Coptisine, the Characteristic Constituent from Coptis chinensis, Exhibits Significant Therapeutic Potential in Treating Cancers, Metabolic and Inflammatory Diseases.

Naturally derived alkaloids belong to a class of quite significant organic compounds. Coptisine, a benzyl tetrahydroisoquinoline alkaloid, is one of the major bioactive constituents in Coptis chinensis Franch., which is a famous traditional Chinese medicine. C. chinensis possesses many kinds of functions, including the ability to eliminate heat, expel dampness, purge fire, and remove noxious substances. In Asian countries, C. chinensis is traditionally employed to treat carbuncle and furuncle, diabetes, jaundice, stomach and intestinal disorders, red eyes, toothache, and skin disorders. Up to now, there has been plenty of research of coptisine with respect to its pharmacology. Nevertheless, a comprehensive review of coptisine-associated research is urgently needed. This paper was designed to summarize in detail the progress in the research of the pharmacology, pharmacokinetics, safety, and formulation of coptisine. The related studies included in this paper were retrieved from the following academic databases: The Web of Science, PubMed, Google scholar, Elsevier, and CNKI. The cutoff date was January 2023. Coptisine manifests various pharmacological actions, including anticancer, antimetabolic disease, anti-inflammatory disease, and antigastrointestinal disease effects, among others. Based on its pharmacokinetics, the primary metabolic site of coptisine is the liver. Coptisine is poorly absorbed in the gastrointestinal system, and most of it is expelled in the form of its prototype through feces. Regarding safety, coptisine displayed potential hepatotoxicity. Some novel formulations, including the [Formula: see text]-cyclodextrin-based inclusion complex and nanocarriers, could effectively enhance the bioavailability of coptisine. The traditional use of C. chinensis is closely connected with the pharmacological actions of coptisine. Although there are some disadvantages, including poor solubility, low bioavailability, and possible hepatotoxicity, coptisine is still a prospective naturally derived drug candidate, especially in the treatment of tumors as well as metabolic and inflammatory diseases. Further investigation of coptisine is necessary to facilitate the application of coptisine-based drugs in clinical practice.

Natural flavones from edible and medicinal plants exhibit enormous potential to treat ulcerative colitis.

Ulcerative colitis (UC) is a chronic aspecific gut inflammatory disorder that primarily involves the recta and colons. It mostly presents as a long course of repeated attacks. This disease, characterized by intermittent diarrhoea, fecal blood, stomachache, and tenesmus, severely decreases the living quality of sick persons. UC is difficult to heal, has a high recurrence rate, and is tightly related to the incidence of colon cancer. Although there are a number of drugs available for the suppression of colitis, the conventional therapy possesses certain limitations and severe adverse reactions. Thus, it is extremely required for safe and effective medicines for colitis, and naturally derived flavones exhibited huge prospects. This study focused on the advancement of naturally derived flavones from edible and pharmaceutical plants for treating colitis. The underlying mechanisms of natural-derived flavones in treating UC were closely linked to the regulation of enteric barrier function, immune-inflammatory responses, oxidative stress, gut microflora, and SCFAs production. The prominent effects and safety of natural-derived flavones make them promising candidate drugs for colitis treatment.

Oxyberberine ameliorates TNBS-induced colitis in rats through suppressing inflammation and oxidative stress via Keap1/Nrf2/NF-κB signaling pathways.

BACKGROUND: Ulcerative colitis (UC) is a chronic, unspecific inflammatory bowel disorder lacking effective therapeutic targets and radical drugs. Oxyberberine (OBB), a novel intestinal flora-elicited oxidative metabolite of berberine (BBR), has been revealed to exhibit diverse pharmacological properties. PURPOSE: In this follow-up study, we attempted to shed light on the possible therapeutic effect and latent mechanism of OBB on 2, 4, 6-trinitrobenzenesulfonic acid (TNBS)-evoked UC in rats. METHODS: UC rats were established via a gentle enema of TNBS. Rats were sacrificed after intragastric administration of drugs for seven days. The weight reduction, disease activity index, macroscopic and histological colonic alterations were assessed. Further investigation on molecular mechanisms was conducted by ELISA, qRT-PCR, immunohistochemistry, or Western blot. RESULTS: OBB treatment remarkably decreased the weight loss, macroscopic scores, and colonal weight/length ratio, as well as mitigated the colonic pathological deterioration and MPO vitality in colitis rats, achieving a superior protective effect to BBR. Additionally, OBB modulated the disequilibrium between pro- and anti-inflammatory factors by promoting the production of IL-13 and IL-4, and lowering the contents of TNF-α, IL-2, IL-8, and IL-22. Furthermore, OBB pretreatment dramatically ameliorated oxidative stress via enhancing antioxidant defense genes expressions (including HO-1, GCLM, GCLC, and NQO-1), thereby increasing SOD and GSH, and decreasing MDA and ROS activities. Furthermore, OBB strikingly restrained the translocation of NF-κB p65 and phosphorylation of IκBα, promoted HO-1 expression, Keap1 degradation and Nrf2 nuclear translocation. CONCLUSION: The study firstly indicated that OBB had a superior therapeutic effect than BBR against TNBS-elicited colitis in rats. The protective effect of OBB might be closely related to the modulation of Keap1/Nrf2/NF-κB-mediated inflammatory response and oxidant stress. The evidences highlight the potentiality of OBB as a prospective candidate for the amelioration of colitis.

Potential of natural flavonols and flavanones in the treatment of ulcerative colitis.

Ulcerative colitis (UC) is an inflammatory bowel disease generally characterized by chronic, persistent, recurrent, and non-specific ulcers of the intestine. Its main clinical manifestations include abdominal pain, diarrhea, and bloody stools. This disease is difficult to cure and even carries the risk of canceration. It has been listed as a modern refractory disease by the World Health Organization. Though a large amount of drugs are available for the inhibition of UC, the conventional treatment such as aminosalicylic acids, glucocorticoids, immunosuppressors, and biological agents possess certain limitations and serious side effects. Therefore, it is urgently needed for safe and effective drugs of UC, and natural-derived flavonols and flavanones showed tremendous potential. The present study concentrated on the progress of natural-derived flavonols and flavanones from edible and pharmaceutical plants for the remedy of UC over the last two decades. The potential pharmaceutical of natural-derived flavonols and flavanones against UC were closely connected with the modulation of gut microflora, gut barrier function, inflammatory reactions, oxidative stress, and apoptosis. The excellent efficacy and safety of natural flavonols and flavanones make them prospective drug candidates for UC suppression.

Nitidine chloride, a benzophenanthridine alkaloid from Zanthoxylum nitidum (Roxb.) DC., exerts multiple beneficial properties, especially in tumors and inflammation-related diseases.

Plant-derived alkaloids are a kind of very important natural organic compounds. Nitidine chloride is one of the main active ingredients in Zanthoxylum nitidum (Roxb.) DC. which is a frequently-used Chinese herbal medicine. Z. nitidum has many kinds of efficacy, such as activating blood circulation and removing stasis, promoting qi circulation and relieving pain, and detoxication and detumescence. In China, Z. nitidum is usually used for the treatment of gastrointestinal diseases, toothache, and traumatic injury. At present, there are numerous studies of nitidine chloride with regard to its pharmacology, pharmacokinetics, toxicology, etc. However, a systematic, cutting-edge review of nitidine-related studies is extremely lacking. The present paper aimed at comprehensively summarizing the information on the extraction, separation and purification, pharmacology, pharmacokinetics, toxicology and formulation of nitidine chloride. The knowledge included in the present study were searched from the following academic databases involving Web of Science, PubMed, Google scholar, Elsevier, CNKI and Wanfang Data, till July 2022. In terms of nitidine chloride extraction, enzymatic method and ultrasonic method are recommended. Resin adsorption and chromatography were usually used for the separation and purification of nitidine chloride. Nitidine chloride possesses diversified therapeutical effects, such as anti-tumor, anti-inflammation, anti-colitis, anti-malaria, anti-osteoporosis, anti-rheumatoid and so on. According to pharmacokinetics, the intestinal absorption of nitidine chloride is passive diffusion, and it is rarely excreted with urine and feces in the form of prototype drug. Nitidine chloride has a moderate binding to plasma protein, which is independent of the drug concentration. As to toxicology, nitidine chloride showed certain toxicity on liver, kidney and heart. Certain new formulations, such as nanoparticle, microsphere and nano-micelle, could increase the therapeutic effect and decrease the toxicity of nitidine chloride. Despite limitations such as poor solubility, low bioavailability and certain toxicity, nitidine chloride is still a promising natural alkaloid for drug candidates. Extensive and intensive exploration on nitidine chloride is essential to promote the usage of nitidine-based drugs in the clinic practice.

Potential of natural products in the treatment of irritable bowel syndrome.

BACKGROUND: Irritable bowel syndrome (IBS) is a kind of functional bowel disease that is characterized by bellyache, abdominal distension, and diarrhea. Although not life-threatening, IBS has a long course and recurrent attacks and seriously affects the life quality of patients. Current drugs for treating IBS possess remarkable limitations, such as limited efficacy and severe adverse reactions. Therefore, developing novel medications to treat IBS is quite essential, and natural products may be a substantial source. PURPOSE: This is the first systematic review elaborating the recent advancement of natural products as potential drugs for the therapy of IBS. METHODS: A comprehensive retrieval of studies was carried out in scientific databases including PubMed, Web of Science, Elsevier, and CNKI. By using ("irritable bowel syndrome" OR "IBS") AND ("natural product" OR "natural compound" OR "phytochemical") as keywords, the eligible studies were screened, and the relevant information about therapeutic action and mechanism of natural products treating IBS was extracted. RESULTS: Natural products against IBS consisted of four categories, namely, terpenoids, flavonoids, alkaloids, and phenols. Furthermore, the underlying mechanisms for natural products treating IBS were tightly associated with increased TJs and mucus protein expression, regulation of the brain-gut axis and gut microbiota structure, and inhibition of inflammatory response and intestinal mucosal damage. CONCLUSION: Natural products could be extremely prospective candidate drugs used to treat IBS, and further preclinical and clinical researches are needed to guarantee their efficacy and safety.

Sanguinarine, a major alkaloid from Zanthoxylum nitidum (Roxb.) DC., inhibits urease of Helicobacter pylori and jack bean: Susceptibility and mechanism.

ETHNOPHARMACOLOGICAL RELEVANCE: Zanthoxylum nitidum (Roxb.) DC. (Z. nitidum) is a traditional Chinese medicine and mainly adopted to treat gastric ulcer, gastritis and stomach cancer. Sanguinarine (SNG), a natural alkaloid isolated from Z. nitidum, possesses significant anti-Helicobacter pylori and gastric protection effects. However, the underlying mechanism is sparsely elucidated. AIM OF THIS STUDY: The present study aims to explore the inhibition effect, kinetics and potential mechanism of SNG against H. pylori urease (HPU) and jack bean urease (JBU). MATERIALS AND METHODS: The improved spectrophotometric berthelot method was applied to estimate the inhibitory effect of SNG against HPU and JBU. The Lineweaver-Burk plots were adopted for investigating the inhibitory pattern in enzymatic kinetics. Sulfydryl-containing compounds and competitive active-site Ni2+ binding depressors were used for mechanism research. RESULTS: SNG remarkably suppressed the activities of HPU and JBU in concentration-and time-dependent mode with IC50 of 0.48 ± 0.14 mM and 0.11 ± 0.02 mM, respectively, in comparison with urease retardant acetohydroxamic acid (0.06 ± 0.01 mM for HPU and 0.03 ± 0.00 mM for JBU, respectively). Kinetic analysis demonstrated that the inhibition of SNG against HPU and JBU were separately characterized by slow-binding, mixed-type and slow-binding, non-competitive type. Addition of sulfydryl-containing reagents (dithiothreitol, glutathione and L-cysteine) and competitive Ni2+ binding restrainers (boric acid and sodium fluoride) significantly abrogated the urease inhibitory effect of SNG, suggesting the significant role of the thiols and Ni2+ for the urease inhibition by SNG. By contrast, interaction with thiol groups possibly contributed to the repression of SNG on JBU. Furthermore, the urease suppression was proved to be partially reversible since the SNG-blocked enzyme could be partly reactivated by glutathione. CONCLUSION: SNG could observably inhibit H. pylori urease targeting the thiols and Ni2+, which indicated that SNG was a new urease suppressant with great promise. The present research also provided scientific evidence for the application of SNG and Z. nitidum treating H. pylori-associated gastrointestinal diseases.

Natural-derived alkaloids exhibit great potential in the treatment of ulcerative colitis.

Ulcerative colitis (UC) is a chronic nonspecific inflammatory disease of colon and rectum with unknown etiology, and the lesions are mainly confined to the mucosa and submucosa of large intestine. The main clinical features of UC include diarrhea, abdominal pain, bloody purulent stool and tenesmus, which seriously affect patients' quality of life. Most of UC patients would receive drug therapy with the exception of surgery for some severe cases. However, current drugs for the treatment of UC have certain limitations including difficulty of radical treatment, adverse reactions and drug resistance after long-term use and exorbitant price of some drugs. The research and development of new drugs for the treatment of UC is urgent, and natural alkaloids are an important source. This research paid close attention to the progress of natural alkaloids from diverse medicinal plants for treating UC in the last twenty years. The potential mechanisms for the natural alkaloids in the treatment of UC was closely related to its modulation of oxidative stress, immune response, intestinal flora and improvement of the gut barrier function. Remarkable effectiveness and safety of natural-derived alkaloids make them potential candidates of UC therapy.

Dihydroberberine, an isoquinoline alkaloid, exhibits protective effect against dextran sulfate sodium-induced ulcerative colitis in mice.

BACKGROUND: As a chronic inflammatory disease, ulcerative colitis (UC) is relevant to a rising risk of colorectal cancer. Dihydroberberine (DHBB), a natural occurring isoquinoline alkaloid with various bioactivities, was found in many plants including Coptis chinensis Franch. (Ranunculaceae), Phellodendron chinense Schneid. (Rutaceae), and Chelidonium majus L. (Papaveraceae). However, its protective effect on UC is sparsely dissected out. PURPOSE: To explore the protective role and underlying mechanism of DHBB on a model of colitis. METHODS: Acute colitis model was established by gavage with 3% dextran sulfate sodium (DSS) for 8 days. Influence of DHBB on DSS-induced clinical symptoms and disease activity index (DAI) was monitored and analyzed. Pathological injury of colon tissues was examined by hematoxylin-eosin and Alcian blue staining. The expression of intestinal mucosal barrier function proteins, immune-inflammation related biomarkers and signal pathway key targets were determined by ELISA kit, Western blot, immunohistochemistry and qRT-PCR. RESULTS: DHBB treatment effectively alleviated DSS-induced UC by relieving clinical manifestations, DAI scores and pathological damage, which exerted similar beneficial effect to azathioprine (AZA), and better than berberine (BBR). In addition, DHBB significantly improved the gut barrier function through up-regulating the levels of tight junction proteins and mucins. Furthermore, DHBB dramatically ameliorated colonic immune-inflammation state, which was related to the decrease of colonic pro-inflammatory cytokines and immunoglobulin through blocking TLR4/MyD88/NF-κB signal pathway. CONCLUSION: These results demonstrated that DHBB exerted a significant protective effect on DSS-induced experimental UC, at least partly through suppressing immune-inflammatory response and maintaining gut barrier function.

Natural-Derived Polysaccharides From Plants, Mushrooms, and Seaweeds for the Treatment of Inflammatory Bowel Disease.

Inflammatory bowel disease (IBD) is a chronic inflammatory disease impairing the gastrointestinal tract, and its incidence and prevalence have been increasing over time worldwide. IBD greatly reduces peoples' quality of life and results in several life-threatening complications, including polyp, toxic colonic dilatation, intestinal perforation, gastrointestinal bleeding, and cancerization. The current therapies for IBD mainly include drugs for noncritical patients and operation for critical patients. However, continuous use of these drugs causes serious side effects and increased drug resistance, and the demand of effective and affordable drugs with minimal side effects for IBD sufferers is urgent. Natural-derived polysaccharides are becoming a research hotspot for their therapeutic effects on IBD. This study focuses on the research progress of various natural polysaccharides from plants, seaweeds, and mushrooms for the treatment of IBD during recent 20 years. Regulation of oxidative stress, inflammatory status, gut microbiota, and immune system and protection of the intestinal epithelial barrier function are the underlying mechanisms for the natural-derived polysaccharides to treat IBD. The excellent efficacy and safety of polysaccharides make them promising candidates for IBD therapy.

The Efficacy and Safety of Compound Danshen Dripping Pill Combined with Percutaneous Coronary Intervention for Coronary Heart Disease.

OBJECTIVE: Compound Danshen dripping pill (CDDP) is a well-known Chinese patent medicine, which is commonly used for the treatment of coronary heart disease (CHD) in China. This study is aimed at systematically assessing the clinical efficacy of CDDP for CHD patients. METHODS: Eight databases were retrieved for eligible research studies from the founding date to April 20, 2020. Risk ratio (RR) was used to assess major adverse cardiac events (MACE) and adverse reactions, and mean difference (MD) was adopted to evaluate the hemorheology and blood lipid indexes, vascular endothelial function, cardiac function, and inflammation. RESULT: Twenty randomized controlled trials involving 2574 participants with CHD were included. The results indicated that, compared with percutaneous coronary intervention (PCI) alone, the combination of CDDP with PCI treatment remarkably reduced MACE (RR = 0.53, 95% confidence interval (CI) (0.44, 0.65), P < 0.00001). Moreover, hemorheology and blood lipid parameters and inflammatory mediators of CHD patients were also dramatically mitigated after the combined therapy (P < 0.01). In addition, vascular endothelial function and cardiac function were prominently improved by this combination (P < 0.001). However, there was no significant difference in adverse reactions between the two groups (P > 0.05). CONCLUSION: Evidence from the meta-analysis demonstrated that CDDP combined with PCI treatment prominently reduced the incidence of MACE, improved cardiovascular functions, and inhibited inflammation in CHD patients. Therefore, CDDP combined with PCI treatment could be an effective and safe therapeutic method for CHD patients.

Zanthoxylum nitidum (Roxb.) DC: Traditional uses, phytochemistry, pharmacological activities and toxicology.

ETHNOPHARMACOLOGICAL RELEVANCE: Zanthoxylum nitidum (Roxb.) DC. (Z. nitidum), which is known in China as Liang-Mian-Zhen, is mainly distributed in southern China and is widely used in traditional Chinese medicine. It is traditionally used for treating stomach ache, toothache, rheumatic arthralgia, traumatic injury and venomous snake bites. Additional medical applications include the treatment of inflammations, various types of cancer, bacterial and viral infections, gastric and oral ulcers and liver damage. AIM OF THIS REVIEW: This paper aims to offer up-to-date information on the botany, traditional uses, phytochemistry, pharmacology and toxicity of Z. nitidum. This review also discussed the perspectives for possible future research on Z. nitidum. MATERIALS AND METHODS: A comprehensive review was carried out on studies about Z. nitidum conducted in the past 60 years by using different resources, including Flora of China, Pharmacopoeia of the People's Republic of China and academic databases. RESULTS: At present, more than 150 chemical constituents have been separated and identified from Z. nitidum, most of which include alkaloids. Biological activities, including anti-inflammation, analgesia, haemostasis, anticancer and antibacterial, were determined via in vitro and in vivo studies. The variations in the efficacy of Z. nitidum can be attributed to the biological activities of its natural products, especially alkaloids. Toxicity studies on Z. nitidum are relatively few, thus requiring further study. CONCLUSIONS: This article generalises the current research achievements related to Z. nitidum, which is an important medicinal material in China. Some traditional uses of Z. nitidum have been assessed by pharmacological studies. Unresolved problems remain, including molecular mechanisms underlying biological activities, pharmacokinetics, toxicology and therapeutic effect, which are still being studied and explored before Z. nitidum can be integrated into clinical medicine.

Oxyberberine, a novel gut microbiota-mediated metabolite of berberine, possesses superior anti-colitis effect: Impact on intestinal epithelial barrier, gut microbiota profile and TLR4-MyD88-NF-κB pathway.

Berberine (BBR), a naturally-occurring isoquinoline alkaloid isolated from several Chinese herbal medicines, has been widely used for the treatment of dysentery and colitis. However, its blood concentration was less than 1 %, and intestinal microflora-mediated metabolites of BBR were considered to be the important material basis for the bioactivities of BBR. Here, we investigated the anti-colitis activity and potential mechanism of oxyberberine (OBB), a novel gut microbiota metabolite of BBR, in DSS-induced colitis mice. Balb/C mice treated with 3 % DSS in drinking water to induce acute colitis were orally administrated with OBB once daily for 8 days. Clinical symptoms were analyzed, and biological samples were collected for microscopic, immune-inflammation, intestinal barrier function, and gut microbiota analysis. Results showed that OBB significantly attenuated DSS-induced clinical manifestations, colon shortening and histological injury in the mice with colitis, which achieved similar therapeutic effect to azathioprine (AZA) and was superior to BBR. Furthermore, OBB remarkably ameliorated colonic inflammatory response and intestinal epithelial barrier dysfunction. OBB appreciably inhibited TLR4-MyD88-NF-κB signaling pathway through down-regulating the protein expressions of TLR4 and MyD88, inhibiting the phosphorylation of IκBα, and the translocation of NF-κB p65 from cytoplasm to nucleus. Moreover, OBB markedly modulated the gut dysbiosis induced by DSS and restored the dysbacteria to normal level. Taken together, the result for the first time revealed that OBB effectively improved DSS-induced experimental colitis, at least partly through maintaining the colonic integrity, inhibiting inflammation response, and modulating gut microflora profile.

Insight into the inhibitory effects of Zanthoxylum nitidum against Helicobacter pylori urease and jack bean urease: Kinetics and mechanism.

ETHNOPHARMACOLOGICAL RELEVANCE: Zanthoxylum nitidum (Roxb.) DC. is a traditional Chinese medicine characterised by anti-inflammatory and anti-Helicobacter pylori, which is widely used to treat H. pylori-induced gastric disease in China. However, the underlying mechanism related to its anti-H. pylori activity remains unclear. Urease plays a crucial role in the colonisation and survival of H. pylori. AIM OF THE STUDY: The root aqueous extract of Z. nitidum against H. pylori urease (HPU) and jack bean urease (JBU) was investigated to illuminate the inhibitory potency, kinetics and potential mechanism. MATERIALS AND METHODS: Z. nitidum components were determined by UPLC. The enzyme inhibitory effects of Z. nitidum were examined using modified spectrophotometric Berthelot (phenol-hypochlorite) method. Urease inhibition kinetics were determined by Lineweaver-Burk plots. Sulfhydryl group reagents and Ni2+-binding inhibitors were used in the mechanism study. Moreover, the molecular docking technique was used to investigate the binding conformations of the main compounds of Z. nitidum on Urease. RESULTS: According to UPLC results, the major components of Z. nitidum were magnoflorine, sanguinarine, nitidine chloride, chelerythrine, skimmianine and L-Sesamin. Z. nitidum has higher enzyme inhibitory activity on HPU (IC50 = 1.29 ± 0.10 mg/mL) than on JBU (IC50 = 2.04 ± 0.27 mg/mL). Enzyme inhibitory kinetic analysis revealed that the type of Z. nitidum inhibition against HPU was a slow-binding and mixed-type, whereas a slow-binding and non-competitive type inhibited JBU. Further mechanism study indicated that the active site of sulfhydryl group might be the target of inhibition by Z. nitidum. The molecular docking study indicated that the above six main components of Z. nitidum exhibited stronger affinity to HPU than to JBU through interacting with the key amino acid residues located on the mobile flap or interacting with the active site Ni2+. Results indicated that these components are potential active ingredients directed against urease. CONCLUSIONS: Z. nitidum inactivated urease in a concentration-dependent manner through slow-binding inhibition and binding to the urease active site sulfhydryl group. Our investigation might provide experimental evidence for the traditional application of Z. nitidum in the treatment of H. pylori-associated gastric disorders.

Comparison of anti-inflammatory effects of berberine, and its natural oxidative and reduced derivatives from Rhizoma Coptidis in vitro and in vivo.

BACKGROUND: Berberine (BBR) is the most abundant and major active constituent of Rhizoma Coptidis (RC), which has been widely used to treat inflammatory diseases in traditional oriental medicine. Despite BBR has been found to exhibit pronounced anti-inflammatory effect, the anti-inflammatory activities of its natural derivatives were sparsely dissected out. PURPOSE: To comparatively investigate the anti-inflammatory potential of BBR, and its natural oxoderivative (oxyberberine, OBB) and reduced derivative (dihydroberberine, DHBB) in vitro and in vivo, and delineate the possible underlying mechanism. METHODS: LC-MS/MS was used to identify the natural derivatives of BBR in RC. The potential anti-inflammatory properties of BBR and its natural derivatives were comparatively evaluated in vitro by lipopolysaccharide (LPS)-induced RAW264.7 macrophages cells, and in vivo via three typical acute inflammation murine models. Some important inflammation-related molecules were analyzed by ELISA, qRT-PCR and Western blotting. RESULTS: LC-MS/MS led to the identification of BBR, OBB and DHBB in RC ethyl acetate extract. The in vitro assay indicated that BBR, OBB and DHBB (1.25, 2.5 and 5 µM) pretreatment significantly decreased the levels of pro-inflammatory cytokines tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), interleukin-6 (IL-6), prostaglandinE2 (PGE2) and nitricoxide (NO), and inhibited the mRNA expressions of cyclooxygenase-2 (COX-2) and inducible nitricoxide synthase (iNOS) in a dose-dependent manner, with relative efficiency of OBB > BBR > DHBB. Furthermore, OBB, BBR and DHBB remarkably inhibited the phosphorylation of nuclear factor-κB (NF-κB) p65 and inhibitory kappa Bα (IκBα). In vivo, BBR (20 mg/kg) and OBB (5, 10, and 20 mg/kg) pretreatment significantly ameliorated the xylene-induced ear edema, carrageenan-stimulated paw edema, and acetic acid-elicited vascular permeability in mice in a dose-dependent manner, with OBB exhibiting superior anti-inflammatory effect at the same dose (20 mg/kg). Histopathological analysis indicated that OBB and BBR could markedly attenuate the inflammatory deterioration and decrease the cellular infiltration in paw tissues. Additionally, the carrageenan-induced increases in TNF-α, IL-6, IL-1ß, PGE2 and NO productions, and COX-2 and iNOS mRNA expressions were effectually and concentration-dependently suppressed by OBB and BBR pretreatment. CONCLUSION: The anti-inflammatory activity of BBR and its natural derivatives was in the order of OBB > BBR > DHBB. OBB was for the first time found to be endowed with pronounced anti-inflammatory property, which was probably associated with suppressing the activation of NF-κB signaling pathway, and the subsequent gene expressions and productions of pro-inflammatory mediators. The results might contribute to illuminating the pharmacodynamic underpinnings of RC and provide evidence for developing OBB as a safe and promising natural lead compound in inflammation treatment.

Therapeutic efficacy and safety of Kang-ai injection combined with platinum-based doublet chemotherapy in advanced NSCLC: A meta-analysis.

AIMS: Kang-ai injection (KA) is a famous Chinese patent medicine authorized by China Food and Drug Administration, which is widely used to treat advanced non-small cell lung cancer (NSCLC) in China. This meta-analysis is aimed to evaluate the therapeutic efficacy and safety of KA on advanced NSCLC. METHODS: Seven databases were examined for related studies until January 15, 2018. Odds ratio (OR) was used to evaluate tumor response, Karnofsky Performance Scale (KPS) improvement and adverse reactions, and mean difference (MD) was used to estimate immune functions. KEY FINDINGS: Thirty randomized controlled trials involving 1956 patients with advanced NSCLC were included. The results showed that compared with the platinum-based doublet chemotherapy (PBDC) alone, KA combined with PBDC could significantly enhance tumor response (OR = 1.69, 95% CI [1.40, 2.04], P < 0.00001), KPS improvement (OR = 3.01, 95% CI [2.36, 3.84], P < 0.00001) and immune functions including the percentages of CD3+ (MD = 8.90, 95% CI [3.06, 14.73], P = 0.003), CD4+ (MD = 9.43, 95% CI [6.32, 12.53], P < 0.00001) and NK (MD = 4.81, 95% CI [1.95, 7.68], P = 0.001) and the ratio of CD4+/CD8+ (MD = 0.29, 95% CI [0.04, 0.53], P = 0.02). Moreover, KA combined with PBDC markedly decreased the incidences of adverse reactions including gastrointestinal reaction (OR = 0.38, 95% CI [0.30, 0.47], P < 0.00001), myelosuppression (OR = 0.32, 95% CI [0.23, 0.45], P < 0.00001) and hair loss (OR = 0.53, 95% CI [0.36, 0.76], P < 0.00001). However, there was no significant difference between the combination treatment group and the control group in the percentage of CD8+ (MD = -2.93, 95% CI [-6.68, 0.82], P = 0.13). SIGNIFICANCE: Despite the small sample size and study limitations, the results of this meta-analysis indicated that the combination therapy of KA and PBDC (especially NP regimen) might be a beneficial therapeutic method for advanced NSCLC patients.

Clinical Efficacy of Jinshuibao Capsules Combined with Angiotensin Receptor Blockers in Patients with Early Diabetic Nephropathy: A Meta-Analysis of Randomized Controlled Trials.

BACKGROUND: Jinshuibao capsules (JSB) have been widely used to treat early diabetic nephropathy (DN), but the specific effects are still inconsistent. A meta-analysis of randomized controlled trials (RCTs) was conducted to evaluate the clinical efficacy of JSB for early DN. METHODS: Four international databases and four Chinese databases were searched from publication dates to March 1, 2018. The RCTs reporting the results of JSB's specific effects were included, and comparisons were between JSB combined with Angiotensin Receptor Blockers (ARBs) as experimental intervention and ARBs as the control. Included studies' quality was evaluated and the extracted data were analyzed with RevMan 5.3 software. RESULTS: Twenty-six RCTs including 2198 early DN participants were adopted in the meta-analysis. The results showed that, compared with the ARBs alone, JSB could remarkably improve the ORR (OR = 3.84; 95% CI: 2.37~6.24; P < 0.00001) and decrease 24 h UTP (MD = -93.32; 95% CI: -128.60 ~-58.04; P < 0.00001), UAER (MD = -24.02; 95% CI: -30.93 ~-17.11; P < 0.00001), BUN (MD = -0.26; 95%: -0.44 ~-0.08; P = 0.005), Scr (MD = -9.07; 95% CI: -14.26 ~-3.88; P = 0.0006), ACR (MD = -17.55; 95% CI: -22.81 ~-12.29; P < 0.00001), Cys-C (MD = -0.60; 95% CI: -0.88 ~-0.32; P < 0.00001), SBP (MD = -3.08; 95% CI: -4.65 ~-1.52; P = 0.0001), DBP (MD = -2.09; 95% CI: -4.00 ~-0.19; P = 0.03), and TG (MD = -0.36; 95% CI: -0.50 ~-0.21; P < 0.00001). However, it showed no significant differences in TC (MD = -0.32; 95% CI: -0.69~0.04; P = 0.08), FBG (MD = 0.04; 95% CI: -0.39~0.47; P = 0.87), HbA1c (MD = -0.26; 95% CI: -0.59~0.06; P = 0.11), and ß2-MG (MD = -15.61; 95% CI: -32.95~1.73; P = 0.08). CONCLUSIONS: This study indicates that JSB is an effective accessory therapeutic medicine for patients with early DN. It contributes to decreasing blood pressure and the content of triglyceride and improving the renal function of early DN patients. However, there is still a need to further verify the auxiliary therapeutic effect of JSB with more strictly designed RCTs with large sample and multiple centers in the future.

Protective Effect of Pogostone on 2,4,6-Trinitrobenzenesulfonic Acid-Induced Experimental Colitis via Inhibition of T Helper Cell.

Inflammatory bowel disease (IBD) is a chronic immune-related disease mainly caused by the disequilibrium of T helper (Th) cell paradigm? Pogostone (PO) is one of the major chemical constituents of Pogostemon cablin (Blanco) Benth. The present study aims to investigate the potential benefit of PO against IBD in a 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced experimental colitis model. PO treatment by enema significantly brought down the disease activity index (DAI) of the TNBS-challenged rats, which was manifested by the ameliorated inflammatory features including ulceration, adhesion, and edema. Hematoxylin-eosin (HE) staining and immunohistochemistry analysis showed that PO effectively relived colon damage by restoring epithelium, and more importantly, by inhibiting the infiltration of pro-inflammatory Th1 and Th17 cells in the colon. Additionally, PO inhibited the activity of myeloperoxidase and secretion of inflammatory cytokines including IFN-γ, IL-12p70, IL-17A, and IL-10. Together with our previous findings, the present data indicated that the anti-IBD effect of PO probably related to its direct inhibition on Th cell proliferation and suppression of the cytokines secretion. These results highlighted the potential of PO as a promising candidate to relieve IBD.

ß-Patchoulene from patchouli oil protects against LPS-induced acute lung injury via suppressing NF-κB and activating Nrf2 pathways.

ß-Patchoulene (ß-PAE), a tricyclic sesquiterpene isolated from the essential oil of the leaves and stems of Pogostemon cablin (Blanco) Benth., has been reported to have potent anti-inflammatory activity. The aim of this study was to evaluate the potential protective effect of ß-PAE on lipopolysaccharide (LPS)-induced acute lung injury (ALI) in mice and to illuminate the underlying mechanisms. ALI was induced by intracheal instillation of LPS into lung, and dexamethasone (DEX) was used as a positive control. Results indicated that pretreatment with ß-PAE significantly decreased the mortality rate of mice and lung W/D weight ratio, ameliorated lung pathological changes as compared to model group. Meanwhile, ß-PAE pretreatment markedly inhibited the increase of TNF-α, IL-6 and IL-1ß secretions in the bronchoalveolar lavage fluid, and prevented LPS-induced elevations of MPO activity and MDA level in the lung. Additionally, ß-PAE pretreatment significantly elevated miR-146a expression and suppressed the LPS-induced activation of NF-κB and expression of its mediated genes (TNF-α, IL-6 and IL-1ß). ß-PAE was also observed to markedly upregulate the Nrf2 and HO-1 expression and activate the antioxidant genes (NQO-1, GCLC and HO-1). Taken together, ß-PAE possessed protective effect against LPS-induced ALI, which might be associated with its differential regulation of NF-κB and Nrf2 activities and up-regulation of expression of miR-146a. The results rendered ß-PAE a promising anti-inflammatory agent worthy of further development into a pharmaceutical drug for the treatment of ALI.

Epiberberine, a natural protoberberine alkaloid, inhibits urease of Helicobacter pylori and jack bean: Susceptibility and mechanism.

In our previous study, Rhizoma Coptidis extract was found to exert more potent inhibitory effect than its major component berberine towards urease from Helicobacter pylori (HPU) and jack bean (JBU). In continuation of our work, the present study was designed to further comparatively investigate the urease inhibitory activities of five major protoberberine alkaloids in Rhizoma Coptidis, namely berberine, palmatine, coptisine, epiberberine, jateorhizine to identify the bioactive constituent, and illuminate the potential mechanism of action. Results indicated that the five protoberberine alkaloids acted as concentration-dependent inactivators of urease with IC50 values ranging between 3.0 and 5087µM for HPU and 2.3->10,000µM for JBU, respectively. Notably, epiberberine (EB) was found to be the most potent inhibitor against both ureases with IC50 values of 3.0±0.01µM for HPU and 2.3±0.01µM for JBU, which was more effective than the standard urease inhibitor, acetohydroxamic acid (83±0.01µM for HPU and 22±0.01µM for JBU, respectively). Further kinetic analysis revealed that the type of EB inhibition against HPU was slow-binding and uncompetitive, with Ki of 10.6±0.01µM, while slow-binding and competitive against JBU with Ki of 4.6±0.01µM. Addition of thiol reagents, such as l-cysteine, glutathione and dithiothreitol, significantly abolished the inhibition, while Ni2+ competitive inhibitors, boric acid and sodium fluoride, synergetically inhibited urease with EB, indicating the obligatory role of the active site sulfhydryl group for the inhibition. In addition, binding of EB with the urease proved to be reversible, as about 65% and 90% enzymatic activity of HPU and JBU, respectively, could be restored by dithiothreitol application. These findings highlighted the potential role of Rhizoma Coptidis protoberberine alkaloids, especially EB, as a lead urease inhibitor in the treatment of diseases associated with ureolytic bacteria. Thus, EB had good potential for further development into a promising therapeutic approach for the treatment of urease-related diseases.