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IntroductionAmdizalisib (HMPL-689) is an ATP-competitive PI3Kδ inhibitor currently under investigation for treating Hodgkin’s lymphoma. This study aimed to evaluate the metabolism, excretion, pharmacokinetics, and safety profile of amdizalisib in healthy human subjects to support its clinical application.MethodsThis Phase I clinical trial included six healthy Chinese male volunteers who received a single oral dose of 30 mg/100 µCi [14C]amdizalisib suspension. Blood, urine, and fecal samples were collected to analyze pharmacokinetics, metabolic pathways, and excretion patterns.ResultsAmdizalisib was rapidly absorbed, with a median Tmax of 2.5 h. The Cmax of 244 ± 48.9 ng/mL, and AUC0-t was 1870 ± 474 h ng/mL after a single oral dose. The blood-to-plasma total radioactivity ratio ranged from 0.561 to 0.645, indicating no significant affinity of [14C]amdizalisib and its metabolites to blood cells and the radioactive material is mainly distributed in plasma. Excretion was primarily via feces and urine, with 62.08% ± 3.00% and 37.15% ± 2.84% of the dose recovered, respectively, and over 94% of the drug excreted within 96 h. The parent drug was the main radioactive component in plasma (51.45% of total radioactivity). Additionally, 11 metabolites were identified, and the metabolic pathways include oxidation on the benzene or pyrimidine rings and conjugation with cysteine or glucuronic acid. The major metabolites in plasma were the di-oxidized and hydrogenated product (M424) and the mono-oxidized product (M406-2), accounting for 16.67% and 20.91%, respectively. Both of them are also the major radioactive components in urine and feces, among of which M424 accounted for 21.01% and 14.26%, M406-2 accounted for 8.08% and 11.30%, of the administered dose in urine and feces, respectively. In addition, the di-oxidized and methylated product (M436) was one of the major metabolites in feces accounting for 17.7% of the administered dose. Few of the parent drug was found in urine and feces, suggesting primary metabolized in the liver. No serious adverse events or drug-related deaths occured, with diarrhea as the most common adverse event.DiscussionThese findings demonstrate that amdizalisib is rapidly absorbed, extensively metabolized, and primarily excreted via feces and urine, supporting its continued development as a potential therapeutic for Hodgkin's lymphoma.Systematic Review Registration:https://www.chinadrugtrials.org.cn/, identifier CTR20212448.

IntroductionDiabetic retinopathy (DR) is a common complication of diabetes. Retinal neuronal degeneration is an early event in DR, indicated by the declined electroretinogram (ERG). Dipeptide alanine-glutamine (Ala-Gln) is widely used as a nutritional supplement in the clinic and has anti-inflammatory effects on the gastrointestinal system. Studies also reported that glutamine has beneficial effects on diabetes. This study aimed to investigate the possible therapeutic effects of Ala-Gln in diabetic retinal neurodegeneration and to delineate its mechanism of action.MethodsThe Streptozotocin (STZ)-induced rat model was used as a DR model. ERG was used to measure the neuronal function of the retina. Western blot analysis was performed to test the expression of proteins. Immunofluorescence staining was used for the detection and localization of proteins.ResultsIn diabetic rats, the amplitudes of ERG were declined, while Ala-Gln restored the declined ERG. Retinal levels of inflammatory factors were significantly decreased in Ala-Gln-treated diabetic rats. Ala-Gln mitigated the declined levels of glutamine synthetase and ameliorated the upregulated levels of glial fibrillary acidic protein (GFAP) in diabetic retinas. Moreover, Ala-Gln upregulated the glycolytic enzymes pyruvate kinase isozymes 2 (PKM2), lactate dehydrogenase A (LDHA) and LDHB and stimulated the mTOR signaling pathway in diabetic retinas. The mitochondrial function was improved after the treatment of Ala-Gln in diabetic retinas.DiscussionAla-Gln ameliorates retinal neurodegeneration by reducing inflammation and enhancing glucose metabolism and mitochondrial function in DR. Therefore, manipulation of metabolism by Ala-Gln may be a novel therapeutic avenue for retinal neurodegeneration in DR.

BackgroundDexmedetomidine (DEX) is a commonly used sedative in the intensive care unit and has demonstrated cardioprotective properties against ischemia-reperfusion injury in preclinical studies. However, the protective effects of early treatment of DEX in patients with acute myocardial infarction (AMI) and its underlying mechanism are still not fully understood. This study aims to investigate the association between early DEX treatment and in-hospital mortality in patients with AMI, and to explore the potential mediating role of white blood cell (WBC) reduction in this relationship.MethodsA retrospective cohort analysis was conducted using the Medical Information Mart for Intensive Care IV (MIMIC-IV) database. Patients with AMI were divided into the DEX and non-DEX group, based on whether they received DEX treatment in the early stage of hospitalization. The primary outcome measured was in-hospital mortality. The study evaluated the association between DEX use and in-hospital mortality using the Kaplan-Meier (KM) method and Cox proportional hazards model. Additionally, 1:1 propensity score matching (PSM) was conducted to validate the results. Furthermore, causal mediation analysis (CMA) was utilized to explore potential causal pathways mediated by WBC reduction between early DEX use and the primary outcome.ResultsThis study analyzed data from 2,781 patients, with 355 in the DEX group and 2,426 in the non-DEX group. KM survival analysis revealed a significantly lower in-hospital mortality rate in the DEX group compared to the non-DEX group. After adjusting for multiple confounding factors, the Cox regression model demonstrated a significant positive impact of DEX on the risk of in-hospital mortality in patients with AMI, with hazard ratios (HR) of 0.50 (95% confidence interval (CI): 0.35–0.71, p < 0.0001). PSM analysis confirmed these results, showing HR of 0.49 (95% CI: 0.31–0.77, p = 0.0022). Additionally, CMA indicated that 13.7% (95% CI: 1.8%–46.9%, p = 0.022) of the beneficial effect of DEX on reducing in-hospital mortality in patients with AMI was mediated by the reduction in WBC.ConclusionThe treatment of DEX was associated with a lower risk of in-hospital mortality in patients with AMI, potentially due to its anti-inflammatory properties.

BackgroundOphiopogon D is an important natural organic compound in Ophiopogon japonicus, which often has significant biological activity.PurposeThe purpose of this review is to systemically summarize and discuss the pharmacological activity and underlying mechanisms of OP-D in recent years.MethodPubMed and Web of Science were searched with the keywords:“Ophiopogon japonicus”, “Ophiopogon D” “pharmacology”, and “pharmacokinetics”. There was no restriction on the publication year, and the last search was conducted on 1 Jan 2024.ResultsEmerging evidence suggests that OP-D possess numerous pharmacological activities, including bone protection, cardiovascular protection, immune regulation, anti-cancer, anti-atherosclerosis, anti-inflammatory and anti-NAFLD.ConclusionOP-D has a potential value in the prevention and treatment of many diseases. We hope that this review will contribute to therapeutic development and future studies of OP-D.

ObjectiveJianPiHuaTan Formula (JPHTF), a traditional Chinese medicine (TCM), has been utilized as an adjunctive therapy for colorectal cancer (CRC). The study aims to evaluate the potential clinical benefits of JPHTF and its effectiveness in inhibiting tumor growth.Methods300 stage II/III CRC patients and 412 advanced CRC patients were enrolled to verify the clinical value of JPHTF in CRC treatment. Furthermore, CRC patient-derived xenograft (PDX) mice were utilized to investigate the regulatory mechanisms of JPHTF.ResultsJPHTF significantly improved abdominal distension, shortness of breath, drowsiness, loss of appetite, sleep, and tiredness in stage II/III CRC patients, thereby improving their quality of life. Simultaneously, JPHTF served as a supportive therapy in extending the overall survival (OS) of stage IV CRC patients with RAS/RAF mutations undergoing chemotherapy. Additionally, JPHTF effectively impeded tumor progression in CRC PDX models with RAS mutation, accompanied by a reduction in tumor cell content in the JPHTF group. Transcriptomic analysis revealed the involvement of the Hippo and Hedgehog signaling pathways in JPHTF-mediated CRC inhibition. Furthermore, mice in the JPHTF group exhibited increased immune cell infiltration.ConclusionThese findings suggested that JPHTF may inhibits tumor growth in CRC with RAS mutation by modulating RAS/RAF downstream signaling pathways, specifically the Hippo and Hedgehog signaling, leading to increased immune cell infiltration.

Pyruvate kinase M2 (PKM2), a rate limiting enzyme in glycolysis, is a cellular regulator that has received extensive attention and regards as a metabolic regulator of cellular metabolism and energy. Kidney is a highly metabolically active organ, and glycolysis is the important energy resource for kidney. The accumulated evidences indicates that the enzymatic activity of PKM2 is disturbed in kidney disease progression and treatment, especially diabetic kidney disease and acute kidney injury. Modulating PKM2 post-translational modification determines its enzymatic activity and nuclear translocation that serves as an important interventional approach to regulate PKM2. Emerging evidences show that PKM2 and its post-translational modification participate in kidney disease progression and treatment through modulating metabolism regulation, podocyte injury, fibroblast activation and proliferation, macrophage polarization, and T cell regulation. Interestingly, PKM2 activators (TEPP-46, DASA-58, mitapivat, and TP-1454) and PKM2 inhibitors (shikonin, alkannin, compound 3k and compound 3h) have exhibited potential therapeutic property in kidney disease, which indicates the pleiotropic effects of PKM2 in kidney. In the future, the deep investigation of PKM2 pleiotropic effects in kidney is urgently needed to determine the therapeutic effect of PKM2 activator/inhibitor to benefit patients. The information in this review highlights that PKM2 functions as a potential biomarker and therapeutic target for kidney diseases.

Methicillin-resistant Staphylococcus aureus (MRSA) is a major inducement of nosocomial infections and its biofilm formation render the high tolerance to conventional antibiotics, which highlights the requirement to develop new antimicrobial agents urgently. In this study, we identified a fluorinated benzimidazole derivative, TFBZ, with potent antibacterial efficacy toward planktonic MRSA (MIC = 4 μg/mL, MBC = 8 μg/mL) and its persistent biofilms (≥99%, MBEC = 8 μg/mL). TFBZ manifested significant irreversible time-dependent killing against MRSA as characterized by diminished cell viability, bacterial morphological change and protein leakage. Furthermore, the results from CBD devices, crystal violet assay in conjunction with live/dead staining and scanning electron microscopy confirmed that TFBZ was capable of eradicating preformed MRSA biofilms with high efficiency. Simultaneously, TFBZ reduced the bacterial invasiveness and exerted negligible hemolysis and cytotoxicity toward mammalian cells, which ensuring the robust therapeutic effect on mouse skin abscess model. The transcriptome profiling and quantitative RT-PCR revealed that a set of encoding genes associated with cell adhesion, biofilm formation, translation process, cell wall biosynthesis was consistently downregulated in MRSA biofilms upon exposure to TFBZ. In conclusion, TFBZ holds promise as a valuable candidate for therapeutic applications against MRSA chronic infections.

Introduction: Drug dosages and combinations are the main factors that affect the efficacy of pleiotropic traditional Chinese medicine (TCM). Coptis chinensis Franch. (CF) is a representative TCM with multiple effects and is often combined with Tetradium ruticarpum (A. Jussieu) T. G. Hartley (TR) to treat cholestasis. The present study assessed the influence of CF dose and its combination with TR on the efficacy of CF in cholestasis treatment, including their effects on fecal metabolism and fecal microorganisms.Methods: Rats with α-naphthylisothiocyanate (ANIT, 50 mg/kg)-induced cholestasis were administered low (0.3 g/kg) and high (0.6 g/kg) doses of CF, as well as CF combined with TR at doses of 0.6 g/kg and 0.9 g/kg, respectively. The anti-cholestatic effects of these treatments were assessed by determining their anti-inflammatory, hypolipidemic, and anti-oxidative stress properties. Additionally, fecal metabolomics and fecal microorganisms were analyzed.Results: Low dose CF had a more potent hypolipidemic effect than high dose CF, whereas high dose CF had more potent anti-inflammatory and anti-oxidative stress effects. Combination with TR enhanced the hypolipidemic effect, but antagonized the anti-inflammatory effect, of CF. Analyses of fecal metabolomics and fecal microorganisms showed differences in the regulation of lipid- and amino acid metabolism-related pathways, including pathways of linoleic acid, tyrosine, and arachidonic acid metabolism, and amino acid biosynthesis between different doses of CF as well as between different doses of CF in combination with TR. These differences may contribute to differences in the anti-cholestatic effects of these preparations.Conclusion: CF dose influences its anti-cholestatic efficacy. The combination with TR had synergistic or antagonistic effects on the properties of CF, perhaps by altering fecal metabolism and fecal microbial homeostasis.

Purpose: HSK16149 is a novel, potent gamma-aminobutyric acid (GABA) analog for the treatment of neuropathic pain. This study aimed to evaluate the safety, tolerability, and pharmacokinetics of HSK16149 after single and multiple doses in healthy Chinese subjects.Methods: The randomized, double-blind, placebo-controlled study comprised two parts: SAD (single ascending-dose study) and MAD (multiple ascending-dose study). A total of 122 healthy subjects were enrolled in this study. HSK16149 capsule or placebo was administered as the protocol required. The safety of the drug was evaluated through clinical examinations and adverse events. Blood and urine samples were collected at the designated time intervals for pharmacokinetic analysis.Results: Subjects were generally well tolerated after HSK16149 administration and the most common treatment-emergent adverse event (TEAEs) was dizziness, which was expected based on the mechanism of action of HSK16149. In SAD, AUC and Cmax were shown to have a dose-proportional relationship in the dose range of 5-120 mg. The t1/2 of HSK16149 is 3.7-6.4 h. In MAD, after a single and multiple administration of 15-80 mg, AUC and Cmax are proportional to the increased dose of HSK16149, and the accumulative ratios of AUC and Cmax at steady-state were 1.05–1.44 and 1.07–1.36, respectively, indicating that HSK16149 only accumulated slightly after repeated administration.Conclusion: HSK16149 was well tolerated in healthy Chinese subjects. Based on the safety and pharmacokinetic data, 80 mg twice daily (BID) was suggested as the highest target dose for further clinical development.Clinical Trial Registration:http://www.chinadrugtrials.org.cn, identifier CTR20182535 and CTR20191317

Intrahepatic cholestasis of pregnancy (ICP) is characterized by unexplained distressing pruritus in the mother and poses significant risk to the fetus of perinatal mortality. Occurring in the second and third trimester, the serum bile acid and aminotransferase are usually elevated in ICP patients. Ursodeoxycholic acid (UDCA) is the first line drug for ICP but the effectiveness for hepatoprotection is to a certain extent. In ICP patients with severe liver damage, combination use of hepatoprotective agents with UDCA is not uncommon. Herein, we reviewed the current clinical evidence on application of hepatoprotective agents in ICP patients. The underlying physiological mechanisms and their therapeutic effect in clinical practice are summarized. The basic pharmacologic functions of these hepatoprotective medications include detoxification, anti-inflammation, antioxidation and hepatocyte membrane protection. These hepatoprotective agents have versatile therapeutic effects including anti-inflammation, antioxidative stress, elimination of free radicals, anti-steatohepatitis, anti-fibrosis and anti-cirrhosis. They are widely used in hepatitis, non-alcoholic fatty liver disease, drug induced liver injury and cholestasis. Evidence from limited clinical data in ICP patients demonstrate reliable effectiveness and safety of these medications. Currently there is still no consensus on the application of hepatoprotective agents in ICP pregnancies. Dynamic monitoring of liver biochemical parameters and fetal condition is still the key recommendation in the management of ICP pregnancies.

Background: Previous studies suggested that anti-TNF drugs might be repurposed as a preventive treatment for colorectal cancer. We aimed to examine whether genetically proxied inhibition of tumor necrosis factor receptor 1 (TNFR1) reduces the absolute risk of colorectal cancer through mendelian randomization (MR) analysis.Methods: We obtained 28 single nucleotide polymorphisms (SNPs) that were located within a ±15 kilobase window of the TNFRSF1A—the gene that encodes the TNFR1 protein, and we used genetic data from three GWAS studies of circulating levels of TNFR1, C-reactive protein (CRP), and white blood counts (WBC) to screen SNPs that proxied the inhibition of TNFR1. Positive control analyses were then performed by using another three GWAS data from the ulcerative colitis cohort (n = 45,975), Crohn’s disease cohort (n = 40,266), and multiple sclerosis cohort (n = 115,803) to confirm the effect of the included SNPs. A two-sample mendelian randomization analysis was performed to examine the association between TNFR1 inhibition and the absolute risk reduction (ARR) of colorectal cancer.Results: We finally included seven SNPs to proxy the anti-TNF effect, and these SNPs caused lower levels of TNFR1, CRP, and white blood counts. In positive control analyses, the included SNPs caused lower odds ratio of ulcerative colitis and Crohn’s disease but a higher odds ratio of multiple sclerosis, consistent with drug mechanistic actions and previous trial evidence. By using the inverse-variance weighted analyses to combine the effects of the seven SNPs, we found that the anti-TNF effect was associated with a 0.988 (95%CI 0.985–0.991) mg/L decrease in CRP levels and a reduction in the risk of colorectal cancer (absolute risk reduction -2.1%, 95%CI -3.8% to -0.4%, p = 0.01).Conclusion: Our study confirmed that anti-TNF drugs were associated with a risk reduction in colorectal cancer. Physicians could consider using anti-TNF drugs for the prevention of colorectal cancer, especially in patients with high risks of developing cancer.

Aim: Vitamin D plays a vital role in Rheumatoid arthritis (RA). However, the mechanism of vitamin D and rheumatism is still unclear. Therefore, a strategy based on network pharmacology and molecular docking was used to explore the mechanism of vitamin D and RA.Methods: The targets of RA were obtained from the GeneCards database and Therapeutic Targets Database, and the targets of vitamin D were obtained from the Drugbank database and STITCH database. Next, overlapping genes were identified by Venny, and further Gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and molecular docking analyses were performed.Results: A total of 1,139 targets of RA and 201 targets of vitamin D were obtained. A total of 76 overlapping genes were identified by Venny. The enrichment analysis showed that cell proliferation, immune response, and apoptotic process were the critical biological processes of vitamin D in treating RA. Antifolate resistance, osteoclast differentiation, and the nuclear factor-kappa B (NF-κB) signalling pathway are fundamental mechanisms of vitamin D in treating RA. According to further molecular docking, ALB, TNF, CASP3, and TP53 may be important punctuation points or diagnostic markers for future RA treatment.Conclusion: By analysing overlapping genes of diseases and drugs, this study confirmed that ALB, TNF, CASP3, and TP53 may be essential markers or diagnostic markers for future RA treatment.

Diabetic kidney disease (DKD) is the major complications of type 1 and 2 diabetes, and is the predominant cause of chronic kidney disease and end-stage renal disease. The treatment of DKD normally consists of controlling blood glucose and improving kidney function. The blockade of renin-angiotensin-aldosterone system and the inhibition of sodium glucose cotransporter 2 (SGLT2) have become the first-line therapy of DKD, but such treatments have been difficult to effectively block continuous kidney function decline, eventually resulting in kidney failure and cardiovascular comorbidities. The complex mechanism of DKD highlights the importance of multiple therapeutic targets in treatment. Chinese herbal medicine (active compound, extract and formula) synergistically improves metabolism regulation, suppresses oxidative stress and inflammation, inhibits mitochondrial dysfunction, and regulates gut microbiota and related metabolism via modulating GLP-receptor, SGLT2, Sirt1/AMPK, AGE/RAGE, NF-κB, Nrf2, NLRP3, PGC-1α, and PINK1/Parkin pathways. Clinical trials prove the reliable evidences for Chinese herbal medicine against DKD, but more efforts are still needed to ensure the efficacy and safety of Chinese herbal medicine. Additionally, the ideal combined therapy of Chinese herbal medicine and conventional medicine normally yields more favorable benefits on DKD treatment, laying the foundation for novel strategies to treat DKD.

Background: Diarrhea is one of the leading causes of death worldwide and is associated with immune dysfunction. The modulatory effects of Shenling Baizhu powder (SLBZS) on immune function in diarrheal disease have been validated in various animal models. However, the results of these studies have not been systematically evaluated. This study aimed to evaluate the preclinical data on SLBZS for the treatment of diarrhea from an immunological perspective.Methods: PubMed, Embase, Cochrane Library, CNKI, Wanfang Database, VIP, and Chinese Medicine Database were searched for all animal trials on SLBZS for the treatment of diarrhea published up to April 2022. Standardized mean differences (SMD) were used as effect sizes in the meta-analysis of continuous variables, including immune organs, immune cells, and immune cytokines. Subgroup analysis was performed according to animal species and disease models. The GRADE was used to assess the quality of evidence.Results: A total of 26 studies were included. Meta-analysis showed that compared to those in the model group, SLBZS significantly increased body weight [SMD = 1.54, 95% confidence interval (CI) (1.06, 2.02)], spleen mass [SMD = 1.42, 95% CI (0.98, 1.87)], thymus mass [SMD = 1.11, 95% CI (0.69, 1.53)], macrophage phagocytic capacity (SMD = 1.07, 95% CI [0.59, 1.54]), sIgA [SMD = 1.04, 95% CI (0.33, 1.74)], RBC-C3b-RR [SMD = 1.16, 95% CI (0.65, 1.67)], IL-2 [SMD = 1.52, 95% CI (0.89, 2.14)] and decreased diarrhea scores [SMD = −1.40, 95% CI (−2.03, −0.87)], RBC-IC-RR [SMD = −1.40, 95% CI (−1.94, −0.87)], and IL-8 [SMD = −2.80, 95% CI (−3.54, −2.07)]. Subgroup analysis showed that SLBZS regulated TNF-α, IL-1β, and IL-10 in rats and mice, and improved IL-6 and IL-10 in different diseases, with differences between subgroups (p < 0.05). Owing to heterogeneity, the reliability of the results remains to be verified. The quality of evidence was “very low”.Conclusion: SLBZS improve diarrhea symptoms by enhancing immune function. It has curative effects with differences between different species and diseases, however, because the reporting in the original studies was too unclear to be assessed, the analysis was inconclusive. For higher quality evidences, future research should pay attention to the scientific rigor of the experimental design and the completeness of the reported results.

Descurainia sophia seeds (DS), Astragalus mongholicus (AM), and their formulas are widely used to treat heart failure caused by various cardiac diseases in traditional Chinese medicine practice. However, the molecular mechanism of action of DS and AM has not been completely understood. Herein, we first used mass spectrometry coupled to UPLC to characterize the chemical components of DS and AM decoctions, then applied MS-based quantitative proteomic analysis to profile protein expression in the heart of rats with isoproterenol-induced cardiomyopathy (ISO-iCM) before and after treated with DS alone or combined with AM, astragaloside IV (AS4), calycosin-7-glucoside (C7G), and Astragalus polysaccharides (APS) from AM. We demonstrated for the first time that DS decoction alone could reverse the most of differentially expressed proteins in the heart of the rats with ISO-iCM, including the commonly recognized biomarkers natriuretic peptides (NPPA) of cardiomyopathy and sarcomeric myosin light chain 4 (MYL4), relieving ISO-iCM in rats, but AM did not pronouncedly improve the pharmacological efficiency of DS. Significantly, we revealed that AS4 remarkably promoted the pharmacological potency of DS by complementarily reversing myosin motor MYH6/7, and further downregulating NPPA and MYL4. In contrast, APS reduced the efficiency of DS due to upregulating NPPA and MYL4. These findings not only provide novel insights to better understanding in the combination principle of traditional Chinese medicine but also highlight the power of mass spectrometric proteomics strategy combined with conventional pathological approaches for the traditional medicine research.

Objective To explore the efficacy and safety of chemotherapy combined with immunotherapy as the first-line treatment of advanced or metastatic squamous NSCLC.Methods Two researchers independently searched PubMed, the Cochrane Library, EMBASE, CNKI, Wanfang Data, and other databases by using a computer, collected the clinical trials or randomized controlled trials published by April 2022 about immunotherapy combined with chemotherapy as the first-line treatment of advanced or metastatic squamous NSCLC, screened the literature, and extracted the data according to the nanodischarge criteria. We used Revman5.4 for statistical analysis of the included studies, and publication bias was analyzed with Egger’s test in Stata12.Results A total of seven clinical trials were included, including 1,510 cases in the chemotherapy combined with the immunotherapy group and 1,519 cases in the chemotherapy group. In terms of effectiveness, compared with the chemotherapy group, chemotherapy combined with immunotherapy for advanced or metastatic squamous NSCLC had longer overall survival (HR = 1.59, 95% CI: 1.46–1.72, p < 0.00001) and progression-free survival (HR = 1.84, 95% CI: 1.66–2.03, p < 0.00001). In terms of safety, the chemotherapy combined with immunotherapy group has a higher risk of adverse reactions at any level and above three levels of hematotoxicity, gastrointestinal abnormalities, and liver dysfunction than the chemotherapy group. Egger’s test has minor publication bias.Conclusion Chemotherapy combined with immunotherapy is effective as the first-line treatment for advanced or metastatic squamous NSCLC, but the risk of adverse reactions is relatively high. If there are adverse reactions in clinical application, it should be treated in time.

Edaravone dexborneol is a novel neuroprotective drug that comprises edaravone and (+)-borneol in a 4:1 ratio. Phase II and III studies have demonstrated that Chinese patients treated with edaravone dexborneol within 48 h of AIS onset have better functional outcomes than those treated with edaravone alone. However, the effect of edaravone dexborneol on subarachnoid hemorrhage (SAH) has not yet been elucidated. This study aimed to investigate the therapeutic effects of edaravone dexborneol on SAH-induced brain injury and long-term behavioral deficits and to explore the possible mechanisms. The experimental rat SAH model was induced by an intraluminal puncture of the left middle cerebral artery (MCA). Edaravone dexborneol or edaravone at a clinical dose was infused into the tail vein for 3 days post-SAH surgery. Behavioral outcomes were assessed by a modified Garcia scoring system and rotarod, foot-fault, and corner tests. Immunofluorescence, Western blot, and ELISA methods were used to evaluate neuronal damage and oxidative stress. Our results showed that a post-SAH therapeutic regimen with edaravone dexborneol helped improve neurological function up to 21 days after SAH surgery and demonstrated a greater beneficial effect than edaravone alone, accompanied by an obvious inhibition of neuronal apoptosis in the CA1 hippocampus and basal cortex regions. Mechanistically, edaravone dexborneol not only suppressed the lipid peroxidation product malondialdehyde (MDA) but also improved the total antioxidant capability (TAC) 3 days after SAH. Notably, edaravone dexborneol treatment significantly inhibited the expression of another lipid peroxidation product, 4-hydroxynonenal (4-HNE), in the CA1 hippocampus and basal cortex, which are vital participants in the process of neuronal oxidative damage and death after SAH because of their acute cytotoxicity. Together, our results demonstrate that edaravone dexborneol confers neuroprotection and stabilizes long-term behavioral ability after SAH injury, possibly by suppressing 4-HNE-associated oxidative stress. These results may help develop new clinical strategies for SAH treatment.

Background: Currently no study has examined the effects of probiotic administration on the symptoms of anxiety, depression, and mania, as well as their correlations with the biomarkers of oxidative stress in patients with bipolar disorder (BPD). The aim of this study is to determine the effects of probiotic supplementation on plasma oxidative stress-related biomarkers and different domains of clinical symptom in patients suffering from BPD.Methods: Eighty first-episode drug-naive patients with BPD were recruited. The subjects were randomized to receive psychotropic drugs supplementing with either probiotic or placebo and scheduled to evaluate with follow-ups for clinical symptom improvements and changes in the oxidative stress biomarkers. The Hamilton Depression Rating Scale, Hamilton Anxiety Rating Scale, and Young Mania Rating Scale were used to assess the clinical symptomatology. The panel of plasma oxidative stress biomarkers were determined by ultra-performance liquid chromatography–mass spectrometry (UPLC–MS/MS) at baseline and for 3 months of follow-up, i.e., at post-treatment month 1, 2, and 3.Results: After 3 months of intervention, decreased levels of plasma lysophosphatidylcholines (LPCs) were found in both placebo and probiotic groups. However, six other oxidative stress biomarkers (i.e., creatine, inosine, hypoxanthine, choline, uric acid, allantoic acid) increased in BPD patients after the two types of therapies. In addition, a positive correlation between changes of LPC (18:0) and YMRS scale was found in BPD patients and this association only existed in the probiotic group. Additionally, the mania symptom greatly alleviated (pretreatment–posttreatment, odds ratio = 0.09, 95%CI = 0.01, 0.64, p= 0.016) in patients who received probiotic supplements as compared with the placebo group.Conclusion: The changes in plasma biomarkers of oxidative stress in patients with BPD have a potential to be trait-like markers, and serve as prognostic indexes for bipolar patients. Daily intakes of probiotics have advantageous effects on BPD patients with certain clinical symptoms, especially manic symptoms. The treatment may be a promising adjunctive therapeutic strategy for BPD patients in manic episode.

Mood disorders, also often referred to as affective disorders, are a group of psychiatric illnesses that severely impact mood and its related functions. The high medical expenditures have placed a significant financial burden on patients and their families. Aromatherapy is an alternative and complementary treatment that utilizes essential oils (EOs) or volatile oils (VOs) to achieve major therapeutic goals. In general, EOs are volatile chemicals that enter the body primarily through skin absorption and/or nasal inhalation. In addition, they can work through oral administration. Inhalation aromatherapy has shown unique advantages for treating mood disorders, especially depression, anxiety and mental disorders such as sleep disorder, which have been validated over the last decade through clinical and animal studies. Accumulating evidence has shown that EOs or VOs can bypass the blood-brain barrier to target brain tissue through the nasal-brain pathway. Subsequently, they act on the cerebral cortex, thalamus, and limbic system in the brain to improve symptoms of anxiety, depression and improve sleep quality. Here, we review the natural aromatic plants’ volatiles or essential oils used commonly as adjuncts to manage mood disorders and illustrate the mechanisms of inhalation aromatherapy, and mainly summarized the application of transnasal inhalation aromatherapy in depression, anxiety, and sleep disorders. We conclude that aromatherapy does not cause side-effects, which is vastly different from commonly used psychotropic drugs. Inhalation aromatherapy via brain-targeted nasal delivery offers potentially efficacious treatment for mental disorders and merits further study.

Renal fibrosis is the common and final pathological process of kidney diseases. As a dynamic and reversible post-translational modification, SUMOylation and deSUMOylation of transcriptional factors and key mediators significantly affect the development of renal fibrosis. Recent advances suggest that SUMOylation functions as the promising intervening target against renal fibrosis, and natural products prevent renal fibrosis via modulating SUMOylation. Here, we introduce the mechanism of SUMOylation in renal fibrosis and therapeutic effects of natural products. This process starts by summarizing the key mediators and enzymes during SUMOylation and deSUMOylation and its regulation role in transcriptional factors and key mediators in renal fibrosis, then linking the mechanism findings of SUMOylation and natural products to develop novel therapeutic candidates for treating renal fibrosis, and concludes by commenting on promising therapeutic targets and candidate natural products in renal fibrosis via modulating SUMOylation, which highlights modulating SUMOylation as a promising strategy for natural products against renal fibrosis.

Zinc is an essential trace element important for the physiological function of the central nervous system. The abnormal accumulation of zinc inside neurons may induce mitochondrial dysfunction and oxidative stress, which contribute to many brain diseases. We hypothesized that natural anthraquinone derivative emodin can protect against neurotoxicity induced by pathological concentrations of zinc via the extracellular signal-regulated kinase 1/2 (ERK1/2) signaling pathway and alleviate oxidative stress and mitochondrial dysfunction. Human neuroblastoma (SH-SY5Y 26 cells) was treated with zinc sulfate and different concentrations of emodin, and changes in the levels of ETK1/2 expression, oxidative stress (DCFH-DA staining), mitochondrial function (JC-1 staining), lipid peroxidation (4-hydroxynonenal staining), and DNA oxidation (8-hydroxy-2-deoxyguanosine staining) were examined. Emodin ameliorated zinc-induced altered expression of levels of phosphorylated ERK1/2 (not total ETK1/2) and synaptic proteins (presynaptic SNAP 25, synaptophysin and postsynaptic PSD95) in SH-SY5Y cells. Moreover, emodin inhibited the generation of reactive oxygen species and oxidative stress and facilitated the collapse of mitochondrial membrane potential (ΔΨm) in SH-SY5Y cells. In conclusion, our results indicated that emodin exerts neuroprotective effects against zinc by normalizing synaptic impairment by decreasing the phosphorylation of ERK1/2, reducing reactive oxygen species and protecting mitochondrial function.

PcActx peptide, identified from the transcriptome of zoantharian Palythoa caribaeorum, was clustered into the phylogeny of analgesic polypeptides from sea anemone Heteractis crispa (known as APHC peptides). APHC peptides were considered as inhibitors of transient receptor potential cation channel subfamily V member 1 (TRPV1). TRPV1 is a calcium-permeable channel expressed in epileptic brain areas, serving as a potential target for preventing epileptic seizures. Through in silico and in vitro analysis, PcActx peptide was shown to be a potential TRPV1 channel blocker. In vivo studies showed that the linear and oxidized PcActx peptides caused concentration-dependent increases in mortality of zebrafish larvae. However, monotreatment with PcActx peptides below the maximum tolerated doses (MTD) did not affect locomotor behavior. Moreover, PcActx peptides (both linear and oxidized forms) could effectively reverse pentylenetetrazol (PTZ)-induced seizure-related behavior in zebrafish larvae and prevent overexpression of c-fos and npas4a at the mRNA level. The excessive production of ROS induced by PTZ was markedly attenuated by both linear and oxidized PcActx peptides. It was also verified that the oxidized PcActx peptide was more effective than the linear one. In particular, oxidized PcActx peptide notably modulated the mRNA expression of genes involved in calcium signaling and γ-aminobutyric acid (GABA)ergic-glutamatergic signaling, including calb1, calb2, gabra1, grm1, gria1b, grin2b, gat1, slc1a2b, gad1b, and glsa. Taken together, PcActx peptide, as a novel neuroactive peptide, exhibits prominent anti-epileptic activity, probably through modulating calcium signaling and GABAergic-glutamatergic signaling, and is a promising candidate for epilepsy management.

Huolisu Oral Liquid (HLS), a well-known traditional Chinese medicine (TCM) prescription, is an over-the-counter drug that is registered and approved by the State Food and Drug Administration (Approval No. Z51020381). HLS has been widely applied in the clinical treatment of cognitive disorders and has effects on delaying aging. The antioxidant effects of HLS are closely related to its antiaging activities, but the underlying mechanisms are unclear. In this study, the potential antioxidant ingredients of HLS were screened based on serum pharmacochemistry and network pharmacology, and the potential mechanisms involved in HLS antioxidant effects were preliminarily explored. Further, the antioxidant effects of HLS were verified by in vivo and in vitro experiments. The results showed that potential antioxidant ingredients could affect the toxic advanced glycation end products-receptor for advanced glycation end products (TAGE-RAGE) signaling, mitogen-activated protein kinase (MAPK) signaling, interleukin (IL)-17 signaling, tumor necrosis factor (TNF) signaling, toll-like receptors (TLRs), cyclic adenosine monophosphate (cAMP) signaling, hypoxia-inducible factor (HIF)-1 signaling, and other related pathways by regulating GAPDH, AKT1, TP53, MAPK1, JUN, and other associated targets. Thus, HLS may reduce inflammation, control the release of inflammatory cytokines, and regulate mitochondrial autophagy and metabolic abnormalities to ultimately play an antioxidant role. This is the first study attempting to construct a multilevel network of “HLS-antioxidant targets” based on serum pharmacochemistry and network pharmacology to explore the relationship between HLS and antioxidation and the molecular mechanisms of antioxidation combined with bioinformatics functional analysis and lays a foundation for further elucidating the antioxidant mechanisms of HLS.

Sepsis is a life-threatening syndrome induced by aberrant host response towards infection. The autophagy-lysosomal pathway (ALP) plays a fundamental role in maintaining cellular homeostasis and conferring organ protection. However, this pathway is often impaired in sepsis, resulting in dysregulated host response and organ dysfunction. Transcription factor EB (TFEB) is a master modulator of the ALP. TFEB promotes both autophagy and lysosomal biogenesis via transcriptional regulation of target genes bearing the coordinated lysosomal expression and regulation (CLEAR) motif. Recently, increasing evidences have linked TFEB and the TFEB dependent ALP with pathogenetic mechanisms and therapeutic implications in sepsis. Therefore, this review describes the existed knowledge about the mechanisms of TFEB activation in regulating the ALP and the evidences of their protection against sepsis, such as immune modulation and organ protection. In addition, TFEB activators with diversified pharmacological targets are summarized, along with recent advances of their potential therapeutic applications in treating sepsis.

Ulcerative colitis (UC) is a chronic nonspecific inflammation that mainly affects the mucosa and submucosa of the rectum and colon. Numerous studies have shown that endoplasmic reticulum stress (ERS)-induced autophagy plays a vital role in the pathogenesis of UC. ERS is the imbalance of internal balance caused by misfolded or unfolded proteins accumulated in the endoplasmic reticulum (ER).Excessive ERS triggers the unfolded protein response (UPR), an increase in inositol-requiring enzyme 1, and a Ca2+ overload, which activates the autophagy pathway. Autophagy is an evolutionarily conserved method of cellular self-degradation. Dysregulated autophagy causes inflammation, disruption of the intestinal barrier, and imbalance of intestinal homeostasis, therefore increasing the risk of colonic diseases. This review summarizes the pathogenesis of ERS, UPR, and ERS-related autophagy in UC, providing potential new targets and more effective treatment options for UC.

Adrenergic nerve fibers in the tumor microenvironment promote tumor growth and represent a potential target for cancer therapy. However, the effectiveness of targeting adrenergic nerve fibers for oral squamous cell carcinoma (OSCC) therapy needs to be evaluated by preclinical data. Herein, the 4NQO-induced and orthotopic xenograft OSCC mice models were established. We demonstrated that using 6OHDA chemical denervation as well as using nebivolol adrenergic blockade could halt the oral mucosa carcinogenesis. Our preclinical studies suggested that nebivolol, which is widely used to treat cardiovascular diseases, can be repositioned as a potential candidate to treat OSCC. Remarkably, we revealed the precise effect and mechanism of nebivolol on OSCC cells proliferation, cell cycle, and cell death. Administration of nebivolol could activate the endoplasmic reticulum (ER) stress signaling pathway through increasing the expression of inducible nitric oxide synthase, which subsequently triggers the integrated stress response and cell growth arrest. Simultaneously, ER stress also induced mitochondrial dysfunction in OSCC cells. We found that the accumulation of dysfunctional mitochondria with the impaired electron transport chain caused increasing reactive oxygen species production, which ultimately resulted in OSCC cell death. Altogether, our finding suggested a novel therapeutic opportunity for OSCC by targeting adrenergic nerve fibers, and repurposing nebivolol to treat OSCC can be represented as an effective strategy.

Chinese vine tea can improve glucose and lipid metabolic disorders. However, its protective effects in non-alcoholic steatohepatitis (NASH) and its underlying molecular mechanisms remain unclear. Liver X receptor α (LXRα) inhibition and adenosine monophosphate-(AMP)-activated protein kinase (AMPK) activation can enhance control of NASH. AMPK activators have also been shown to inactivate LXRα. Here, the anti-NASH effects of vine tea extract (VTE) dosed at 1 g.100 g−1 diet were investigated using NASH mice challenged with a methionine and choline-deficient l-amino acid diet (MCDD) and a high-fat diet (HFD). Pharmacological mechanisms of VTE were explored using TUNEL staining, AMPK inhibition, Western blot, reporter assays, qRT-PCR analyses, and immunofluorescence. VTE treatment improved fatty liver in HFD-induced mice, while it alleviated the progression of NASH including protecting against liver lipid accumulation, steatosis, endoplasmic reticulum stress, apoptosis, inflammation, and functional injury in MCDD-fed mice. VTE reduced the action of hepatic lipogenic genes, F4/80, pro-inflammatory cytokines, CHOP, and cleaved Caspase-3 expression, while promoting expression of fatty acid oxidation genes CPT1α, ß. VTE also enhanced AMPK and blocked LXRα signaling in mouse livers. In vitro results indicated that VTE increased AMPK phosphorylation and reduced LXRα activity in HepG2 cells. Conversely, the antagonistic effect of VTE on LXRα was decreased through AMPK inhibition. Our data suggests that VTE may improve diet-induced NASH, which involves the pharmacological modulation of the AMPK-LXRα signaling pathway.

Objective: To explore the clinical efficacy of paliperidone palmitate long-acting injection combined with electroacupuncture in the treatment of methamphetamine addicts.Methods: This study focused on methamphetamine addicts who were admitted to our hospital from January 2020 to December 2020 as the main research object, with a total of 89 cases. The patients were divided into a control group of 45 cases and a study group of 44 cases according to the treatment method. The control group was treated with electroacupuncture, and the study group was treated with paliperidone palmitate long-acting injection on the basis of electroacupuncture in the control group. After 6 months of continuous treatment, the treatment effect of methamphetamine withdrawal symptom score before and after treatment was used; Hamilton Anxiety Scale score and Hamilton Depression Scale were used to compare the anxiety and depression situation of the two groups; the brain wave α and θ wave situation of the two groups were compared.Result: The results showed that there was no significant difference in the scores of Ma withdrawal symptoms, Hamilton Anxiety and Hamilton Depression between the two groups before treatment (p < 0.05); after 3 and 6 months of treatment, the scores of Ma withdrawal symptoms, Hamilton Anxiety and Hamilton Depression in the study group were significantly lower than those in the control group and the difference was statistically significant (p < 0.05); 6 months after the completion of the treatment, the α wave amplitude and Fourier transformed α brain wave (FFTα) in the study group were significantly higher than those in the control group, and the difference was statistically significant (p < 0.05).Conclusion: Paliperidone palmitate long-acting injection combined with electroacupuncture is better than electroacupuncture alone in the treatment of methamphetamine addicts, and can significantly improve anxiety, depression and brain waves, thereby preventing addicts from relapse.

Cognitive impairment is a shared abnormality between type 2 diabetes mellitus (T2DM) and many neurodegenerative and neuropsychiatric disorders, such as Alzheimer’s disease (AD) and schizophrenia. Emerging evidence suggests that brain insulin resistance plays a significant role in cognitive deficits, which provides the possibility of anti-diabetic agents repositioning to alleviate cognitive deficits. Both preclinical and clinical studies have evaluated the potential cognitive enhancement effects of anti-diabetic agents targeting the insulin pathway. Repurposing of anti-diabetic agents is considered to be promising for cognitive deficits prevention or control in these neurodegenerative and neuropsychiatric disorders. This article reviewed the possible relationship between brain insulin resistance and cognitive deficits. In addition, promising therapeutic interventions, especially current advances in anti-diabetic agents targeting the insulin pathway to alleviate cognitive impairment in AD and schizophrenia were also summarized.

Objectives: Danhong injections (DHI) are widely used in the treatment of acute myocardial infarction (AMI). As there are no guidelines for the timing of DHI in the peri-percutaneous coronary intervention (PCI) period for AMI, we investigated the effects of DHI timing.Methods: We reviewed reports published before September 30, 2020 in PubMed, embase, the Cochrane Central Register of Controlled Trials, the Chinese BioMedical database, Chinese VIP database, Wanfang database, and Chinese National Knowledge Infrastructure database. Only randomized controlled trials of DHI with percutaneous coronary intervention for AMI were included. Methodological quality was assessed using the Cochrane evaluation manual 5.3.3 criteria. A meta-analysis was performed, and forest plots were drawn.Results: We included 23 studies which all revealed that patients in DHI groups had better efficacy than control groups. Subgroup analysis revealed that DHI administered intraoperatively and continued postoperatively was more effective in increasing left ventricular ejection fraction when compared to other time-points (p < 0.001). The pre- and intraoperative use of DHI could improve reflow more effectively than conventional treatment, while the effect was not significant in the postoperative intervention study (p = 0.654). The 16 postoperative interventions revealed that the effect of DHI at 14 days was better than that at 7 and 10 days for hs-CRP (p = 0.013), the 10-days treatment produced better results for CK-MB than for the other treatments (p < 0.001) and a dosage of 30 ml proved most effective for IL-6 (p < 0.001).Conclusion: DHI proved to be superior to conventional Western medicine in reducing the incidence of adverse cardiac events, promoting reperfusion, improving cardiac function, reducing inflammatory factors, and protecting the myocardium. DHI should be administered early in the perioperative period and continued postoperatively because of its ability to improve cardiac function. Furthermore, in the PCI postoperative, 30 ml is recommended to inhibit IL-6 levels, for patients with high hs-CRP, a course of 14 days is most effective, for patients with obvious abnormalities of CK-MB, a 10-days course of treatment is recommended. However, due to the limited number and quality of the original randomized controlled trials, our conclusions need large, multi-centre RCTs to validation.

Ketamine exposure can model cognitive deficits associated with schizophrenia. Progesterone (PROG) and its active metabolite allopregnanolone (ALLO) have neuroprotective effects and the pathway involving progesterone receptor membrane component 1 (PGRMC1), epidermal growth factor receptor (EGFR), glucagon-like peptide-1 receptor (GLP-1R), phosphatidylinositol 3 kinase (PI3K), and protein kinase B (Akt) appears to play a key role in their neuroprotection. The present study aimed to investigate the effects of PROG (8,16 mg kg−1) and ALLO (8,16 mg kg−1) on the reversal of cognitive deficits induced by ketamine (30 mg kg−1) via the PGRMC1 pathway in rat brains, including hippocampus and prefrontal cortex (PFC). Cognitive performance was evaluated by Morris water maze (MWM) test. Western blot and real-time quantitative polymerase chain reaction were utilized to assess the expression changes of protein and mRNA. Additionally, concentrations of PROG and ALLO in plasma, hippocampus and PFC were measured by a liquid chromatography-tandem mass spectrometry method. We demonstrated that PROG or ALLO could reverse the impaired spatial learning and memory abilities induced by ketamine, accompanied with the upregulation of PGRMC1/EGFR/GLP-1R/PI3K/Akt pathway. Additionally, the coadministration of AG205 abolished their neuroprotective effects and induced cognitive deficits similar with ketamine. More importantly, PROG concentrations were markedly elevated in PROG-treated groups in hippocampus, PFC and plasma, so as for ALLO concentrations in ALLO-treated groups. Interestingly, ALLO (16 mg kg−1) significantly increased the levels of PROG. These findings suggest that PROG can exert its neuroprotective effects via activating the PGRMC1/EGFR/GLP-1R/PI3K/Akt pathway in the brain, whereas ALLO also restores cognitive deficits partially via increasing the level of PROG in the brain to activate the PGRMC1 pathway.

Subretinal fibrosis is a common pathological change that causes vision loss in neovascular age-related macular degeneration (nAMD). Treatment modalities for subretinal fibrosis are limited. In the present study, the effects of fenofibrate, a specific peroxisome proliferator–activated receptor alpha agonist, on subretinal fibrosis of nAMD were tested, and its molecular mechanisms of action were delineated. Collagen deposition and protein expression of fibrotic markers, such as vimentin, collagen-1, alpha-smooth muscle actin, and fibronectin, were increased in very low–density lipoprotein receptor (VLDLR) knockout mouse, indicating Vldlr−/− mice can be used as a model for subretinal fibrosis. Fenofibrate suppressed subretinal fibrosis of Vldlr−/− mice by reducing collagen deposition and protein expression of fibrotic markers. Two fibrotic pathways, TGF-β—Smad2/3 signaling and Wnt signaling, were significantly up-regulated, while inhibited by fenofibrate in Vldlr−/− retinas. Moreover, fenofibrate significantly reduced the downstream connective tissue growth factor (CTGF) expression of these two pathways. Müller cells were a major source of CTGF in Vldlr−/− retinas. Fenofibrate was capable of suppressing Müller cell activation and thus reducing the release of CTGF in Vldlr−/− retinas. In cultured Müller cells, fenofibrate reversed TGF-β2–induced up-regulation of Wnt signaling and CTGF expression. These findings suggested that fenofibrate inhibits subretinal fibrosis by suppressing TGF-β—Smad2/3 signaling and Wnt signaling and reducing CTGF expression, and thus, fenofibrate could be a potential treatment for nAMD with subretinal fibrosis.

Myostatin is a crucial cytokine that is widely present in skeletal muscle and that negatively regulates the growth and development of muscle cells. Recent research has shown that myostatin might play an essential role in bone metabolism. In RAW264.7 cells and bone marrow monocytes (BMMCs), myostatin activates the expression of the II type receptor ActR II B. Here, we report that myostatin significantly promoted RANKL/M-CSF-induced osteoclastogenesis and activated NF-κB and MAPK pathways in vitro via the Ccdc50 gene. Overexpression of myostatin promoted osteoclastogenesis and osteoclastogenesis-related markers including c-Src, MMP9, CTR, CK, and NFATc1. Specifically, myostatin increased the phosphorylation of Smad2, which led to the activation of NF-κB and MAPK pathways to activate osteoclastogenesis. Ccdc50 was identified as a gene whose expression was highly decreased in osteoclastogenesis upon myostatin treatment, and it could inhibit the function of myostatin in osteoclastogenesis by blocking NF-κB and MAPKs pathways. Our study indicates that myostatin is a promising candidate target for inhibiting RANKL-mediated osteoclastogenesis and might participate in therapy for osteoporosis, and that the Ccdc50 gene plays a significant role in the regulatory process.

Aberrant fibroblast growth factor receptor-1 (FGFR1), a key driver promoting gastric cancer (GC) progression and chemo-resistance, has been increasingly recognized as a potential therapeutic target in GC. Hereon, we designed and synthesized a series of asymmetric analogues using Af23 and NDGA as lead compounds by retaining the basic structural framework (bisaryl-1,4-dien-3-one) and the unilateral active functional groups (3,4-dihydroxyl). Thereinto, Y14 showed considerable inhibitory activity against FGFR1. Next, pharmacological experiments showed that Y14 could significantly inhibit the phosphorylation of FGFR1 and its downstream kinase AKT and ERK, thus inhibiting the growth, survival, and migration of gastric cancer cells. Furthermore, compared with 5-FU treatment alone, the combination of Y14 and 5-FU significantly reduced the phosphorylation level of FGFR1, and enhanced the anti-cancer effect by inhibiting the viability and colony formation in two gastric cancer cell lines. These results confirmed that Y14 exerted anti-gastric activity and chemosensitizing effect by inhibiting FGFR1 phosphorylation and its downstream signaling pathway in vitro. This work also provides evidence that Y14, an effective FGFR1 inhibitor, could be used alone or in combination with chemotherapy to treat gastric cancer in the future.

Sertoli cells play crucial roles in spermatogenesis and are impaired by aging. Icariin, a flavonoid from Epimedium, has been reported to exhibit anti-aging effects and improve testicular dysfunction in the clinical setting. However, whether icariin improves age-related degeneration of testicular function via protection from Sertoli cell injury remains unclear. In the present study, we evaluated the protective effect of icariin on Sertoli cell injury and explored the possible mechanism(s) in vivo and in vitro. Dietary administration of icariin for 4 months significantly ameliorated the age-related decline in testicular function by increasing testicular and epididymal weights and indices, sperm count and sperm viability, testicular testosterone and estradiol concentrations, and seminiferous tubule diameters and heights. In addition, icariin protected age-related Sertoli cells from injury as evidenced by an analysis of Sertoli cell number, ultrastructure, and function. Such changes were accompanied by upregulation of ERα and Nrf2 signaling in Sertoli cells. Parallel in vitro studies also demonstrated that icariin inhibited untoward effects on the TM4 mouse Sertoli cell line with concomitant upregulation of ERα and Nrf2 signaling. Conversely, ERα siRNA reversed icariin-mediated protection of Sertoli cell injury. Our data suggest that icariin effectively ameliorates age-related degeneration of testicular function by alleviating Sertoli cell injury via the ERα/Nrf2 signal-transduction pathway. Thus, mitigating Sertoli cell damage via the ERα/Nrf2 signaling pathway likely represents a promising strategy for the prevention of age-related testicular dysfunction.

Left ventricular hypertrophy (LVH) is an important characteristic of hypertensive heart disease. Renin-angiotensin system (RAS) blockers have been shown to be effective drugs for the reversal of LVH. Clinical and experimental studies have shown that Zi Shen Huo Luo Formula (ZSHLF) can improve the efficacy of perindopril in the treatment of hypertensive LVH, but its mechanism is unclear. This study aimed to investigate the possible mechanism to improve the efficacy of perindopril. First, we identified 23 compounds in ZSHLF by ultra performance liquid chromatography/tandem mass spectrometry (UPLC-MS/MS) analysis, among which ferulic acid, caffeic acid, vanillic acid, berberine, rutin, quercetin, kaempferol, stachydrine, and tiliroside have been reported to reduce blood pressure and exhibit cardioprotective effects. Second, we treated spontaneously hypertensive rats (SHRs) with perindopril and ZSHLF for 12 continuous weeks and found that chronic use of perindopril could increase the aldosterone (ALD) levels and cause aldosterone breakthrough (ABT). ZSHLF combined with perindopril reduced the ALD levels, interfered with ABT, decreased blood pressure, improved left ventricular diastolic dysfunction, and decreased the collagen volume fraction; these effects were superior to those of perindopril alone. In vitro experiments, ALD-induced cardiomyocytes (H9c2 cells) and cardiac fibroblasts were treated with ZSHLF-containing serum, which suppressed ALD-induced cardiomyocyte hypertrophy and cardiac fibroblast proliferation, increased mineralocorticoid receptor (MR) and Cav-1 colocalization and decreased phosphorylated epidermal growth factor receptor (pEGFR) and phosphorylated extracellular signal-regulated kinase (pERK) protein expression the cells. In conclusion, ZSHLF can interfere with ABT and affect the pathological role of ALD by affecting MR and Cav-1 interactions and EGFR/ERK signaling pathway. These effects represent a possible mechanism by which ZSHLF improves the efficacy of angiotensin-converting enzyme inhibitors (ACEIs) in hypertensive LVH treatment. However, the major bioactive components or metabolites responsible for the effects and the implications of these findings in patients need further verification.

Glioma is the most common type of primary brain tumors. After standard treatment regimen (surgical section, radiotherapy and chemotherapy), the average survival time remains merely around 14 months for glioblastoma (grade IV glioma). Recent immune therapy targeting to the immune inhibitory checkpoint axis, i.e., programmed cell death protein 1 (PD-1) and its ligand PD-L1 (i.e., CD274 or B7-H1), has achieved breakthrough in many cancers but still not in glioma. PD-L1 is considered a major prognostic biomarker for immune therapy in many cancers, with anti-PD-1 or anti-PD-L1 antibodies being used. However, the expression and subcellular distribution of PD-L1 in glioma cells exhibits great variance in different studies, severely impairing PD-L1's value as therapeutic and prognostic biomarker in glioma. The role of PD-L1 in modulating immune therapy is complicated. In addition, endogenous PD-L1 plays tumorigenic roles in glioma development. In this review, we summarize PD-L1 mRNA expression and protein levels detected by using different methods and antibodies in human glioma tissues in all literatures, and we evaluate the prognostic value of PD-L1 in glioma. We also summarize the relationships between PD-L1 and immune cell infiltration in glioma. The mechanisms regulating PD-L1 expression and the oncogenic roles of endogenous PD-L1 are discussed. Further, the therapeutic results of using anti-PD-1/PD-L1 antibodies or PD-L1 knockdown are summarized and evaluated. In summary, current results support that PD-L1 is not only a prognostic biomarker of immune therapy, but also a potential therapeutic target for glioma.

Accumulating data demonstrated that hepatic endoplasmic reticulum (ER) stress was involved in the pathogenesis of liver fibrosis. Long-term chronic hepatocyte death contributed to liver fibrosis initiation and progression. Previous researches reported that ER stress sensor inositol-requiring enzyme 1 alpha (IRE1α) was first activated in the process of liver fibrosis. STF-083010 was an IRE1α RNase specific inhibitor. This study aimed to explore the effects of STF-083010 on carbon tetrachloride (CCl4)-induced liver injury and subsequent liver fibrosis. Mice were intraperitoneally (i.p.) injected with CCl4 (0.15 ml/kg) for 8 weeks. In STF-083010+CCl4 group, mice were injected with STF-083010 (30 mg/kg, i.p.), twice a week, beginning from the 6th week after CCl4 injection. CCl4 treatment markedly enhanced the levels of serum ALT, TBIL, DBIL and TBA, and STF-083010 had obviously extenuated CCl4-induced exaltation of ALT, DBIL, and TBA levels. CCl4-induced hepatic hydroxyproline and collagen I, major indicators of liver fibrosis, were alleviated by STF-083010. Additionally, CCl4-induced α-smooth muscle actin, a marker for hepatic stellate cells activation, was obviously attenuated in STF-083010-treated mice. Moreover, CCl4-induced upregulation of inflammatory cytokines was suppressed by STF-083010. Mechanistic exploration found that hepatic miR-122 was downregulated in CCl4-treated mice. Hepatic MCP1, CTGF, P4HA1, Col1α1, and Mmp9, target genes of miR-122, were upregulated in CCl4-treated mice. Interestingly, STF-083010 reversed CCl4-induced hepatic miR-122 downregulation. Correspondingly, STF-083010 inhibited CCl4-induced upregulation of miR-122 target genes. This study provides partial evidence that STF-083010 alleviated CCl4-induced liver injury and thus protected against liver fibrosis associated with hepatic miR-122.

Tubulointerstitial fibrosis is the final common pathway for all kidney diseases leading to chronic kidney disease (CKD). TGF-β/Smad signaling pathway plays a key role in renal fibrosis. Previous studies have revealed that rhubarb extracts attenuated the increase of transforming growth factor-β 1 (TGF-β1) in CKD rats. To gain an in-depth insight into the mechanism of the anti-fibrotic activities of the rhubarb extracts, we investigated the influence of rhubarb extracts on TGF-β/Smad signaling pathway and the influence on metabolome in a rat model of CKD with adenine-induced chronic tubulointerstitial nephropathy. Male Sprague-Dawley rats were divided into four groups, including control, CKD, CKD + petroleum ether extract, CKD + ethyl acetate extract, and CKD + n-butanol extract groups. Kidneys harvested on the week three were evaluated for renal fibrosis, the expression of proteins in TGF-β/Smad signaling pathway and metabolomic study. We found rhubarb extracts suppressed TGF-β/Smad3-mediated renal fibrosis by reducing the TGF-β1, transforming growth factor-β receptor I (TGF-β RI), transforming growth factor-β receptor II (TGF-β RII), Smad2, p-Smad2, Smad3, p-Smad3, and Smad4, meanwhile increased Smad7. In addition, rhubarb extracts mitigated renal injury and dysfunction, and either fully or partially reversed the abnormalities of tissue metabolites. Thus, rebalancing the disorder of TGF-β/Smad signaling and metabolic dysfunction by treatment with rhubarb extracts may represent as an effective therapy for CKD associated with fibrosis.

Hypertrophic scars formed after burns remain a challenge in clinical practice. Development of effective scar therapies relies on validated animal models that mimic human hypertrophic scars. A consistent porcine full-thickness burn hypertrophic scar model has yet to be developed. We have previously reported that Shikonin induces apoptosis and reduces collagen production in hypertrophic scar fibroblasts in vitro and may therefore hold potential as a novel scar remediation therapy. In this study, we aimed to validate the potential of Shikonin on scar remediation in vivo. A novel porcine hypertrophic scar model was created after full-thickness burn wounds, and the effect of Shikonin on scar remediation was investigated. Clinical scar assessments, histology, and immunohistochemistry were used to evaluate scar appearance, morphology, and protein expression. Eight weeks after scar formation, clinical scar assessment indicated that the score of hypertrophic scars treated with Shikonin was significantly lower than that of the control group. Hypertrophic scars treated with Shikonin appeared flat, pink, and pliable. In addition, histological analysis indicated that hypertrophic scars treated with Shikonin exhibited reduced thickness of the epidermis and dermis, thin and even epithelial layers, reduced numbers of keratinocytes, uniform distribution of fibroblasts, and a parallel and loose arrangement of collagen fibers in the dermis. Moreover, immunohistochemical analysis indicated that Shikonin inhibited the expression of p63, cytokeratin 10, alpha-smooth muscle actin, transforming growth factor-beta 1, and collagen I, which play important roles in hypertrophic scar formation. Based on these results, we conclude that Shikonin has potential as a novel scar therapy.

Objective: Mangiferin (MGF) is a natural xanthone, with regulation effect on lipid metabolism. However, the molecular mechanism remains unclear. We purposed after oral administration, MGF is converted to its active metabolite(s), which contributes to the effects on lipid metabolism.Methods: KK-Ay mice were used to validate the effects of MGF on lipid metabolic disorders. Liver biochemical indices and gene expressions were determined. MGF metabolites were isolated from MGF administrated rat urine. Mechanism studies were carried out using HepG2 cells treated by MGF and its metabolite with or without inhibitors or small interfering RNA (siRNA). Western blot and immunoprecipitation methods were used to determine the lipid metabolism related gene expression. AMP/ATP ratios were measured by HPLC. AMP-activated protein kinase (AMPK) activation were identified by homogeneous time resolved fluorescence (HTRF) assays.Results: MGF significantly decreased liver triglyceride and free fatty acid levels, increased sirtuin-1 (SIRT-1) and AMPK phosphorylation in KK-Ay mice. HTRF studies indicated that MGF and its metabolites were not direct AMPK activators. Norathyriol, one of MGF’s metabolite, possess stronger regulating effect on hepatic lipid metabolism than MGF. The mechanism was mediated by activation of SIRT-1, liver kinase B1, and increasing the intracellular AMP level and AMP/ATP ratio, followed by AMPK phosphorylation, lead to increased phosphorylation level of sterol regulatory element-binding protein-1c.Conclusion: These results provided new insight into the molecular mechanisms of MGF in protecting against hepatic lipid metabolic disorders via regulating SIRT-1/AMPK pathway. Norathyriol showed potential therapeutic in treatment of non-alcoholic fatty liver disease.