Roles of Thermosensitive Transient Receptor Channels TRPV1 and TRPM8 in Paclitaxel-Induced Peripheral Neuropathic Pain.

Paclitaxel, a microtubule-stabilizing chemotherapy drug, can cause severe paclitaxel-induced peripheral neuropathic pain (PIPNP). The roles of transient receptor potential (TRP) ion channel vanilloid 1 (TRPV1, a nociceptor and heat sensor) and melastatin 8 (TRPM8, a cold sensor) in PIPNP remain controversial. In this study, Western blotting, immunofluorescence staining, and calcium imaging revealed that the expression and functional activity of TRPV1 were upregulated in rat dorsal root ganglion (DRG) neurons in PIPNP. Behavioral assessments using the von Frey and brush tests demonstrated that mechanical hyperalgesia in PIPNP was significantly inhibited by intraperitoneal or intrathecal administration of the TRPV1 antagonist capsazepine, indicating that TRPV1 played a key role in PIPNP. Conversely, the expression of TRPM8 protein decreased and its channel activity was reduced in DRG neurons. Furthermore, activation of TRPM8 via topical application of menthol or intrathecal injection of WS-12 attenuated the mechanical pain. Mechanistically, the TRPV1 activity triggered by capsaicin (a TRPV1 agonist) was reduced after menthol application in cultured DRG neurons, especially in the paclitaxel-treated group. These findings showed that upregulation of TRPV1 and inhibition of TRPM8 are involved in the generation of PIPNP, and they suggested that inhibition of TRPV1 function in DRG neurons via activation of TRPM8 might underlie the analgesic effects of menthol.

[Effect of electroacupuncture on transforming growth factor-ß1 and renal tubular epithelial mesenchymal transformation in renal tissue of spontaneously hypertensive rats].

OBJECTIVE: To observe the effects of electroacupuncture (EA) on renal fibrosis, the expression of transforming growth factor-ß1 (TGF-ß1) and epithelial mesenchymal transition (EMT) marker proteins in renal tissue of spontaneously hypertensive rats (SHR), so as to explore the underlying mechanism on EA alleviating hypertensive renal impairment. METHODS: Twenty-four male SHR were randomly divided into model group, losartan group and EA group, with 8 rats in each group, and eight male Wistar-Kyoto rats were taken as the normal group. Rats in the losartan group received gavage of losartan potassium solution (3 mg/mL, 30 mg·kg-1·d-1),once every other day for 12 weeks. Rats in the EA group received EA stimulation at bilateral "Shenshu" (BL23) and "Geshu" (BL17) (2 Hz/15 Hz, 1.0 mA), 15 min each time, once every other day for 12 weeks. The systolic blood pressure of caudal artery was measured before, and 4, 8 and 12 weeks after the intervention. The 24-hour urinary protein was measured before, and 6 and 12 weeks after the intervention. Histopathological changes of the left renal tissue were observed under light mircoscope after H.E. stain. Extracellular matrix (ECM) in renal tissues was observed after periodate Schiff staining. Basement membrane and collagen fibers were observed after Masson staining with collagen volume fraction (CVF) evaluated. The expression of TGF-ß1 mRNA in the right renal was detected by real-time fluorescence quantitative PCR. The expression of TGF-ß1 and EMT marker E-cadherin, α-SMA and fibronectin (FN) proteins in the left renal tissue was measured by immunohistochemistry. RESULTS: In the model group, irregular arrangement of nephrocytes, renal tubule atrophy, lumen stenosis, ECM hyperplasia and deposition, scar and sclerosis were observed, which were relatively milder in the EA and losartan groups. Compared with the normal group, tubulointerstitium CVF, systolic blood pressure of caudal artery before, and at 4, 8 and 12 weeks after the intervention, 24-hour urinary protein before, and at 6 and 12 weeks after the intervention, the expression of TGF-ß1 mRNA, area of TGF-ß1, α-SMA and FN positive staining in renal tissues were significantly increased (P<0.01), while the area of E-cadherin positive staining was significantly decreased (P<0.01) in the model group. Compared with the model group, tubulointerstitium CVF, systolic blood pressure of caudal artery at 4, 8 and 12 weeks after the intervention, 24-hour urinary protein at 6 and 12 weeks after the intervention, the expression of TGF-ß1 mRNA, area of TGF-ß1, α-SMA and FN positive staining in renal tissues were significantly decreased (P<0.01，P<0.05), while area of E-cadherin positive staining was significantly increased (P<0.01) in the losartan and EA groups. Compared with the losartan group, the area of E-cadherin was conside-rately increased (P<0.01), while the area of α-SMA protein decreased (P<0.01) in the EA group. CONCLUSION: EA could effectively alleviate hypertension and renal interstitial fibrosis in SHR, the mechanism of which may be related to its function in reducing the expression of TGF-ß1 and inhibiting EMT in renal tissue.

Carnosine attenuates cyclophosphamide-induced bone marrow suppression by reducing oxidative DNA damage.

Oxidative DNA damage in bone marrow cells is the main side effect of chemotherapy drugs including cyclophosphamide (CTX). However, not all antioxidants are effective in inhibiting oxidative DNA damage. In this study, we report the beneficial effect of carnosine (ß-alanyl-l-histidine), a special antioxidant with acrolein-sequestering ability, on CTX-induced bone marrow cell suppression. Our results show that carnosine treatment (100 and 200mg/kg, i.p.) significantly inhibited the generation of reactive oxygen species (ROS) and 8-hydroxy-2'-deoxyguanosine (8-oxo-dG), and decreased chromosomal abnormalities in the bone marrow cells of mice treated with CTX (20mg/kg, i.v., 24h). Furthermore, carnosine evidently mitigated CTX-induced G2/M arrest in murine bone marrow cells, accompanied by reduced ratios of p-Chk1/Chk1 and p-p53/p53 as well as decreased p21 expression. In addition, cell apoptosis caused by CTX was also suppressed by carnosine treatment, as assessed by decreased TUNEL-positive cell counts, down-regulated expressions of Bax and Cyt c, and reduced ratios of cleaved Caspase-3/Caspase-3. These results together suggest that carnosine can protect murine bone marrow cells from CTX-induced DNA damage via its antioxidant activity.

Personalized evaluation based on quantitative proteomics for drug-treated patients with chronic kidney disease.

The patient's response to drug treatment is usually systems-wide based on multi-spots through either direct or indirect targets. Thus, the evaluation of the treatment cannot rely on single targeted biomarker, especially for complex diseases such as chronic kidney disease. In the present study, we performed a systems-wide analysis using proteomic approach to quantify changes in the proteomic profiles of the plasma from IgA nephropathy (IgAN) patients before and after treatment. In particular, the patient-to-health distances based on global proteome quantification before and after treatment were calculated and considered as quantitative readouts to measure patient divergences from the healthy condition. We found that the patient-to-health distance nicely correlated with the patient's response to drug treatment and long-term prognosis, which created a self-tracking platform for personalized evaluation. In addition, the steroid treatment plays a role in immunosuppression, while the Chinese Traditional Medicine (TCM) can modulate whole-body systems. Our results indicated that STC therapy normalized the proteomic profile more significantly than SA therapy. This work provides an omics-based and systematic platform for personalized evaluation of disease treatment. This strategy could help us to evaluate treatment outcomes and predict prognosis in patients with IgAN and other complex diseases.

Cordyceps cicadae extracts ameliorate renal malfunction in a remnant kidney model.

BACKGROUND AND OBJECTIVES: Chronic kidney disease (CKD) is a growing public health problem with an urgent need for new pharmacological agents. Cordyceps cicadae is widely used in traditional Chinese medicine (TCM) and has potential renoprotective benefits. The current study aimed to determine any scientific evidence to support its clinical use. METHODS: We analyzed the potential of two kinds of C. cicadae extract, total extract (TE) and acetic ether extract (AE), in treating kidney disease simulated by a subtotal nephrectomy (SNx) model. Sprague-Dawley rats were divided randomly into seven groups: sham-operated group, vehicle-treated SNx, Cozaar, 2 g/(kg∙d) TE SNx, 1 g/(kg∙d) TE SNx, 92 mg/(kg∙d) AE SNx, and 46 mg/(kg∙d) AE SNx. Renal injury was monitored using urine and serum analyses, and hematoxylin and eosin (HE) and periodic acid-Schiff (PAS) stainings were used to analyze the level of fibrosis. The expression of type IV collagen (Col IV), fibronectin (FN), transforming growth factor-ß1 (TGF-ß1), and connective tissue growth factor (CTGF) was detected by immunohistochemistry. RESULTS: Renal injury, reflected in urine and serum analyses, and pathological changes induced by SNx were attenuated by TE and AE intervention. The depositions of Col IV and FN were also decreased by the treatments and were accompanied by reduced expression of TGF-ß1 and CTGF. In some respects, 2 g/(kg∙d) of TE produced better effects than Cozaar. CONCLUSIONS: For the first time, we have shown that C. cicadae may inhibit renal fibrosis in vivo through the TGF-ß1/CTGF pathway. Therefore, we conclude that the use of C. cicadae could provide a rational strategy for combating renal fibrosis.

[Analysis on the occupational poisoning case of trichloroethylene reported in Dongguan during 2002 to 2009 ].

OBJECTIVE: To understand the demographic, occupational and clinic characteristics of occupational poisoning case due to trichloroethylene in Dongguan in recent years for the purpose of prevention. METHODS: Using the trichloroethylene patients of poisoning diagnosed in the years between 2002 to 2009 as subjects, their age, sex, industry, job, working duration and exposure level were analysed. RESULTS: In Dongguan between 2002 and 2009 altogether 82 cases were reported, among the 82 cases 8 patients were dead with case fatality rate of 9.8%. among them there were 12 cases of poisonings(8 females ,4 males); 9 cases were classified as mild poisonings and the rest serious ones, among the 12 cases 3 patients were dead with case fatality rate of 25.0%; Dermatitis caused by TCE there were 70 cases (37 males and 33 females), among the 70 cases 5 patients were dead with case fatality rate of 7.1%. 11 persons (91.7%) were engaged in the job of cleaning and 1 (8.3%) in water gun, and they performed the job only for 3 days in shortest and for 450 days in longest. The cases were distributed in the jobs as the following: 29 (41.4%), 12 (17.1%), 8 (11.4%), 5 (7.1%), 4 (5.7%), cases respectively in the job of cleaning, parts hanging, board washing, painting, gun water spraying; a job duration of 1-50 d (27.4 days in average). CONCLUSION: In summary the TCE poisonings in Dongguan were two types of poisoning, i.e., systematic poisonings and drug rash-like dermatitis, occupational TCE poisonings took place mainly in the cleaning workers. Dermatitis caused by TCE can cure but hard to prevent, we should strengthen the early examination of new works.

[Correlation between traditional Chinese medicine syndromes in primary immunoglobulin A nephropathy and A267G in 5'-untranslated region within exonal of megsin gene].

OBJECTIVE: To observe the correlation between traditional Chinese medicine (TCM) syndromes ("deficiency of qi and yin" and "deficiency of liver yin and kidney yin") and A267G in 5'-untranslated region within exonal of megsin gene, and to search the substantial genetic basis for micro-differentiation of TCM syndromes in primary immunoglobulin A nephropathy (IgAN). METHODS: A total of 120 IgAN cases meeting the diagnostic criteria were enrolled. The sequence of single nucleotide polymorphism (SNP) of A267G in 5'-untranslated region within exonal of megsin gene was tested. The correlation between SNP and TCM syndromes was observed. RESULTS: There were 83 cases carrying GG genotype, 34 cases carrying GA genotype and 3 cases carrying AA genotype in 120 cases of primary IgAN. There was a high proportion of "deficiency of liver yin and kidney yin" in IgAN cases with AA and GA genotypes, and a high proportion of "deficiency of qi and yin" in IgAN cases with GG genotype (P<0.01). Odds ratio in TCM syndrome distribution between GG genotype and GA plus AA genotype was 9.800, and 95% confidence interval was 3.969-24.199. The discrepancy also resided in IgAN patients with different genders and ages. CONCLUSION: A267G in 5'-untranslated region within exonal of the megsin gene may be one of the substantial genetic basis for differentiating "deficiency of liver yin and kidney yin" syndrome and "deficiency of qi and yin" syndrome in primary IgAN.