Mechanistic studies on the alleviation of ANIT-induced cholestatic liver injury by Polygala fallax Hemsl. polysaccharides.

ETHNOPHARMACOLOGICAL RELEVANCE: Polygala fallax Hemsl. is a traditional folk medicine commonly used by ethnic minorities in the Guangxi Zhuang Autonomous Region, and has a traditional application in the treatment of liver disease. Polygala fallax Hemsl. polysaccharides (PFPs) are of interest for their potential health benefits. AIM OF THIS STUDY: This study explored the impact of PFPs on a mouse model of cholestatic liver injury (CLI) induced by alpha-naphthyl isothiocyanate (ANIT), as well as the potential mechanisms. MATERIALS AND METHODS: A mouse CLI model was constructed using ANIT (80 mg/kg) and intervened with different doses of PFPs or ursodeoxycholic acid. Their serum biochemical indices, hepatic oxidative stress indices, and hepatic pathological characteristics were investigated. Then RNA sequencing was performed on liver tissues to identify differentially expressed genes and signaling pathways and to elucidate the mechanism of liver protection by PFPs. Finally, Quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting were used to verify the differentially expressed genes. RESULTS: Data analyses showed that PFPs reduced the levels of liver function-related biochemical indices, such as ALT, AST, AKP, TBA, DBIL, and TBIL. PFPs up-regulated the activities of SOD and GSH, down-regulated the contents of MDA, inhibited the release of IL-1ß, IL-6, and TNF-α, or promoted IL-10. Pathologic characterization of the liver revealed that PFPs reduced hepatocyte apoptosis or necrosis. The RNA sequencing indicated that the genes with differential expression were primarily enriched for the biosynthesis of primary bile acids, secretion or transportation of bile, the reactive oxygen species in chemical carcinogenesis, and the NF-kappa B signaling pathway. In addition, the results of qRT-PCR and Western blotting analysis were consistent with those of RNA sequencing analysis. CONCLUSIONS: In summary, this study showed that PFPs improved intrahepatic cholestasis and alleviated liver damage through the modulation of primary bile acid production, Control of protein expression related to bile secretion or transportation, decrease in inflammatory reactions, and inhibition of oxidative pressure. As a result, PFPs might offer a hopeful ethnic dietary approach for managing intrahepatic cholestasis.

In Situ Activation of Azaarenes and Terminal Alkynes to Construct Bridged Polycyclic Compounds Containing Isoquinolinones.

A copper-catalyzed [4+2] cyclization reaction of isoquinolines and alkynes is developed for the one-step construction of isoquinolinone derivatives with multisubstituted bridging rings. The unique feature of this three-component tandem cyclization reaction is the functionalization of the C1, N2, C3, and C4 positions of 3-haloisoquinolines via the construction of new C-N, C═O, and C-C bonds. This dearomatization strategy for the synthesis of structurally complex isoquinolinone-bridged cyclic compounds offers good chemoselectivity, broad functional group compatibility, greenness, and high step economy.

Prevalence of HIV Transmitted Drug Resistance in Nanjing from 2018 to 2021.

Background: Transmitted drug resistance (TDR) is a major challenge in the clinical management of acquired immunodeficiency syndrome (AIDS). Therefore, this study aimed to investigate the epidemic characteristics of and risk factors for human immunodeficiency virus (HIV)-1 TDR in Nanjing from 2018 to 2021 to provide support for clinical management. Methods: The HIV-1 Pol gene was amplified by nested reverse transcription polymerase chain reaction from venous blood of 1190 HIV-infected patients who did not receive antiviral therapy, and the amplified product was sequenced using an in-house sequencing method. The sequencing result was compared with the HIV drug resistance database from Stanford University to elucidate the rates of antiviral drug resistance and distribution of drug-resistant mutation sites. Factors associated with TDR were evaluated using a logistic regression model. Results: Detection of drug resistance at the gene level was successful in 1138 of 1190 HIV-1-infected patients (95.6%), and the overall 4-year drug resistance rate was 8.2% (93/1138). The drug resistance rate was higher for non-nucleoside reverse transcriptase inhibitors (NNRTIs; 6.7%) than for nucleoside reverse transcriptase inhibitors (NRTIs; 2.5%) or protease inhibitors (PIs; 0.1%) (χ 2 = 83.907, P<0.0001). The most common NNRTI-related mutation was V179D/E followed by K103N. M184V was the dominant NRTI-associated mutation, and M46L/I was the most prevalent PI-associated mutation. A CD4+ T cell count of <50 cells/µL was significantly associated with an increased risk of TDR (OR=3.62, 95% CI: 1.38-9.51, P=0.009). Conclusion: The prevalence of TDR in the city of Nanjing from 2018 to 2021 was at a moderate epidemic risk according to World Health Organization standards. Continuous monitoring of TDR can inform clinical diagnosis and treatment. Patients with advanced disease and a low CD4+ T lymphocyte count are more likely to have TDR in Nanjing.

Efficacy and Safety of a Simplified Lamivudine Plus Dolutegravir Dual Therapy in HIV-1-Infected Patients: A Multicenter Cohort Study in China.

BACKGROUND: Results from both clinical trials and real-world observational studies suggest that lamivudine plus dolutegravir (3TC + DTG) dual therapy has excellent virological efficacy and safety in HIV-1-infected patients. However, there is still no relevant study related to this dual therapy reported in China. METHODS: In this multicenter, retrospective, observational study that included HIV-1-infected patients in China, baseline and follow-up data were collected to analyze the virological suppression rate, immune restoration, and adverse events during follow-up in HIV-1-infected patients who switched to the 3TC + DTG dual therapy. RESULTS: This study recruited 112 HIV-1-infected patients, including 101 men (90.2%), with a median age of 44.0 years (IQR: 33.00-57.75) and median CD4+ T-cell count of 432.13 cells/µL (IQR: 237.75-578.50). The overall virological suppression rate was 94.5% at the 24-week follow-up. However, the virological suppression rates of men who have sex with men patients and patients with CD4+ T-cell count of <350 cells/µL were higher than the baseline value (P < 0.05) at week 24. The results of Cox regression analysis showed that the baseline CD4+ T-cell count was an independent determinant of immune restoration in patients, and patients with baseline CD4+ T-cell count of 350-500 cells/µL outperformed patients with baseline CD4+ T-cell count of <350 cells/µL in immune restoration (hazard ratio: 4.469, 95% confidence interval: 1.801 to 11.091, P = 0.001). Adverse events were reported in 5 patients (incidence rate of 4.5%); among them, 3 patients developed neuropsychiatric symptoms. Results from the laboratory data analysis showed that patients with grade 1 and 2 adverse events had elevated levels of low-density lipoprotein cholesterol and total bilirubin. Furthermore, grade 3 and 4 adverse events were associated with the elevation of blood glucose level in 4 patients. CONCLUSIONS: Thus, the 3TC + DTG dual therapy displayed an excellent virological efficacy against HIV-1 infections and had an acceptable safety profile, with predominantly mild adverse events in HIV-1-infected patients in China.

Hydrogen Transfer Coupling with 100% Atom Economy: Synthesis of 2-Indolyltetrahydronaphthyridine Derivatives.

An iridium-catalyzed hydrogen transfer strategy, enabling straightforward access to tetrahydropyridine derivatives from aryl-1,8-naphthyridines and indolines was developed. This method has unprecedented advantages, including high step economy. In addition, it does not produce any byproducts or require an external high-pressure H2 gas source. The method offers an important platform for the transformation of 1,8-naphthyridines and indolines into functionalized products.

Marchantia polymorpha L. Flavonoids Protect Liver From CCl4-Induced Injury by Antioxidant and Gene-Regulatory Effects.

Marchantia polymorpha L. (MPL), a common type of liverwort, has been used as herbal medicine to improve liver function in China for many years. Although modern studies revealed that MPL contains various polyphenols, terpenoids, and bis[bibenzyls], its biological effects on liver function have never been systemically studied in any animal model. In this study, flavonoids were extracted from MPL and the components in the MPL flavonoids as well as the antioxidant capacity of MPL flavonoids were analysed. A rat model of liver injury was induced by intraperitoneal injection of 10% carbon tetrachloride (CCl4). MPL flavonoids were administered daily at a dose of 50, 100, and 200 mg/kg body weight to the rats for 2 weeks prior to injection of CC14. Treatment with MPL flavonoids, especially at a dose of 200 mg/kg, attenuated CCl4-induced increases in alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, γ-glutamyl transpeptidase, nitric oxide, malondialdehyde, tumour necrosis factor-α, interleukin-1ß, and interleukin-6, as well as reductions in superoxide dismutase and glutathione peroxidase. Microarray analyses showed that co-treatment with MPL flavonoids and CCl4 up-regulated many antioxidant and anti-apoptotic genes, but down-regulated several pro-inflammatory genes, compared to treatment with CCl4 alone. PCR and western blot assays further identified that MPL flavonoids increased GPX1, TMX1, TXN, and XIAP expression, but decreased IL-1 and IL1RAP expression and inhibited Jak/stat3 signalling. In conclusion, MPL flavonoids exerted hepatoprotective effects via antioxidant and gene regulatory mechanisms. (Altern Ther Health Med.

A retrospective clinical study of dolutegravir- versus efavirenz-based regimen in treatment-naïve patients with advanced HIV infection in Nanjing, China.

Currently, there are limited data related to the efficacy and safety of ART regimens, as well as factors influencing immune recovery in antiretroviral therapy (ART)-naïve patients with advanced HIV infection, especially in China. We designed a single-center, retrospective cohort study from March 1, 2019, to May 31, 2022, at The Second Hospital of Nanjing, China. ART-naïve adults with advanced HIV infection (CD4+ T-cell count < 200 cells/µL) who met the study criteria were included. The plasma viral load (VL), CD4+ T-cell count, CD4/CD8 ratio, treatment discontinuation, and immune reconstitution inflammatory syndrome (IRIS) events were collected to compare the efficacy and safety of the dolutegravir (DTG) and the efavirenz (EFV) regimens. Factors of immune recovery were analyzed using the Cox regression model. Study enrolled 285 ART-naïve adults with advanced HIV-1 infection, of which 95 (33.3%) started regimens including DTG and 190 (66.7%) were treated with EFV. After ART initiation, the proportion of patients with HIV-1 RNA < 50 copies/mL was higher (22.5% versus 6.5%, P < 0.001) in those on DTG-based regimens at month 1, but no significant difference at other follow-up points. Compared to the baseline, the median CD4+ T-cell count and CD4/CD8 ratio increased significantly during follow-up both in the EFV and the DTG groups. However, the CD4+ T-cell count increased greater in patients on DTG-based regimens at months 6, 12, 24, and 36 (P < 0.05). A total of 52 (18.2%) patients discontinued treatment, with no significant difference between ART regimens in treatment discontinuation rates. Only 7 patients reported IRIS, without significant difference between ART regimens (P=0.224). Overall, 34.0% (97/285) achieved a CD4+ T-cell count ≥ 350 cells/µL during follow-up. Age (P < 0.001), baseline CD4+ T-cell count (P < 0.001), baseline VL (P < 0.001) and ART regimens (P = 0.019) were associated with the CD4+ T-cell count ≥ 350 cells/µL after adjusting for potential confounders. Among ART-naïve adults with advanced HIV infection, it appeared that DTG-based regimens were better options for initial therapy compared to regimens including EFV; in addition, ART regimens, age, baseline VL and CD4+ T-cell count were associated with immune recovery.

Ferrite Nanoparticles-Based Reactive Oxygen Species-Mediated Cancer Therapy.

Ferrite nanoparticles have been widely used in the biomedical field (such as magnetic targeting, magnetic resonance imaging, magnetic hyperthermia, etc.) due to their appealing magnetic properties. In tumor acidic microenvironment, ferrite nanoparticles show intrinsic peroxidase-like activities, which can catalyze the Fenton reaction of hydrogen peroxide (H 2 O 2) to produce highly toxic hydroxyl free radicals (•OH), causing the death of tumor cell. Recent progresses in this field have shown that the enzymatic activity of ferrite can be improved via converting external field energy such as alternating magnetic field and near-infrared laser into nanoscale heat to produce more •OH, enhancing the killing effect on tumor cells. On the other hand, combined with other nanomaterials or drugs for cascade reactions, the production of reactive oxygen species (ROS) can also be increased to obtain more efficient cancer therapy. In this review, we will discuss the current status and progress of the application of ferrite nanoparticles in ROS-mediated cancer therapy and try to provide new ideas for this area.

Study on the protective effect and mechanism of Dicliptera chinensis (L.) Juss (Acanthaceae) polysaccharide on immune liver injury induced by LPS.

The purpose of this study is to use Dicliptera chinensis (L.) Juss (Acanthaceae) polysaccharide (DCP) to act on the NF-κB inflammatory pathway and Fas/FasL ligand system, in order to find a new method to improve immune liver injury. Lipopolysaccharide (LPS) was used to establish an injury model in vivo (Kunming mice) and in vitro (LO2 cells). In this experiment, hematoxylin-eosin (H&E) staining and related biochemical indicators were used to observe the pathological changes of liver tissues, oxidative stress and inflammatory reactions. Immunohistochemistry, ELISA, RT-PCR and Western blot were used to detect protein or mRNA expressions associated with inflammation response and apoptosis. The experimental results show that the model group has obvious liver cell damage and inflammatory infiltration. After DCP intervention, it could significantly reduce the levels of ALT, AST, ALP, TBIL and MDA in serum, and increase the content of SOD and GSH-Px. In addition, DCP can reduce the expression level of NF-κB in the liver and reduce the release of downstream inflammatory factors TNF-α, IL-6 and IL-1ß, thereby reducing the inflammation. At the same time, DCP can significantly inhibit the expression of Fas/FasL ligand system and apoptosis related-proteins and mRNA, which in turn can reduce cell apoptosis. In conclusion, DCP can alleviate liver injury by inhibiting liver inflammation and apoptosis, which provides a new strategy for clinical treatment of immune liver injury.

Effects of taraxasterol against ethanol and high-fat diet-induced liver injury by regulating TLR4/MyD88/NF-κB and Nrf2/HO-1 signaling pathways.

Studies have reported that taraxasterol (TAR) is effective in the treatment of immune liver injury and alcoholic liver injury. The mechanism of action is mainly related to the inhibition of inflammation. To determine the key molecular mechanisms for the effect of TAR on alleviating ethanol and high-fat diet-induced liver injury, pathological morphology, biochemistry, oxidative stress, inflammatory response and lipid metabolism were examined. Our results showed that TAR could inhibit ethanol-induced hepatocyte death or lipid accumulation, and suppress oxidative stress, inflammatory response and lipid metabolism disorders. More specifically, ethanol-induced TLR-4 and MyD88 inflammatory response were down-regulated, when treated with TAR. Production of CYP2E1, Nrf2 and HO-1, which produced in response to increased oxidative stress, were regulated in TAR treated, ethanol-induced hepatocytes. In summary, TAR could inhibit the inflammatory response and oxidative stress, which was related to the regulation of TAR on TLR-4/MyD88/NF-κB and Nrf2/HO-1 pathways.

Scoparone alleviates hepatic fibrosis by inhibiting the TLR-4/NF-κB pathway.

The aim of this study was to investigate the role of scoparone (SCO) in hepatic fibrosis. For this, we conducted in vivo and in vitro experiments. In vivo rats that were divided into six groups, control, carbon tetrachloride, and colchicine, as well as SCO groups, SCO50, SCO100, and SCO200 treated with 50, 100, and 200 mg/kg SCO doses, respectively. Furthermore, SCO was shown to inhibit Toll-like receptor-4 (TLR-4)/nuclear factor kappa-B (NF-κB; TLR-4/NF-κB) signals by inhibiting TLR-4, which in turn downregulates the expression of MyD88, promotes NF-κB inhibitor-α, NF-κB inhibitor-ß, and NF-κB inhibitor-ε activation, while inhibiting NF-κB inhibitor-ζ. Subsequently, the decrease of phosphorylation of nuclear factor-κB levels leads to the downregulation of the downstream inflammatory factors' tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and IL-1 beta, thus weakening hepatic fibrosis. Notably, the SCO200 treated group presented the most significant improvement. Hence, we conclude that SCO alleviates hepatic fibrosis by inhibiting TLR-4/NF-κB signals.

Polysaccharides from Dicliptera chinensis ameliorate liver disturbance by regulating TLR-4/NF-κB and AMPK/Nrf2 signalling pathways.

The purpose of this study was to alleviate liver disturbance by applying polysaccharides from Dicliptera chinensis (DCP) to act on the adenosine monophosphate-activated protein kinase/ nuclear factor erythroid 2-related factor 2 (AMPK/ Nrf2) oxidative stress pathway and the Toll-like receptor 4 (TLR-4)/ nuclear factor kappa-B (NF-κB) inflammatory pathway and to establish an in vivo liver disturbance model using male C57BL/6J and TLR-4 knockout (-/- ) mice. For this, we evaluated the expression levels of SREBP-1 and Nrf2 after silencing the expression of AMPK using siRNA technology. Our results show that with regard to the TLR-4/ NF-κB inflammatory pathway, DCP inhibits TLR-4, up-regulates the expression of peroxisome proliferator-activated receptor-γ (PPAR-γ), reduces the expression of phospho(p)-NF-κB and leads to the reduction of downstream inflammatory factors, such as tumour necrosis factor-α (TNF-α), interleukin (IL)-6 and IL-1ß, thereby inhibiting the inflammatory response. Regarding the AMPK/ Nrf2 oxidative stress pathway, DCP up-regulates the expression of p-AMPK and Nrf2, in addition to regulating glucose and lipid metabolism, oxidative stress and ameliorating liver disturbance symptoms. In summary, our study shows that DCP alleviates liver disturbances by inhibiting mechanisms used during liver inflammation and oxidative stress depression, which provides a new strategy for the clinical treatment of liver disturbance.

GVS-12 attenuates non-alcoholic steatohepatitis by suppressing inflammatory responses via PPARγ/STAT3 signaling pathways.

Non-alcoholic steatohepatitis (NASH), a type of fatty liver disease, is characterized by excessive inflammation and fat accumulation in the liver. Peroxisome proliferator-activated receptor γ (PPARγ) agonist rosiglitazone has great potential in protecting against the development of NASH. However, long-term usage of rosiglitazone probably leads to many adverse reactions. In this research, GVS-12 was designed and synthesized as a PPARγ agonist with high selectivity, evidenced by increasing the activity of the PPARγ reporter gene and promoting the mRNA expression of the PPARγ responsive gene cluster of differentiation 36 (CD36). It was noteworthy that GVS-12 could ameliorate dysfunction and lipid accumulation by down-regulating the mRNA expression of interleukin-1ß (IL-1ß), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) in the liver of high fat diet (HFD)-induced rats and palmitic acid (PA)-stimulated hepatocellular carcinoma G2 (HepG2) cells. Moreover, PPARγ siRNA (siPPARγ) markedly diminished GVS-12 induced the down-regulation of mRNA expression of IL-1ß, IL-6 and TNF-α in PA-stimulated HepG2 cells. Additionally, GVS-12 could reduce the phosphorylation level of STAT3 and up-regulate the protein expression of a suppressor of cytokine signaling 3 (SOCS3), which could be reversed by siPPARγ. In detail, SOCS3 siRNA (siSOCS3) diminished the inhibitory effect of GVS-12 on the mRNA expression of IL-1ß, IL-6 and TNF-α. In conclusion, GVS-12 suppressed the development of NASH by down-regulating the mRNA expression of IL-1ß, IL-6 and TNF-α via PPARγ/STAT3 signaling pathways.

VSP-17, a New PPARγ Agonist, Suppresses the Metastasis of Triple-Negative Breast Cancer via Upregulating the Expression of E-Cadherin.

Triple-negative breast cancer (TNBC), an aggressive subtype of breast cancer, shows higher metastases and relapse rates than other subtypes. The metastasis of TNBC is the main reason for the death of TNBC patients. Increasing evidence has shown that inhibiting the metastasis of TNBC is a good method for TNBC treatment. Here, VSP-17 was designed and synthesized as an agonist of PPARγ, evidenced by upregulating the expression of CD36 and increasing the activity of PPARγ reporter gene. VSP-17 obviously inhibited the migration and invasion process of MDA-MB-231 cells but showed little effect on the viability of MDA-MB-231 cells. Notably, VSP-17 could selectively promote the expression of E-cadherin without affecting the expression of BRMS1, CXCL12, MMP9, Orai1, Stim1, TGF-ß, and VEGF. In addition, VSP-17 significantly suppressed the metastasis of liver and promoted the expression of E-cadherin in MDA-MB-231 xenograft model. In conclusion, VSP-17 inhibited the metastasis process of TNBC via upregulating the expression of E-cadherin.

Isolation, characterization and bioactivities of the polysaccharides from Dicliptera chinensis (L.) Juss.

The polysaccharides of Dicliptera chinensis (L.) Juss. (DCP-1 and DCP-2) were extracted and isolated using the methods of water extract-ethanol precipitate and sephadex column chromatography and characterized by gel permeation chromatography (GPC), Fourier transform infrared spectrometry (FT-IR) and gas chromatography (GC), respectively. The antioxidant activity of DCPs was evaluated by scavenging activity of DPPH, hydroxyl, superoxide anion and ABTS radical. Moreover, the anti-aging activity of DCP-2 was investigated using an aging model-induced by D-galactose (D-gal) in mice. The results show that the weight average molecular weight (Mw) of DCP-2 was 2 273Da with a narrow polydispersity index of 1.01, and it was a heteropolysaccharide and consisted of glucose, galactose, arabinose, rhamnose and mannose with a molar ratio of 3.20:2.54:1.69:1.58:1.00. DCP-2 had stronger antioxidant activity against DPPH, hydroxyl, superoxide anion and ABTS radical, while DCP-1 had hardly any antioxidant activity and DCP had weaker antioxidant activity. Furthermore, DCP-2 can enhance antioxidant capacity and had anti-aging activity against D-gal induced aging mice. These results proposed that DCP-2 might be developed as a potential functional food with the activity of anti-aging.

Natakalim Ameliorates Isoproterenol-Induced Chronic Heart Failure by Protecting against Endothelial Dysfunction.

The pharmacological effects and underlying mechanisms of natakalim, a novel SUR2B/Kir6.1-KATP channel opener, against chronic heart failure induced by isoproterenol in rats were investigated. Male Wistar rats were administered isoproterenol subcutaneously (85 mg/kg, 7 days) to induce chronic heart failure and were then treated with natakalim or saline for 6 weeks. Their blood pressure, heart rates and cardiac functions were measured using an 8-channel physiological recorder. Sophisticated technologies such as histological analysis, ELISA, radioimmunoassay, immunohistochemistry, real-time PCR and western blotting were employed for analysis. Natakalim (1, 3, 9 mg/kg/day, orally) or saline was administered for 6 weeks orally via a gastric tube to rats that had been injected with isoproterenol. Natakalim remarkably inhibited changes in left ventricular hemodynamic parameters and decreased the heart mass index, the left ventricular weight index, right ventricular weight index and lung weight index. Histological examination demonstrated no significant hypertrophy or fibrosis in the hearts of the natakalim-treated rats. Mechanistically, natakalim attenuates the elevation of plasma nitric oxide (NO) level and inducible NO synthase in cardiac tissue induced by isoproterenol. Additionally, natakalim inhibits the endothelin signaling system by decreasing both the content of endothelin-1 in the plasma and the protein levels of cardiac endothelin receptors A and B. Moreover, natakalim could augment the plasma prostacyclin concentration. In conclusion, our study provides evidence that natakalim effectively ameliorates isoproterenol-induced chronic heart failure in rats by protecting against endothelial dysfunction.

Hepatoprotective effects of Dicliptera chinensis polysaccharides on dimethylnitrosamine-induced hepatic fibrosis rats and its underlying mechanism.

ETHNOPHARMACOLOGICAL RELEVANCE: Dicliptera chinensis is a traditional herbal medicine used anciently in China for hepatopathy treatment, especially in south areas. Our several studies have demonstrated that dicliptera chinensis polysaccharides (DCP), which has a markedly protective effects on chemistry-induced models of acute liver injury in rats. In this study, we further investigated the potentially hepatoprotective effect of dicliptera chinensis polysaccharides (DCP) on hepatic fibrosis (HF) rats induced by dimethylnitrosamine (DMN). MATERIAL AND METHODS: The 96 rats were randomly divided into six groups (n=16, per group), the normal control group intragastrically administrated normal saline, model control group intraperitoneally injected with 0.5% DMN solution at 1.6mL per kg (three times a week); colchicine intragastrically administrated group (0.2mgkg(-)(1)d(-1))+DMN-treated rats; DCP intragastrically administrated groups (100mgkg(-)(1)d(-)(1), 200mgkg(-1)d(-1), 300mgkg(-1)d(-1))+DMN-treated rats. At the end of 8 weeks, all rats were sacrificed. RESULTS: Pathological examination showed that high and medium doses of DCP presented remarkable effect in ameliorating hepatic fibrosis, alleviate the inflammation, necrosis and reduced collagen deposits. DCP effectively improved the liver function, as revealed in being lowered sero-enzyme levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TBIL) while increased albumin (ALB), and being reduced sero-concentrations of tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6) in the HF rats. Additionally, the contents of hyaluronic acid (HA), collagen type Ⅳ (Ⅳ-C), type III precollagen (PCIII) and laminin (LN) in the hepatic tissue of HF rats were markedly decreased, whereas the expressions of transforming growth factor-ß l (TGF-ß l), collagen type I (Col- I), metal protease-1 (TIMP-1), nuclear factor-kappa B (NF-κB) expression in the hepatic tissue were notably down-regulated. CONCLUSION: DCP exerts effectively antagonistic activity on DMN-caused hepatotoxicity in HF rats, which the anti-fibrotic mechanisms are associated with regulating functionally serous enzymes, improving metabolic function and inhibiting inflammatory reaction in liver tissue.

Synergisms of cardiovascular effects between iptakalim and amlodipine, hydrochlorothiazide or propranolol in anesthetized rats.

The primary object of this fundamental research was to survey the synergistic cardiovascular effects of iptakalim, a novel ATP-sensitive potassium channel (K(ATP)) opener, and clinical first-line antihypertensive drugs, such as calcium antagonists, thiazide diuretics and ß receptor blockers by a 2 x 2 factorial-design experiment. It would provide a theoretical basis for the development of new combined antihypertensive therapy program after iptakalim is applied to the clinic. Amlodipine besylate, hydrochlorothiazide and propranolol were chosen as clinical first-line antihypertensive drugs. Blood pressure, heart rate (HR) and cardiac functions were observed in anesthetized normal rats by an eight-channel physiological recorder. The results showed that iptakalim monotherapy in a low dose could produce significant antihypertensive effect. There was no interaction between iptakalim and amlodipine on the maximal changes of systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial blood pressure (MABP), the left ventricular systolic pressure (LVSP), and the left ventricular end-diastolic pressure (LVEDP) (P > 0.05). However, the effects of combination iptakalim/amlodipine on the maximal changes of SBP, DBP, MABP, LVSP and LVEDP were more obvious than those of iptakalim or amlodipine monotherapy. And there was strong positive interaction between iptakalim and amlodipine on the maximal changes of HR (P>0.05). According to the maximal changes of DBP, MABP, LVSP and LVEDP (P < 0.05) of combination iptakalim with hydrochlorothiazide, there was strong positive interaction between them. But there was no interaction between iptakalim and hydrochlorothiazide on the maximal drop of SBP and HR (P > 0.05). According to the maximal drops of DBP, MABP of combination iptakalim with propranolol, there was strong positive interaction between them (P < 0.05). But there was no interaction between iptakalim and propranolol on the maximal changes of SBP, LVSP, LVEDP and HR (P > 0.05). In conclusion, it was the first time to study the effects of amlodipine, hydrochlorothiazide or propranolol, which had different mechanisms of action from iptakalim, on cardiovascular effects of iptakalim in anesthetized normal rats. This study proved that the combination of iptakalim with hydrochlorothiazide or propranolol respectively had significant synergism on lowering blood pressure, while the combination of iptakalim/amlodipine had additive action on lowering blood pressure. Meanwhile the antihypertensive effect was explicit, stable and long-lasting. Iptakalim thus appears suitable for the clinical treatment of hypertensive people who need two or more kinds of antihypertensive agents.

Natakalim improves post-infarction left ventricular remodeling by restoring the coordinated balance between endothelial function and cardiac hypertrophy.

Endothelial dysfunction can lead to congestive heart failure and the activation of endothelial ATP-sensitive potassium (K(ATP)) channels may contribute to endothelial protection. Therefore, the present study was carried out to investigate the hypothesis that natakalim, a novel K(ATP) channel opener, ameliorates post-infarction left ventricular remodeling and failure by correcting endothelial dysfunction. The effects of myocardial infarction were assessed 8 weeks following left anterior descending coronary artery occlusion in male Wistar rats. Depressed blood pressure, cardiac dysfunction, evidence of left ventricular remodeling and congestive heart failure were observed in the rats with myocardial infarction. Treatment with natakalim at daily oral doses of 1, 3 or 9 mg/kg/day for 8 weeks prevented these changes. Natakalim also prevented the progression to cardiac failure, which was demonstrated by the increase in right ventricular weight/body weight (RVW/BW) and relative lung weight, signs of cardiac dysfunction, as well as the overexpression of atrial and brain natriuretic peptide mRNAs. Our results also demonstrated that natakalim enhanced the downregulation of endothelium-derived nitric oxide, attenuated the upregulation of inducible nitric oxide synthase-derived nitric oxide (NO), inhibited the upregulated endothelin system and corrected the imbalance between prostacyclin and thromboxane A(2). Overall, our findings suggest that natakalim prevents post-infarction hypertrophy and cardiac failure by restoring the coordinated balance between endothelial function and cardiac hypertrophy.