Aconitine - A promising candidate for treating cold and mechanical allodynia in cancer induced bone pain.

BACKGROUND AND AIMS: Patients suffering from cancer induced bone pain (CIBP) have a poor quality of life that is exacerbated by the lack of effective therapeutic drugs. Monkshood is a flowering plant that has been used in traditional Chinese medicine where it has been used to relieve cold pain. Aconitine is the active component of monkshood, but the molecular mechanism for how this compound reduces pain is unclear. METHODS AND RESULTS: In this study, we employed molecular and behavioral experiments to explore the analgesic effect of aconitine. We observed aconitine alleviated cold hyperalgesia and AITC (allyl-isothiocyanate, TRPA1 agonist) induced pain. Interestingly, we found aconitine directly inhibits TRPA1 activity in calcium imaging studies. More importantly, we found aconitine alleviated cold and mechanical allodynia in CIBP mice. Both the activity and expression of TRPA1 in L4 and L5 DRG (Dorsal Root Ganglion) neurons were reduced with the treatment of aconitine in the CIBP model. Moreover, we observed aconiti radix (AR) and aconiti kusnezoffii radix (AKR), both components of monkshood that contain aconitine, alleviated cold hyperalgesia and AITC induced pain. Furthermore, both AR and AKR alleviated CIBP induced cold allodynia and mechanical allodynia. CONCLUSIONS: Taken together, aconitine alleviates both cold and mechanical allodynia in cancer induced bone pain via the regulation of TRPA1. This research on the analgesic effect of aconitine in cancer induced bone pain highlights a component of a traditional Chinese medicine may have clinical applications for pain.

Randomised clinical trial: Efficacy and safety of Qing-Chang-Hua-Shi granules in a multicenter, randomized, and double-blind clinical trial of patients with moderately active ulcerative colitis.

Qing-Chang-Hua-Shi (QCHS) is a Chinese herbal formula, which is composed of 11 herbs. Studies have also shown that QCHS granules can alleviate colitis in animal models by preventing inflammatory responses and suppressing apoptosis through the MEK/ERK signaling pathway. To determine the efficacy and safety of QCHS granules in patients with moderately active UC. We performed a multicenter, randomized, placebo-controlled, double-blind study of patients with moderately active UC who did not respond to 4 weeks of mesalazine therapy at the maximum dose. Patients were randomly assigned to groups and administered QCHS granules (125 g/day, n = 59) or an identical placebo, which was similar to the QCHS granules in color and taste (125 g/day, n = 60), with continued 5-ASA 4 g/d therapy for 12 weeks. The primary outcome was the rate of clinical response and clinical remission at week 12. The secondary outcomes were health-related quality of life, endoscopic response rate, and mucosal healing rate. Any changes in mucus/bloody stool and diarrhea were recorded. Out of the 119 enrolled patients at 10 different centers in China, 102 patients completed the trial. Clinical remission and clinical response were seen in 31.48% and 92.59% of QCHS-treated patients, and 12.50% and 72.92% of placebo-treated patients, respectively. There was a significant difference between the two treatment groups. More patients receiving QCHS granules vs. placebo achieved remission of mucus/bloody stool (70.37% vs. 47.92%, P = 0.0361). Adverse event rates were similar (QCHS granules 38.33%; placebo 25.42%). In conclusion, QCHS granules were superior to the placebo in introducing clinical remission and mucosal healing, as well as in relieving mucus/blood stool in patients with moderately active and 5-ASA-refractory UC.

Electroacupuncture at ST36 Relieves Visceral Hypersensitivity via the NGF/TrkA/TRPV1 Peripheral Afferent Pathway in a Rodent Model of Post-Inflammation Rectal Hypersensitivity.

PURPOSE: The aim of the study was to investigate the effects of electroacupuncture (EA) at ST36 on rectal hypersensitivity and compliance in DSS-treated post-inflammation rats. In addition, we explored the involvement of mast cells-triggered NGF/TrkA/TRPV1 peripheral afferent pathway. METHODS: Rats were provided water with 5% dextran sulphate sodium (DSS) for 7 days. Two weeks after the DSS treatment they were subjected to initial and repetitive EA. Different sets of parameters were compared in the initial test and then EA with the selected parameters were performed for 2 weeks. Rectal compliance was assessed by colorectal distension while visceral sensitivity was evaluated by abdominal withdraw reflexes (AWR) and electromyogram (EMG). Masson's trichrome staining was performed to stain collagen and toluidine blue staining was applied to assess the degranulation of mast cells. Nerve growth factor (NGF), tryptase, TrkA and TRPV1 were measured by Western blot or immunofluorescence staining. RESULTS: EA at 100 Hz was more effective in improving rectal compliance and visceral hypersensitivity. Daily EA improved visceral hypersensitivity but not rectal compliance. Five weeks after DSS treatment, fibrosis was noted in both sham-EA and EA groups. The expression and activation of mast cells were significantly reduced after the 2-week EA treatment with a concurrent decrease in the expression of colonic NGF/TrkA and TRPV1 in both colon and dorsal root ganglions. CONCLUSION: EA at ST36 with a special set of parameters has no effect on reduced rectal compliance but relieves visceral hypersensitivity via the mast cells-triggered NGF/TrkA/TRPV1 peripheral afferent pathway in DSS-treated post-inflammation rats.

Effects of Salvia miltiorrhiza and Radix astragali on the TGF-ß/Smad/Wnt pathway and the pathological process of liver fibrosis in rats.

Traditional Chinese medicine has made some progress in the study of liver fibrosis, and provides valuable experience for clinical treatment of liver fibrosis. The aim of this study was to investigate the rationality of compatibility use of Salvia miltiorrhiza and Radix astragali on liver fibrosis in rats. For this purpose, the rat model of liver fibrosis was treated with single or different compatibilities of herbals extracts for 4 weeks. Saline and colchicine were set as a negative and positive control, respectively. Liver histopathology, liver function, and expressions of key proteins in the TGF-ß/Smad/Wnt pathway were assessed. Results showed that compared with colchicine, herbal extracts showed better ability to reduce deposition of α-SMA and type I collagen, and improve liver function. The effect of R. astragali extracts and 1:1 compound on improving liver fibrosis and liver function was relatively better than other treatment options. The compound groups showed a particularly significant effect on reducing Cyclin D1 expression. It was concluded that the 1:1 compatibility use of S. miltiorrhiza extracts and R. astragali extracts can preferably attenuate liver fibrosis by regulating the expression of TGF-ß1 and Cyclin D1.

Potential of Electrical Neuromodulation for Inflammatory Bowel Disease.

Inflammatory bowel disease (IBD) is a common chronic inflammatory disease of the digestive tract that is often debilitating. It affects patients' quality of life and imposes a financial burden. Despite advances in treatment with medications such as biologics, a large proportion of patients do not respond to medical therapy or develop adverse events. Therefore, alternative treatment options such as electrical neuromodulation are currently being investigated. Electrical neuromodulation, also called bioelectronic medicine, is emerging as a potential new treatment for IBD. Over the past decade, advancements have been made in electrical neuromodulation. A number of electrical neuromodulation methods, such as vagus nerve stimulation, sacral nerve stimulation, and tibial nerve stimulation, have been tested to treat IBD. A series of animal and clinical trials have been performed to evaluate efficacy with promising results. Although the exact underlying mechanisms of action for electrical neuromodulation remain to be explored, this modality is promising. Further randomized controlled trials and basic experiments are needed to investigate efficacy and clarify intrinsic mechanisms.

Qing Chang Hua Shi granule ameliorate inflammation in experimental rats and cell model of ulcerative colitis through MEK/ERK signaling pathway.

Ulcerative colitis (UC), a bowel disease with significant morbidity, is associated with inflammation. In this study, the effect of Qingchang Huashi granule (QCHS) on UC and its underlying mechanisms were explored using both animal and cell culture experiments. A rat UC model was induced with trinitro-benzene-sulfonic acid (TNBS), concentrations of the cytokines IL-1α, IL-6, IL-8, IL-1ß, and TNF-α were significantly up-regulated and the concentrations of IL-4, IL-10, and IL-13 were significantly down-regulated compared with the control group (P < 0.05). In contrast, the QCHS and salicylazosulfapyridine (SASP) groups reversed these modulations (P < 0.05). A UC cell model in HT-29 cells was generated using TNF-α combined with lipopolysaccharide treatment. Cells treated with QCHS were used to investigate the possible mechanisms. The expression of apoptosis-related proteins, including Bax/Bcl-2, caspase-3, caspase-9, Fas/Fas-L, and Rafl in the QCHS and SASP groups, were significantly lower than that in the control group in both animal and cell experiments (P < 0.05). In addition, the in vitro results indicate changes in these indicators mediate the MEK/ERK signaling pathways via SGK1. Our results suggested that QCHS could be beneficial in preventing UC progression as an alternative drug for UC treatment.

[Effect of Jianpi Bushen Qingchang Huashi Recipe on Proliferation of Bone Marrow Mesenchymal Stem Cells].

OBJECTIVE: To observe the effect of Jianpi Bushen Qingchang Huashi Recipe (JBQHR) on proliferation and migration of bone marrow mesenchymal stem cells (BMSCs). METHODS: BMSCs were isolated and cultured in vitro with adherence screening method to prepare cell suspension. No drug intervention was given to BMSCs in the vehicle control group. JBQHR at 0.39, 0.78, 1.56 µg/mL was added in BMSCs of low, mid, and high dose JBQHR groups for co-incubation. Its effect on the proliferation of BMSCs was detected by CCK-8. BMSCs migration and chemotactic ability was detected using Transwell method. Each dose JBQHR combined ERK kinase inhibitor U0126 was set up as control. The phosphorylation of extracellular regulated protein kinase (ERK) and CAMP responsive element-binding protein (CREB) were detected by Western blot. RESULTS: Compared with the vehicle control group, the proliferation of BMSCs and BMSCs migration number could be promoted in the 3 JBQHR groups (P < 0.05). Besides, the proliferation of BMSCs was better in mid and high dose JBQHR groups than in the low dose JBQHR group (P < 0.05). Compared with the vehicle control group, the phosphorylation of ERK and CREB could be elevated in the 3 JBQHR groups (P < 0.05), and could be inhibited by U0126 (P < 0.01). Compared with the low dose JBQHR group, the phosphorylation of ERK increased in mid and high dose JBQHR groups with statistical difference (P < 0.05). CONCLUSION: JBQHR could promote the proliferation and migration of BMSCs, and its mechanism might be related to ERK/CREB signaling pathway