Efficacy and safety of berberine for dyslipidemia: study protocol for a randomized double-blind placebo-controlled trial.

BACKGROUND: Dyslipidemia is a major risk factor for atherosclerotic cardiovascular disease and a leading cause of death worldwide. The clinical utility of commonly used lipid-lowering drugs such as statins and fibrates is sometimes limited by the occurrence of various adverse reactions. Recently, berberine (BBR) has received increasing attention as a safer and more cost-effective option to manage dyslipidemia. Thus, a high-quality randomized controlled trial to evaluate the efficacy and safety of BBR in the treatment of dyslipidemia is deemed necessary. METHODS/DESIGN: This is a randomized, double-blind, and placebo-controlled clinical trial. A total of 118 patients with dyslipidemia will be enrolled in this study and randomized into two groups at a ratio of 1:1. BBR or placebo will be taken orally for 12 weeks. The primary outcome is the percentage of low-density lipoprotein cholesterol reduction at week 12. Other outcome measures include changes in other lipid profiles, high sensitivity C-reactive protein, blood pressure, body weight, Bristol Stool Chart, traditional Chinese medicine symptom form, adipokine profiles, and metagenomics of intestinal microbiota. Safety assessment includes general physical examination, blood and urine routine test, liver and kidney function test, and adverse events. DISCUSSION: This trial may provide high-quality evidence on the efficacy and safety of BBR for dyslipidemia. Importantly, the findings of this trial will help to identify patient and disease characteristics that may predict favorable outcomes of treatment with BBR and optimize its indication for clinical use. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR1900021361 . Registered on 17 February 2019.

Effects of 1,8-cineole on neuropathic pain mediated by P2X2 receptor in the spinal cord dorsal horn.

As an intractable health threat, neuropathic pain is now a key problem in clinical therapy, which can be caused by lesions affecting the peripheral nervous systems. 1,8-cineole is a natural monoterpene cyclic ether present in eucalyptus and has been reported to exhibit anti-inflammatory and antioxidant effects. Research has shown that 1,8-cineole inhibits P2X3 receptor-mediated neuropathic pains in dorsal root ganglion. The P2X2 and P2X3 receptors participate in the transmission of algesia and nociception information by primary sensory neurons. In the present study, We thus investigated in the spinal cord dorsal horn whether 1,8-cineole inhibits the expression of P2X2 receptor-mediated neuropathic pain. This study used rats in five random groups: group of chronic constriction injury(CCI) with dimethysulfoxide control (CCI + DMSO); group of CCI; sham group(Sham); group of CCI treated with a low dose 1,8-cineole (CCI + 50 mg/kg); group of CCI with a high dose (CCI + 100 mg/kg). We observed the effects of 1,8-cineole on thermal withdrawal latency (TWL) and mechanical withdrawal threshold (MWT). We examined P2X2 receptors mRNA change in rat spinal cord dorsal horn by In situ nucleic acid hybridization(ISH) and Quantitative realtime polymerase chain reaction (qRT-PCR) methods. Western Blotting and Immunohistochemical staining methods were used to observe P2X2 receptor protein expressions in the rat spinal cord dorsal horn. It demonstrated that oral administration of 1,8-cineole inhibits over-expression of P2X2 receptor protein and mRNA in the spinal cord and dorsal horn in the CCI rats. And the study explored new methods for the prevention and treatment of neuropathic pain.

Microencapsulated Schwann cell transplantation inhibits P2X3 receptor expression in dorsal root ganglia and neuropathic pain.

Schwann cell transplantation is a promising method to promote neural repair, and can be used for peripheral nerve protection and myelination. Microcapsule technology largely mitigates immune rejection of transplanted cells. We previously showed that microencapsulated olfactory ensheathing cells can reduce neuropathic pain and we hypothesized that microencapsulated Schwann cells can also inhibit neuropathic pain. Rat Schwann cells were cultured by subculture and then microencapsulated and were tested using a rat chronic constriction injury (CCI) neuropathic pain model. CCI rats were treated with Schwann cells or microencapsulated Schwann cells and were compared with sham and CCI groups. Mechanical withdrawal threshold and thermal withdrawal latency were assessed preoperatively and at 1, 3, 5, 7, 9, 11 and 14 days postoperatively. The expression of P2X3 receptors in L4-5 dorsal root ganglia of the different groups was detected by double-label immunofluorescence on day 14 after surgery. Compared with the chronic constriction injury group, mechanical withdrawal threshold and thermal withdrawal latency were higher, but the expression of P2X3 receptors was remarkably decreased in rats treated with Schwann cells and microencapsulated Schwann cells, especially in the rats transplanted with microencapsulated Schwann cells. The above data show that microencapsulated Schwann cell transplantation inhibits P2X3 receptor expression in L4-5 dorsal root ganglia and neuropathic pain.

1,8-cineole decreases neuropathic pain probably via a mechanism mediating P2X3 receptor in the dorsal root ganglion.

1,8-cineole is a natural monoterpene cyclic ether present in eucalyptus and has been reported to exhibit anti-inflammatory and antioxidant effects. The therapeutic effects of 1,8-cineole on neuropathic pain and the molecular mechanisms of its pharmacological actions remain largely unknown. In the present study, we investigated the analgesic mechanisms of orally administered 1,8-cineole in a rat model of chronic constriction injury (CCI) and examined the drug-induced modulation of P2X3 receptor expression in dorsal root ganglia. The mechanical withdrawal threshold and thermal withdrawal latency were measured in rats to assess behavioural changes 7 and 14 days after CCI surgery. Changes in P2X3 receptor mRNA expression of L4-5 dorsal root ganglia were analysed using quantitative real-time polymerase chain reaction at the 7th and 14th postoperative day. Additionally, we examined the expression of P2X3 receptor protein in L4-5 dorsal root ganglia 7 and 14 days after surgery using immunohistochemistry and western blots. We found that 1,8-cineole can alleviate pathological pain caused by P2X3 receptor stimulation and explored new methods for the prevention and treatment of neuropathic pain.

Microencapsulated Schwann cell transplantation inhibits P2X2/3 receptors overexpression in a sciatic nerve injury rat model with neuropathic pain.

Transplantation of Schwann cells (SCs) can promote axonal regeneration and formation of the myelin sheath, reduce inflammation, and promote repair to the damaged nerve. Our previous studies have shown that transplantation of free or micro-encapsulated olfactory ensheathing cells can relieve neuropathic pain. There are no related reports regarding whether the transplantation of micro-encapsulated SCs can alleviate neuropathic pain mediated by P2X2/3 receptors. In the present study, we micro-encapsulated SCs in alginic acid and transplanted them into the region surrounding the injured sciatic nerve in the rat model of chronic constriction injury (CCI). The mechanical withdrawal threshold and thermal withdrawal latency were measured to assess changes in behavior 14 days after the surgery in CCI model rats. Ultrastructural changes in the injured sciatic nerve were assessed using transmission electron microscopy. Co-expression of P2X2/3 receptors with other markers in neurons in the L4-5 dorsal root ganglia (DRG) were assessed using double-label immunofluorescence 14 days after surgery. We determined P2X2/3 mRNA expression and protein level changes in the DRG using quantitative real-time polymerase change reaction technology and Western blotting analysis. We have investigated that the transplantation of micro-encapsulated SCs can alleviate pathological pain caused by P2X2/3 receptor stimulation and explored new methods for the prevention and treatment of neuropathic pain.

Microencapsulation improves inhibitory effects of transplanted olfactory ensheathing cells on pain after sciatic nerve injury.

Olfactory bulb tissue transplantation inhibits P2X2/3 receptor-mediated neuropathic pain. However, the olfactory bulb has a complex cellular composition, and the mechanism underlying the action of purified transplanted olfactory ensheathing cells (OECs) remains unclear. In the present study, we microencapsulated OECs in alginic acid, and transplanted free and microencapsulated OECs into the region surrounding the injured sciatic nerve in rat models of chronic constriction injury. We assessed mechanical nociception in the rat models 7 and 14 days after surgery by measuring paw withdrawal threshold, and examined P2X2/3 receptor expression in L4-5 dorsal root ganglia using immunohistochemistry. Rats that received free and microencapsulated OEC transplants showed greater withdrawal thresholds than untreated model rats, and weaker P2X2/3 receptor immunoreactivity in dorsal root ganglia. At 14 days, paw withdrawal threshold was much higher in the microencapsulated OEC-treated animals. Our results confirm that microencapsulated OEC transplantation suppresses P2X2/3 receptor expression in L4-5 dorsal root ganglia in rat models of neuropathic pain and reduces allodynia, and also suggest that transplantation of microencapsulated OECs is more effective than transplantation of free OECs for the treatment of neuropathic pain.

[Observation of Qigui Tongfengshu granules in treatment of sixteen cases of gouty arthritis].

OBJECTIVE: To investigate the efficacy of Qigui Tongfengshu granule in treating gouty arthritis. METHOD: Qigui Tongfengshu granule was used to treat 16 patients with gouty arthritis for 14 d. RESULT: The recovery rate, marked effective rate, effective rate and improvement rate were 37.5%, 50%, 6.25%, 6.25%, respectively. The total effective rate was 100%. Before and after treatment, the comparison showed statistical significance. CONCLUSION: Qigui Tongfengshu granule is significantly effective for gouty arthritis, and has the effect of anti-inflammation, analgesia and reduction in blood uric acid.

Effect of shunting of collateral flow into the venous system on arteriogenesis and angiogenesis in rabbit hind limb.

The aim of this study was to characterize the vascular remodeling in the external iliac artery (EIA) and the lower leg muscles in a rabbit shunt model created between the distal stump of the occluded femoral artery and the accompanying vein. Histology and immunoconfocal microscopy were used in this study. We found that: 1) both endothelial nitric oxide synthase (eNOS) and phosphorylated eNOS (P-eNOS) proteins were significantly increased in the shunt-side EIA; 2) matrix metalloproteinase-2 (MMP-2) expression was 5.5 times in shunt side EIA over that in normal EIA; 3) intercellular adhension molecule-1 (ICAM-1) expression was strongly induced in endothelial cells (EC) and vascular adhension molecule-1 (VCAM-1) expression was significantly increased in both EC and the adventitia of the shunt-side EIA; 4) augmentation of cell proliferation and extracellular proteolysis by macrophage infiltration was observed in shunt-side EIA; 5) cell proliferation was active in shunt side EIA, but quiet in shunt side lower leg's arterial vessels; 6) capillary density in shunt side lower leg muscles was 2 times over that in normal side. In conclusion, our data demonstrate the paradigm that the power of shear stress takes the reins in arteriogenesis, whereas ischemia in angiogenesis, but not in arteriogenesis.

Comparative proteome analysis of 3T3-L1 adipocyte differentiation using iTRAQ-coupled 2D LC-MS/MS.

Adipose tissue is critical in obesity and type II diabetes. Blocking of adipocyte differentiation is one of the anti-obesity strategies targeting on strong rise in fat storage and secretion of adipokine(s). However, the molecular basis of adipocyte differentiation and its regulation remains obscure. Therefore, we exposed 3T3-L1 cell line to appropriate hormonal inducers as adipocyte differentiation model. Using iTRAQ-coupled 2D LC-MS/MS, a successfully exploited high-throughput proteomic technology, we nearly quantitated 1,000 protein species and found 106 significantly altered proteins during adipocyte differentiation. The great majority of differentially expressed proteins were related to metabolism enzymes, structural molecules, and proteins involved in signal transduction. In addition to previously reported differentially expressed molecules, more than 20 altered proteins previously unknown to be involved with adipogenic process were firstly revealed (e.g., HEXB, DPP7, PTTG1IP, PRDX5, EPDR1, SPNB2, STEAP3, TPP1, etc.). The partially differential proteins were verified by Western blot and/or real-time PCR analysis. Furthermore, the association of PCX and VDAC2, two altered proteins, with adipocyte conversion was analyzed using siRNA method, and the results showed that they could contribute considerably to adipogenesis. In conclusion, our data provide valuable information for further understanding of adipogenesis.

Collateral vessel growth induced by femoral artery ligature is impaired by denervation.

Innervation plays an important role in development and remodeling of blood vessels. However, very little is known whether innervation is involved in arteriogenesis. In the present study, we tested the hypothesis that innervation may contribute to the process of arteriogenesis induced by ligature of femoral artery in rat/rabbit hind limb with or without denervation. We found that: (1) angiography showed more collateral vessels in the ligature side than that in ligature plus denervation side; (2) collateral vessels in denervation side was characterized by an inward remodeling; (3) in both collateral vessels (CVs) from only femoral ligature side as well as the ligature plus denervation side, ICAM-1 and VCAM-1 expression was up-regulated but increased VCAM-1 was more evident in the adventitia of collateral vessels of only femoral ligature side; (4) 7 days after surgery, in CVs from the femoral ligature side only, numerous macrophages (RAM11 positive cells) and high cell proliferation ratio (ki67 positive cells) were detected, but they were less in the denervation side. In conclusion, our data demonstrate for the first time that neural regulation is one of the factors that contributes to collateral vessel growth in rat/rabbit hind limb ischemic model by showing collateral vessel growth induced by femoral artery ligature is impaired by denervation.

[Clinical study of shuizhitong capsule in treating senile vascular dementia].

OBJECTIVE: To observe the clinical therapeutic effect of Shuizhitong capsule (SZT) in treating senile vascular dementia (VD) and on changes of related physio-chemical criteria. METHODS: Eighty-five patients with VD were randomly divided into the treated group (n = 51) and the control group (n = 34) in the ratio of 3:2, treated with SZT and Piracetam respectively. Before and after treatment, the Zhang's Dementia Scoring (HDS) and Function of Social Activity Questionnaire (FAQ) scoring, cerebral blood flow and hemorrheologic properties were determined. RESULTS: SZT could significantly improve the patients' clinical symptoms, intracranial hemodynamic condition and the hyperviscosity, hypercoagulation and hyperaggregation status, lower the whole blood and plasma specific viscosity, raise the living standard of partial patients, with significant difference between before and after treatment (P < 0.05). CONCLUSION: The therapeutic effect of SZT in treating senile VD is definite.