Enhanced Mechanical Strength and Sustained Drug Release in Carrier-Free Silver-Coordinated Anthraquinone Natural Antibacterial Anti-Inflammatory Hydrogel for Infectious Wound Healing.

The persistent challenge of healing infectious wounds and the rise of bacterial resistance represent significant hurdles in contemporary medicine. In this study, based on the natural small molecule drug Rhein self-assembly to form hydrogels and coordinate assembly with silver ions (Ag+), a sustained-release carrier-free hydrogel with compact structure is constructed to promote the repair of bacterial-infected wounds. As a broad-spectrum antimicrobial agent, Ag+ can avoid the problem of bacterial resistance caused by the abuse of traditional antibiotics. In addition, due to the slow-release properties of Rhein hydrogel, continuous effective concentration of Ag+ at the wound site can be ensured. The assembly of Ag+ and Rhein makes the hydrogel system with enhanced mechanical stability. More importantly, it is found that Rhein effectively promotes skin tissue regeneration and wound healing by reprogramming M1 macrophages into M2 macrophages. Further mechanism studies show that Rhein realizes its powerful anti-inflammatory activity through NRF2/HO-1 activation and NF-κB inhibition. Thus, the hydrogel system combines the excellent antibacterial properties of Ag+ with the excellent anti-inflammatory and tissue regeneration ability of Rhein, providing a new strategy for wound management with dual roles.

Immunosuppression Reversal Nanovaccines Substituting Dendritic Cells for Personalized Cancer Immunotherapy.

Although immunotherapy has paved a new avenue for cancer treatment, inadequate immune response often executes suboptimal therapeutic effects. In general, an effective immune response undergoes presentation of antigen by antigen-presenting cells, proliferation and differentiation of lymphocytes, and attack of cancer cells by cytotoxic T lymphocytes (CTLs). The antigen self-presentation and immunosuppression reversal (ASPIRE) nanovaccine derived from dendritic cells provides a simplified and immune deregulated procedure for immunotherapy profiting from its orientable peculiarity. By integrating major histocompatibility complex class I (MHC-I) molecules into present specific epitopes and co-delivering anti-PD-1 antibody and B7 costimulatory molecules through the programmed biomimetic synthesis, the ASPIRE nanovaccine demonstrates a milestone in personalized cancer immunotherapy.

A super-stable homogeneous Lipiodol-hydrophilic chemodrug formulation for treatment of hepatocellular carcinoma.

Background: Though lipiodol formulations are major options in transcatheter arterial chemoembolization (TACE) of advanced unresectable hepatocellular carcinoma (HCC) in the clinic, their application is severely limited by insufficient physical stability between the hydrophobic lipiodol and hydrophilic drugs; thus, most chemotherapeutic drugs are quickly released into systemic circulation resulting in poor therapeutic outcomes and serious side effects. Methods: The typical hydrophilic drug doxorubicin hydrochloride (DOX) was prepared as a pure nanomedicine and then stably and homogeneously dispersed in lipiodol (SHIFT&DOX) via slightly ultrasonic dispersion. The drug release profiles of SHIFT&DOX were defined in a decellularized liver model. In vivo therapeutic studies were performed in rat-bearing N1S1 orthotopic HCC models and rabbit-bearing VX2 orthotopic HCC models. Results: SHIFT&DOX features an ultrahigh homogeneous dispersibility over 21 days, which far surpassed typical Lipiodol-DOX formulations in clinical practice (less than 0.5 h). SHIFT&DOX also has excellent sustained drug release behavior to improve the local drug concentration dependence and increase the time dependence, leading to remarkable embolic and chemotherapeutic efficacy, and eminent safety in all of the orthotopic HCC models. Conclusions: The carrier-free hydrophilic drug nanoparticle technology-based lipiodol formulation provides a promising approach to solve the problem of drug dispersion in TACE with the potential for a translational pipeline.

Clinical Efficacy and Safety of Eculizumab for Treating Myasthenia Gravis.

Myasthenia gravis (MG) is an autoimmune disease primarily mediated by acetylcholine receptor antibodies (AChR-Ab), cellular immune dependence, and complement system involvement. Since the AChR on the postsynaptic membrane is destroyed by an immune attack, sufficient endplate potential cannot be generated, resulting in the development of a synaptic transmission disorder at the neuromuscular junction and in muscle weakness. The role of the complement system in MG has been demonstrated in animal models and clinical tests, and it has been determined that complement inhibition in patients with MG can prevent disease induction and reverse its progression. Eculizumab is a humanized monoclonal antibody that inhibits the cleavage of complement protein C5 and prevents autoimmune damage; additionally, it has received subsequent approval by the Federal Drug Administration of the United States for MG treatment. However, various concerns regarding the use of eculizumab persist. In this review, we have discussed the treatment time, cost effectiveness, long-term efficacy, and tolerability of eculizumab for MG treatment. We have also summarized historical information and have presented perspectives on this new therapeutic modality.

Pharmacological targets and mechanisms of calycosin against meningitis.

This report aimed to identity the potential anti-meningitis targets and mechanisms functioned by calycosin through network pharmacology approach. The bioinformatics databases were used to screen and collect the candidate genes/targets of calycosin and meningitis prior to identification of vital biotargets of calycosin-anti-meningitis. Additionally, the functional processes, signaling pathways of calycosin-anti-meningitis were screened and identified before further data visualization. As a result, all candidate and mapped biotargets of calycosin and meningitis were harvested before the vital targets of epidermal growth factor receptor (EGFR), tumor necrosis factor (TNF), epidermal growth factor (EGF), ataxia telangiectasia mutated protein (ATM), estrogen receptor alpha (ESR1), caspase-8 (CASP8), nerve growth factor (NGF) of calycosin-anti-meningitis were identified. The molecular processes of calycosin-anti-meningitis were screened and identified, including reduction of inflammatory development. Furthermore, the molecular pathways of calycosin-anti-meningitis were revealed, including suppression of NF-kappa B, Toll-like receptor, TNF signaling pathways. Molecular docking findings uncovered the docking capacity of calycosin with meningitis and potential pharmacological activity of calycosin against meningitis. In conclusion, these bioinformatic data uncovered the network targets and mechanisms of calycosin-anti-meningitis. And the current findings indicated that the vital targets might be used as potent biomarkers for detecting meningitis.

Pharmacological targets and molecular mechanisms of plumbagin to treat colorectal cancer: A systematic pharmacology study.

Plumbagin (PL) pharmacologically plays the anti-proliferative effects in cancer cells, including effective suppression of colorectal cancer (CRC). However, the exact molecular mechanism of PL to treat CRC remains unclear. Using available SwissTargetPrediction and SuperPred databases, the anti-cancer biotargets of PL were identified, and the CRC-diseased targets were obtained through a DisGeNET database. The biological processes, and signaling pathways of PL to treat CRC were identified and visualized. Further, clinical and cell culture data were used to validate some bioinformatic findings. As shown in bioinformatics findings, 64 predictive biotargets of PL to treat CRC were collected, and 7 most important biotargets of tumor protein p53 (TP53), glyceraldehyde-3-phosphate dehydrogenase (GAPDH), mitogen-activated protein kinase 1 (MAPK1), E1A-associated protein p300 (EP300), poly (ADP-ribose) polymerase 1 (PARP1), nuclear factor kappa p65 protein (RELA), Bcl-2 like protein 1 (BCL2L1) were identified respectively. In addition, top 20 functional biological processes, signaling pathways of PL to treat CRC were screened and prioritized. In human study, CRC samples showed elevated expressions of neoplastic MAPK1, PARP1 mRNAs and reduced EP300 mRNA level. In cell culture study, PL-treated CRC cells resulted in down-regulated MAPK1, PARP1 mRNA expressions and up-regulation of EP300 mRNA level, characterized with suppressed cell proliferation. Taken together, the therapeutic biotargets and molecular mechanisms of PL to treat CRC were screened and identified by using a systematic pharmacology analysis, and some bioinformatic findings were validated in clinical and cell line experiments. Potentially, these hub biotargets may be the biomarkers for CRC detection and treatment.

Infliximab clinically treating ulcerative colitis: A systematic review and meta-analysis.

OBJECTIVE: This review aimed to evaluate the efficacy and safety of infliximab against ulcerative colitis (UC). METHODS: Collection of databases: PubMed, Cochrane Library, Medline, Embase, CBM, and CNKI. This meta-analysis included randomized controlled trials comparing infliximab vs. placebo's, steroids, or immunosuppressants. SEARCH STRATEGY: Searching terms were ('infliximab', OR 'anti-tumor necrosis factor', OR 'tumor necrosis factor', OR 'tumor necrosis factor alpha antibody', OR 'tumor necrosis factor antibody', OR 'IFX') and ('ulcerative colitis' OR 'UC'). Study quality: Independently assessed by two reviewers. DATA SYNTHESIS: Meta-analysis combined the odds ratios (OR). RESULTS: Twenty-two studies (2080 patients) evaluated infliximab therapy in UC, and the patients were randomly assigned into infliximab (1149 cases) and control groups (931 cases). The meta-analysis showed the advantage of infliximab in three endpoints (short/long-term response and long-term remission). The main outcomes considered in this meta-analysis were percentage of response (defined by the authors of each study as partial or complete symptomatic response) and remission (defined by the authors as complete symptomatic response), both at the short-term (the first control performed in the study) and the long-term (the last control performed in the study). Compared to the control group, the infliximab group was significantly more effective (short-term response: OR = 4.01, 95%CI = 3.08-5.23, p < 0.00001; long-term response: OR = 3.53, 95%CI = 2.55-4.89, p < 0.00001; long-term remission: OR = 2.80, 95%CI = 1.89-4.14, p < 0.00001; colectomy (3 months): OR = 0.38, 95%CI = 0.19-0.75, P = 0.005; colectomy (12 months): OR = 0.47, 95%CI = 0.33-0.67, p < 0.0001), but there were no significant differences in the short-term remission (OR = 1.88, 95%CI = 0.91-3.86, P = 0.09), and infliximab was notably effective in all the subgroups with different treatment doses (all p < 0.00001). In the comparison of differences in adverse effects there was no obvious difference between the two groups (OR = 0.76, 95%CI = 0.48-1.19, P = 0.23). CONCLUSION: Infliximab is more effective than placebo's, steroids, or immunosuppressants, while the drug safety between the two groups was not obvious. Further studies are necessary to confirm the long-term efficacy of infliximab in ulcerative colitis.

Clinical features of aflatoxin B1-exposed patients with liver cancer and the molecular mechanism of aflatoxin B1 on liver cancer cells.

Aflatoxin B1 (AFB1) induces hepatocellular carcinoma (HCC) through consumption of contaminated food in Southern China. Aldo-keto reductase-7A (AKR7A) functionally plays a potent role in the biodetoxification in the liver. In addition, hepatocellular lipid disorder has found to be closely linked to the development of HCC. This study was, therefore, designed to investigate the potent bioeffect of AKR7A on the lipid metabolism in AFB1-exposed hepatocellular carcinoma cells through assaying human cancerous samples and cell culture. In the baseline data, the HCC patients showed increased contents of AFB1 in sera and cancerous samples. In the clinical parameters, the HCC patients demonstrated changed lipid settings in sera. As revealed by immunostaining and immunoblotting, AFB1-elevated HCC sections showed marked down-regulation of AKR7A expression, accompanied with reduced ApoB expression and increased CD36, S6K1 expressions in the HCC. Studies in the human hepatocarcinoma line HepG2 also showed AFB1-exposure to increase ApoA1, LDL, TC, and TG contents; induce cell proliferation; and reduce hepatocellular AKR7A expression. Furthermore, AKR7A bioactivity was inactivated after treatment with perfluorooctane sulfonate (PFOS), an ApoB activator, in AFB1-dosed HepG2 cells. Collectively, our current findings suggest that hepatocellular AKR7A has a protective role against AFB1-induced cytotoxicity through the regulation of CD36, S6K1 and ApoB expression through the reduction of lipid utilization in malignant liver cells.

To reveal pharmacological targets and molecular mechanisms of curcumol against interstitial cystitis.

This study was designed to reveal the predictive targets and biological mechanisms of curcumol against interstitial cystitis (IC). By use of available databases and bioinformatic assays, pathogenetic targets of IC and functional targets of curcumol were identified respectively. A network of functional protein-protein interaction (PPI) was produced before screening the main predictive targets, biological processes and signaling pathways of curcumol against IC. In bioinformatic findings, the data of ingenuity pathway analysis (IPA) delineated that curcumol exerted anti-IC benefits through regulating multipronged signaling pathways, including tyrosine protein kinase-2 (PTK2) pathway. Further, optimal 18 biotargets of curcumol against IC were harvested through differential expression analysis. And the predictive targets of receptor tyrosine-protein kinase erbB-2 (ERBB2), epidermal growth factor receptor (EGFR) and PTK2 were the most important molecules. In further validated experiments, PTK2 and phosphorylation PTK2 (p-PTK2) were representatively selected for testing by human and animal IC samples. As results, increased immunoreactive proteins of tumor necrosis factor alpha (TNF-α), PTK2 and p-PTK2Tyr397 in human IC sections were observed, accompanied with altered urinary parameters. Interestingly, curcumol-treated IC mice showed that intracellular expressions of PTK2, p-PTK2Tyr397 in bladder samples were reduced, accompanied with lowered blood inflammatory cytokines of interleukin 6 (IL-6), TNF-α. In conclusion, the current bioinformatic data and preliminary findings unravel that the predominant targets of curcumol against IC may be the potential biological markers for screening and treating IC, such as PTK2 molecule.

Lipidomic characteristics and clinical findings of epileptic patients treated with valproic acid.

Our early study has found valproic acid (VPA)-induced lipid dysmetabolism in animal model, however, the details of lipid profiling of VPA-treated epileptic patients remain unknown. Therefore, in this study, the blood samples of VPA-treated epileptic patients and VPA-free controls were collected for lipidomic and biochemical assays. As results, clinical data showed the changes of some blood lipid molecules in VPA-treated epileptic patients. In lipidomic assays, all 3797 annotated positive ions were identified prior to the data validation. In addition, the number of differentially expressed lipids were identified. And the 133 lipid molecules in VPA-treated cases were significantly up-regulated when compared to those in controls, while other 250 lipid metabolites were down-regulated. Further, these lipid metabolites were mainly constituted with glycerolipids, glycerophopholipids, fatty acyls, sterol lipids. In addition, the most significant elevations of metabolite molecules of triglyceride, sphingomyelin, phosphorylcholine, ceramides, phenolic phthiocerol, as well as topped reductions of phosphoethanolamines, diradylglycerols, 1α,25-dihydroxy-24-oxo-22-oxavitamin D3, 2-deoxy-20-hydroxy-5alpha-ecdysone 3-acetate, dolichyl-4 phosphate were identified respectively. Taken together, these clinical findings demonstrate that negative impacts of exposure to VPA on expression of lipid mediators, progressively disrupting the functions of lipid molecules. Interestingly, these differentially expressed metabolites may be potential biomarkers for screening VPA-induced dyslipidemia.

Effect of prenatal PFOS exposure on liver cell function in neonatal mice.

Perfluorooctane sulfonate (PFOS), a hepatotoxic pollutant, is detected in the human cord blood, and it may induce health risk to an embryo. In this study, we established intrauterine exposure to PFOS in mice to evaluate potential impacts of PFOS on postnatal day 1 (PND1) offspring through conducting biochemical tests, quantitative PCR, and immunostaining. As results, PFOS-exposed maternal mice showed marked hepatomegaly and induced liver steatosis in a high dose of 5 mg PFOS/kg. In PND1 mice, intrahepatic contents of triglyceride, total cholesterol, and LDL were elevated by high-dose PFOS exposure, while intracellular HDL content was decreased. As shown in quantitative PCR, functional messenger RNAs of cytochrome P4A14 (CYP4A14) for fatty acid oxidation, CD36 for hepatic fatty acid uptake, and apolipoprotein B100 (APOB) and fibroblast growth factor 21 (FGF21) for hepatic export of lipids in PND1 livers were changed when compared to those in PFOS-free controls. In further validations, immunofluorescence stains showed that hepatic CYP4A14 and CD36 immunoreactive cells were increased in PFOS-exposed PND1 mice. In addition, reduced immunofluorescence-positive cells of APOB and FGF21 were observed in PND1 livers. Collectively, these preliminary findings demonstrate that prenatal exposure to PFOS may affect lipid metabolism in liver cells of PND1 mice.

Potential biomarker of fibroblast growth factor 21 in valproic acid-treated livers.

BACKGROUND: Valproic acid (VPA) is a clinical medicine primarily prescribed to control epileptic symptoms. VPA has potential side-effects, such as hepatotoxicity. Fibroblast growth factor 21 (FGF21) is a functional cytokine for metabolic regulation. In this article, we aimed to evaluate the possible clinical application of FGF21 in VPA-treated livers in early undetected liver injury (EULI). METHODS: Methodologically, plasma samples of VPA-treated epileptic patients were isolated for biochemical and high-performance liquid chromatography tests. In addition, VPA-dosed mice were subjected to determinations of serological parameters, key regulatory effectors and FGF21 expressions through biochemical analyses, enzyme-linked immunosorbent assay, immunohistochemistry stain, immunofluorescence stain, and reverse transcription-polymerase chain reaction (RT-PCR) test, respectively. RESULTS: The serological data suggested that VPA-treated epileptic patients showed visibly elevated FGF21 contents in plasma samples. However, other diagnostic parameters showed inconspicuous changes. As revealed in animal study, VPA-dosed mice exhibited undetected morphological alterations and hormonal changes in the liver, pancreas, and kidneys. Furthermore, serological parameters and key regulatory proteins in VPA-dosed livers and controls showed inconspicuous changes. Interestingly, endogenous FGF21 expressions in VPA-dosed mice were increased in sera. In further experiments, the findings showed that intracellular expressions of FGF21 mRNA and protein were upregulated in VPA-dosed livers as revealed in RT-PCR and immunoassay. CONCLUSIONS: Taken together, these preliminary data reveal that functional FGF21 cytokine may serve as a potent predictor in VPA-related EULI.

Adverse impact of carbon tetrachloride on metabolic function in mice.

Carbon tetrachloride (CCl4 ), a potent hepatotoxin, is linked to the histopathological outcomes of inflammatory or oxidative stress, and cell death. However, further study of additional dysmetabolism induced by CCl 4 toxicant has not yet been investigated. In current study, chronical and acute exposures of CCl 4 in mice were used to unmask the biological molecular mechanism responsible for insulin-dependent metabolic disorder. In experimental methods, a number of biochemical assays were used in assessment of biological impacts on insulin-produced pancreas and insulin-responsive hepatocyte after long- and short-term exposures of CCl 4 toxicant, respectively. As a result, data from oral glucose tolerance test showed that CCl 4 exposures induced glucose tolerance and disrupted blood insulin and glucagon levels time-dependently. Meanwhile, biochemical and histocytological analyses further indicated that CCl 4 exposures significantly resulted in liver cell damage, induced abnormal changes of hepatic and skeletal glycogen synthesis. In addition, acute CCl 4 -exposed mice showed reduced functional proteins of glucose transporter 2 (GLUT2), insulin receptor ß, insulin receptor substrate 1, glycogen synthase kinase 3ß (GSK3ß), p-AKT Ser473 associated with AKT signaling pathway in liver cells, whereas acute CCl 4 exposure downregulated the endogenous expressions of the insulin and glucagon hormonal proteins in the pancreas. Taken together, the current findings highlight that CCl 4 impaired insulin-dependent glucose homeostasis through modulating hepatocellular AKT signaling pathway in acute CCl 4 exposure and GLUT2/GSK3ß pathway in chronic CCl 4 -exposed liver cells.

Antineoplastic effects of sorafenib on primary liver cancer: a systematic review and meta-analysis.

OBJECTIVE: The current study aimed to investigate the therapeutic efficacy of sorafenib against primary liver cancer (PLC). METHODS: Four databases (PubMed, CNKI, WanFang and Civip) were used to search and assess all clinical randomized controlled trials regarding the clinical efficacy of sorafenib-exerted anti-PLC from November 20, 2006 to May 8, 2018. RESULTS: A total of 15 randomized controlled trials were included in this analysis, and 1102 patients with PLC were randomly assigned as sorafenib group (521 cases), and control group (581 cases). Compared to controls, the sorafenib group showed significant clinical efficacy (overall: OR, 3.38; 95% CI, 2.57-4.46; P < 0.05), which was notably effective in all subgroups with different treatment durations (all P < 0.05). In addition, further analysis in subgroups exhibited that the clinical efficacy of treatment duration greater than 100 days was higher than that of control groups (OR, 4.61; 95% CI, 2.58-8.29; P < 0.05). CONCLUSION: Sorafenib has clinical efficacy for treating PLC, and the treatment duration in PLC patients shows limited impact on the therapeutic efficacy of sorafenib. Furthermore, sorafenib can extend the survival rate in patients with PLC.

Therapeutic targets of vitamin C on liver injury and associated biological mechanisms: A study of network pharmacology.

In our previous studies, vitamin C (VC) exerts potent pharmacological activities against liver injury (LI). Therefore, this report was designed to use network pharmacology-based strategy to predict therapeutic targets of VC against LI, and further to investigate the pharmacological molecular mechanisms. Pathological targets of LI were identified, followed by acquisition of verified targets of VC. After constructing target-functional protein interaction network of VC against LI, the core therapeutic targets of VC against LI were obtained. Further, biological function and pathway enrichment analyses were performed on core therapeutic targets to evaluate the biological processes and key signaling pathways of VC against LI. As revealed in network pharmacology assays, 6 key therapeutic targets for VC against LI were identified, showing tumor necrosis factor (TNF), nuclear factor-kappa-B p65 (RELA), nuclear factor-kappa-B p105 (NFKB1), TNF receptor-associated factor 2 (TRAF2), interleukin 6 (IL-6) and interleukin 1 beta (IL1B). On the basis of data analyses from DAVID database and omicshare cloud platform, bio-functional enrichment assays showed that the therapeutic effects of VC against LI were closely associated with regulating inflammatory reaction and apoptosis. Further, pathway enrichment analysis indicated the anti-LI benefits of VC were principally implicated in regulating the top 20 signaling pathways, such as inflammation-associated TNF signaling pathway, NF-κB signaling pathway. Taken together, the bioinformatics data elucidate that anti-LI pharmacological activities of VC may be predominantly related to inhibition of inflammatory stress, contributing to suppression of LI development. These resultant findings highlight the predicted therapeutic targets may be potential biomarkers for anti-LI.

Hepatoprotective benefits of vitamin C against perfluorooctane sulfonate-induced liver damage in mice through suppressing inflammatory reaction and ER stress.

Our previous studies show that vitamin C (VC) plays promising hepatoprotection in mice. Intrahepatic exposure of perfluorooctane sulfonate (PFOS) can induce dose-dependent cytotoxicity. However, pharmacology-based assessment of VC on PFOS remains uninvestigated. This study aimed to evaluate the therapeutic benefits of VC on inhibiting PFOS-induced liver steatosis in mice, followed by representative biochemical analysis and immunoassay. As results, VC was beneficial for reduced PFOS-induced liver damages, as showed in reductions of serological levels of transaminases (ALT and AST), lipids (TG and TC), fasting glucose and insulin, inflammatory cytokines (TNF-α and IL6), while content of fibroblast growth factor 21 (FGF21) in serum was increased. In addition, VC reduced histiocytic changes of PFOS-lesioned livers, as revealed in reduced TNF-α-labeled cells and increased FGF21-labeled cells in immunofluorescence assay. Further, intrahepatic expressions of endoplasmic reticulum (ER) stress-based ATF6, eIF2α, GRP78, XBP1 proteins were down-regulated by treatments of VC. Taken together, our preliminary findings set forth that VC exerts pharmacological benefits against PFOS-induced liver steatosis in mice, and the underlying biological mechanism may be linked to suppressing hepatocellular inflammatory reaction and ER stress.