Zn(II)-curcumin solid dispersion impairs hepatocellular carcinoma growth and enhances chemotherapy by modulating gut microbiota-mediated zinc homeostasis.

Zinc(II) complexes of curcumin display moderate cytotoxicity towards cancer cells at low micromolar concentrations. However, the clinical use of zinc(II) complexes is hampered by hydrolytic insolubility and poor bioavailability and their anticancer mechanisms remain unclear. Here, we investigated the efficacy and mechanism of action of a polyvinylpyrrolidone (PVP-k30)-based solid dispersion of Zn(II)-curcumin (ZnCM-SD) against hepatocellular carcinoma (HCC) in vitro and in vivo. In vitro assays revealed ZnCM-SD not only reduced the viability of HepG2 cells and SK-HEP1 cells in a dose-dependent manner, but also potently and synergistically enhanced cell growth inhibition and cell death in response to doxorubicin by regulating cellular zinc homeostasis. ZnCM-SD was internalized into the cells via non-specific endocytosis and degraded to release curcumin and Zn2+ ions within cells. The anticancer effects also occur in vivo in animals following the oral administration of ZnCM-SD, without significantly affecting the weight of the animals. Interestingly, ZnCM-SD did not reduce tumor growth or affect zinc homeostasis in HepG2-bearing mice after gut microbiome depletion. Moreover, administration of ZnCM-SD alone or in combination with doxorubicin significantly attenuated gut dysbiosis and zinc dyshomeostasis in a rat HCC model. Notably, fecal microbiota transplantation revealed the ability of ZnCM-SD to regulate zinc homeostasis and act as a chemosensitizer for doxorubicin were dependent on the gut microbiota. The crucial role of the gut microbiota in the chemosensitizing ability of ZnCM-SD was confirmed by broad-spectrum antibiotic treatment. Collectively, ZnCM-SD could represent a simple, well-tolerated, safe, effective therapy and function as a novel chemosensitizing agent for cancer.

Zn(ii)-Curcumin supplementation alleviates gut dysbiosis and zinc dyshomeostasis during doxorubicin-induced cardiotoxicity in rats.

Doxorubicin is a powerful anticancer agent used to treat a variety of human neoplasms. However, the clinical use of doxorubicin is hampered by cardiotoxicity and effective cardioprotective adjuvants do not exist. Dietary zinc, an essential nutrient, is required to maintain steady-state tissue zinc levels and intestinal homeostasis and may yield therapeutic benefits in diseases associated with zinc dysregulation or gut dysbiosis. Here, we investigated the effects of dietary Zn(ii)-curcumin (ZnCM) solid dispersions on gut dysbiosis and zinc dyshomeostasis during doxorubicin-induced cardiotoxicity in rats. Rats were injected with multiple low doses of doxorubicin and orally administered ZnCM daily over four weeks. Daily administration of ZnCM not only alleviated Dox-induced gut dysbiosis-as indicated by the increased Firmicutes-to-Bacteroidetes ratio and the maintenance of the relative abundances of major beneficial bacteria including Clostridium_XIVa, Clostridium_IV, Roseburia, Butyricicoccus and Akkermansia-but also maintained intestinal barrier integrity and decreased the lipopolysaccharide (LPS) contents of feces and plasma. ZnCM also significantly attenuated doxorubicin-induced zinc dyshomeostasis, which was mirrored by preservation of zinc levels and expression of zinc-related transporters. Furthermore, ZnCM significantly improved heart function and reduced cardiomyocyte apoptosis and myocardial injury in doxorubicin-treated rats. Notably, the regulation of zinc homeostasis and cardioprotective and microbiota-modulating effects of ZnCM were transmissible through horizontal feces transfer from ZnCM-treated rats to normal rats. Thus, ZnCM supplementation has potential as an effective therapeutic strategy to alleviate gut dysbiosis and zinc dyshomeostasis during doxorubicin-induced cardiotoxicity.

Madecassoside prevents acute liver failure in LPS/D-GalN-induced mice by inhibiting p38/NF-κB and activating Nrf2/HO-1 signaling.

Madecassoside (MA), a triterpenoid saponin isolated from Centella asiatica, exerts various pharmacological activities including antioxidative and anti-inflammatory effects. The aim of this study was to explore the protective effect of MA in the treatment of lipopolysaccharide (LPS) and D-galactosamine (D-GalN)-induced acute liver failure(ALF) in mice. We hypothesized that MA administration may decrease the degree of liver injury caused by LPS/D-GalN. In this study, we investigated this hypothesis by treating a mouse model of LPS/D-GalN-induced liver injury with MA. Our study demonstrated that MA (20 mg/kg and 40 mg/kg) treatment for 10 days attenuated LPS/D-GalN-induced liver injury by protecting liver function, suppressing the production of inflammatory cytokines such as tumor necrosis factor (TNF)-α, interleukin (IL)-1ß and IL-6, and recovering antioxidant enzyme activity. MA also significantly suppressed LPS-stimulated protein levels of inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX)-2 by blocking the phosphorylation of p38 mitogen-activated protein kinase (MAPK) and eukaryotic transcription factor nuclear factor-kappa B (NF-κB). In addition, MA treatment enhanced protein levels of heme oxygenase (HO)-1 and anti-oxidant enzymes (superoxide dismutase, catalase, and glutathione peroxidase) through the upregulation of nuclear factor E2-related factor 2 (Nrf2) in LPS-stimulated liver injury. These results suggest that MA is a promising agent for the treatment of LPS/D-GalN-induced liver injury that could serve as a candidate for the development of a hepatoprotective drug against ALF.

Effects of Sanyinjiao (SP6) with electroacupuncture on labour pain in women during labour.

OBJECTIVE: To evaluate the effects of Sanyinjiao (SP6) with electroacupuncture on labour pain in women during the labour process. METHODS: A total of 350 women in labour from three centres were randomly divided into the electroacupuncture group (acupuncture group), the sham electroacupuncture group (sham group) and the control group. Women in labour in the electroacupuncture group received the electroacupuncture on the point Sanyinjiao (SP6). The analgesic effect was self-rated by women in labour, using visual analogue scale (VAS). The duration and paralysis time of uterine contraction, uterine contraction regularity, degree of cervical extension, presentation of foetal descent, the condition of intra-partum haemorrhage and postpartum haemorrhage, labour manner, lochia, involution of uterus, milk secretion, neonate Apgar Score and neonate body height and weight were also measured. All data were analysed with Statistical Package for Social Sciences (SPSS) 12.0. RESULTS: Labour pain scores from women in the acupuncture group were less than in the control group at needle retaining at 30min, 2 and 4h after needle withdrawal. Other evaluated indices did not show significant differences among the three groups. No adverse events were observed during the labour process. CONCLUSION: SP6 with electroacupuncture could be an effective way for decreasing labour pain.

[Clinical application of acupuncture and moxibustion to the treatment of gouty arthritis and analysis on their therapeutic effects].

In the present paper, the authors make a summary on the clinical application of acu-moxibustion therapy in the treatment of gouty arthritis in recent 10 years. Acupuncture needles often used are filiform needle, red-hot needle, moxibustion-warmed needle and three-edged needle. Clinical studies have showed that acupuncture therapy has a definite efficacy in relieving gouty arthritis and has its clinical characteristics, such as faster efficacy, lower relapse rate, etc. in comparison with medication.

[Effect of electroacupuncture on caspase-9 expression in hippocampus and neuroethology in hyperlipemia rats with concurrent cerebral ischemia].

OBJECTIVE: To observe the effect of electroacupuncture (EA) on hippocampal apoptosis protein caspase-9 expression and neuroethology in hyperlipemia plus cerebral ischemia (HL-CI) rats. METHODS: Seventy male SD rats were randomized into control, hyperlipemia (HL), CI, HL-CI, CI + EA, HL-CI + EA I , and HL-CI + EA II groups, with 10 cases in each. HL model was established by feeding the animals with high fat forage for 6 weeks and CI model was established by occlusion of the unilateral middle cerebral artery. EA (1-3 mA, 15 Hz) was applied to bilateral "Sanyinjiao" (SP 6) and "Fenglong" (ST 40) for 20 min every time; and "Baihui" (GV 20) and "Shuigou" (GV 26) were punctured and stimulated by twirling the acupuncture needle with hand continuously for 1 min. Acupuncture was given once daily for 17 days (beginning from the 10th day on before CI) in HL-CI + EA I group, and for 7 days (beginning after CI) in HL-CI + EA II group. The expression of hippocampal Caspase-9 was detected with immunohistochemistry. The score of neuroethology was also measured according to modified Bederson's method. RESULTS: In comparison with normal control and hyperlipemia model groups, Caspase-9 immune reaction (IR) positive cells in the hippocampus in HL-CI group increased significantly (P<0.01). After acupuncture Caspase-9 IR-positive cells decreased remarkably. In comparison with group HL-CI + EA II, Caspase-9 IR-positive cells decreased significantly in HL-CI + EA I (P<0.01). The score of neuroethology also degraded obviously. CONCLUSION: Acupuncture can improve neuroethology symptom, lessen over expression of hippocampal Caspase-9, and prevent CI injury in hyperlipemia rats with concurrent CI.