant difference in MH-related AE occurrence was identified between medication groups (aOR=0.96, 95 % CI 0.4 to 2.2, p-value = 0.94). CONCLUSION: Comparable MH-related AEs were observed between smokers with and without MHDs, suggesting that cytisine, like varenicline, may be well-tolerated by those with MHDs. However, larger clinical trials focused on MH-related AEs are needed for more conclusive evidence.

Study on co-amorphous emerging solubilization behavior after gelation during dissolution: The importance of complexation and anti-crystallization.

Co-amorphous (CM) is a promising technology for enhancing the aqueous solubility of insoluble drugs, but the gelation phenomenon has often occurred during the dissolution process and seriously threatened their solubility/dissolution performance. Therefore, it's quite important to design favorable CM systems to alleviate or even avoid the adverse effects of gelation phenomenon. In this study, CM systems of taxifolin (TAX) and oxymatrine (OMT) (TAX-OMT CMs) were constructed to improve the solubility and dissolution properties of TAX. Interestingly, TAX-OMT CMs gradually aggregated and obviously gelled during dissolution, but the solubility and dissolution of TAX in TAX-OMT CMs were significantly enhanced compared to crystalline TAX. Consequently, the underlying solubilization mechanisms of TAX-OMT CMs after gelation were systematically explored. For one thing, the complexation between the two components in TAX-OMT CMs was verified by phase solubility, fluorescence spectroscopy and isothermal titration calorimetry. For another, the residual solids of TAX-OMT CMs after dissolution evaluation were thoroughly characterized by means of powder X-ray diffraction, fourier transform infrared spectroscopy, scanning electron microscopy, which showed the anti-crystallization property of TAX-OMT CMs. Furthermore, molecular simulation demonstrated the intermolecular interactions of TAX-OMT CMs alone and TAX-OMT complexes in aqueous solution. Finally, pharmacokinetics study in rats suggested that the bioavailability of TAX in TAX-OMT CM (1:2) was approximately 5.5-fold higher than that of crystalline TAX after oral administration. Collectively, this study reveals the importance of complexation and anti-crystallization effects of CM systems on maintaining solubilization behavior after gelation, providing an effective strategy to improve the absorption performance of pharmaceutical CM systems.

The synergy effect of matrine and berberine hydrochloride on treating colibacillosis caused by an avian highly pathogenic multidrug-resistant Escherichia coli.

Infection by multidrug-resistant avian pathogenic Escherichia coli (APEC) in chickens always leads to the uselessness of antibiotics, highlighting the need for alternative antibacterial agents. Sophora flavescens and Coptis chinensis have been a classical combination used together in Traditional Chinese Medicine (TCM) formulas to treat diseases with similar symptoms to colibacillosis for an extended period, but the effect of their active ingredients' combination on APEC infection remains unstudied. The objective of this study was to explore the synergistic effect of matrine and berberine hydrochloride on colibacillosis caused by an isolated multidrug-resistant APEC. In this study, a highly pathogenic E. coli was isolated from the liver of a diseased chicken in a farm suspected of colibacillosis, and it was resistant to multiple antibiotics. The LD50 of the strain was approximately 3.759×108 CFU/mL. The strain harbored several antibiotic resistance genes and virulence genes. Matrine and berberine hydrochloride have synergistic antibacterial effect against the isolated strain in vitro. The combined use of matrine and berberine hydrochloride exhibited synergistic effects in the treatment of APEC infection by regulating the organ indices, improving the pathological situation, decreasing the bacterial load, and regulating the inflammatory factors to enhance the survival rate of chickens in vivo. These results provided a foundation for revealing the effective effects and possible mechanisms of matrine and berberine hydrochloride as potential antimicrobial agents on diseases caused by multidrug-resistant APEC in chickens.

Matrine Suppresses Arsenic-Induced Malignant Transformation of SV-HUC-1 Cells via NOX2.

Arsenic (As) has been classified as a carcinogen for humans. There is abundant evidence indicating that arsenic increases the risk of bladder cancer among human populations. However, the underlying mechanisms have yet to be fully understood and elucidated. NADPH oxidases (NOXs) are the main enzymes for ROS production in the body. NADPH Oxidase 2 (NOX2), which is the most distinctive and ubiquitously expressed subunit of NOXs, can promote the formation and development of tumors. The utilization of NOX2 as a therapeutic target has been proposed to modulate diseases resulting from the activation of NOD-like receptor thermal protein domain associated protein 3 (NLRP3). Matrine has been reported to exhibit various pharmacological effects, including anti-inflammatory, antifibrotic, antitumor, and analgesic properties. However, it has not been reported whether matrine can inhibit malignant transformation induced by arsenic in uroepithelial cells through NOX2. We have conducted a series of experiments using both a sub-chronic NaAsO2 exposure rat model and a long-term NaAsO2 exposure cell model. Our findings indicate that arsenic significantly increases cell proliferation, migration, and angiogenesis in vivo and in vitro. Arsenic exposure resulted in an upregulation of reactive oxygen species (ROS), NOX2, and NLRP3 inflammasome expression. Remarkably, both in vivo and in vitro, the administration of matrine demonstrated a significant improvement in the detrimental impact of arsenic on bladder epithelial cells. This was evidenced by the downregulation of proliferation, migration, and angiogenesis, as well as the expression of the NOX2 and NLRP3 inflammasomes. Collectively, these findings indicate that matrine possesses the ability to reduce NOX2 levels and inhibit the transformation of bladder epithelial cells.

Public Health Impact of FDA's Request for Additional Safety Data on Cytisine for Tobacco Cessation.

Importance: No new tobacco cessation medication has been licensed in the US since 2006. Cytisine, a plant-based partial agonist of nicotinic acetylcholine receptors, has demonstrated safety and efficacy in several randomized clinical trials and is currently available in many countries. However, the drug is not commercially available in the US. A New Drug Application to license cytisine as a smoking cessation medication in the US is being prepared for review by the US Food and Drug Administration, whose request for additional safety data will delay submission of the application by approximately 1 year. Objective: To project the potential public health impact of cytisine, and delays in its availability, as a smoking cessation aid in the US. Design, Setting, and Participants: This mathematical model estimated life expectancy gains from smoking cessation for people aged 18 to 99 years in the US, reflecting the civilian, noninstitutionalized population. The model also accounted for cytisine uptake and effectiveness, as well as potential relapse among people who stop smoking. Exposure: Cytisine availability as a tobacco cessation treatment immediately or after 1 year. Main Outcomes and Measures: The main outcomes were the number of adults able to stop smoking and sustain long-term abstinence and aggregate life-years gained. Results: The base case includes an estimated 29.4 million US civilian noninstitutionalized adults who smoke cigarettes (age distribution, 18-24 years: 5.5%; 25-44 years: 37.3%; 45-64 years: 41.8%; ≥65 years: 15.5%). With a conservative assumption that 3.8% of these individuals would use cytisine in the first year of availability, immediate cytisine availability could lead 71 000 more people to quit smoking over 1 year and maintain long-term abstinence. This would produce more than 500 000 additional life-years compared to the status quo in which cytisine is unavailable and fewer people stop smoking. Each additional year of delay in the availability of cytisine might reduce population-level life expectancy by 10 000 years. The model results were most sensitive to changes in cytisine uptake and effectiveness. Conclusions and Relevance: Smoking cessation generates large gains in life expectancy. This mathematical model demonstrated that immediate cytisine availability, even if used successfully by only a small fraction of people who smoke, could produce major public health benefits. Given the need for new tobacco cessation pharmacotherapy options, the magnitude of cytisine's potential public health benefits, and the morbidity and mortality associated with delay in its availability, a timely review of cytisine for approval in the US is warranted.