Molecular basis for heat desensitization of TRPV1 ion channels.

The transient receptor potential vanilloid 1 (TRPV1) ion channel is a prototypical molecular sensor for noxious heat in mammals. Its role in sustained heat response remains poorly understood, because rapid heat-induced desensitization (Dh) follows tightly heat-induced activation (Ah). To understand the physiological role and structural basis of Dh, we carried out a comparative study of TRPV1 channels in mouse (mV1) and those in platypus (pV1), which naturally lacks Dh. Here we show that a temperature-sensitive interaction between the N- and C-terminal domains of mV1 but not pV1 drives a conformational rearrangement in the pore leading to Dh. We further show that knock-in mice expressing pV1 sensed heat normally but suffered scald damages in a hot environment. Our findings suggest that Dh evolved late during evolution as a protective mechanism and a delicate balance between Ah and Dh is crucial for mammals to sense and respond to noxious heat

Further validation of the Health Scale of Traditional Chinese Medicine (HSTCM)

<p>Abstract</p> <p>Background</p> <p>Few health measurement scales are based on Chinese medicine theory. The Health Scale of Traditional Chinese Medicine (HSTCM) was developed to fill this gap. The aim of this study is to validate the HSTCM.</p> <p>Methods</p> <p>A convenience sample of 630 participants was recruited in 11 settings. All participants were asked to complete the HSTCM and World Health Organization Quality of Life Measure-Abbreviated Version (WHOQOL-BREF).</p> <p>Results</p> <p>Properties of the HSTCM were tested. Intra-class correlation coefficient representing the inter-interviewer reliability was 0.99 (95%CI) for the overall instrument. Spearman-Brown correlation coefficient and Cronbach's coefficient alpha were 0.81 and 0.94 respectively, indicating satisfactory internal reliability and inter-interviewer reliability. Spearman's rho correlation coefficient between the HSTCM and WHOQOL-BREFF was -0.67. A receiver operating characteristic (ROC) curve analysis was performed to test the discriminate validation. Areas under the ROC curve analysis for the HSTCM and its domains ranged 0.71–0.87 and all the lower levels of 95%CI were greater than 0.50.</p> <p>Conclusion</p> <p>The HSTCM was validated as a generic health scale and may complement existing health measurement scales in Chinese medicine health care.</p

Pharmacokinetic and Pharmacogenetic Factors Contributing to Platelet Function Recovery After Single Dose of Ticagrelor in Healthy Subjects

Objectives: This study aimed to elucidate the contribution of candidate single nucleotide polymorphisms (SNPs) related to pharmacokinetics on the recovery of platelet function after single dose of ticagrelor was orally administered to healthy Chinese subjects.Methods: The pharmacokinetic profiles of ticagrelor and its metabolite AR-C124910XX (M8), and the platelet aggregation (PA), were assessed after 180 mg of single-dose ticagrelor was orally administered to 51 healthy Chinese subjects. Effects of CYP2C19*2, CYP2C19*3, CYP3A5*3, UGT1A1*6, UGT1A1*28, UGT2B7*2, UGT2B7*3, SLCO1B1 388A&gt;G, and SLCO1B1 521T&gt;C, on the pharmacokinetics of ticagrelor and M8, and platelet function recovery were investigated.Results: The time to recover 50% of the maximum drug effect (RT50) ranging from 36 to 126 h with 46.9% CV had a remarkable individual difference and was positively associated with the half-life (t1/2) of M8 (r = 0.3901, P = 0.0067). The time of peak concentration (Tmax) of ticagrelor for CYP2C19*3 GG homozygotes was significantly higher than that of GA heterozygotes (P = 0.0027, FDR = 0.0243). Decreased peak concentration (Cmax) of M8 was significantly associated with SLCO1B1 388A&gt;G A allele (P = 0.0152, FDR = 0.1368). CYP2C19*2 A was significantly related to decreased Cmax of M8 (P = 0.0455, FDR = 0.2048). While, the influence of these nine SNPs on the recovery of platelet function was not significant.Conclusion: Our study suggests that the elimination of M8 is an important factor in determining the recovery of platelet function. Although CYP2C19 and SLCO1B1 genetic variants were related to the pharmacokinetics of ticagrelor or M8, they did not show a significant effect on the platelet function recovery in this study.Clinical Trial Registration:https://clinicaltrials.gov/ct2/show/NCT03092076, identifier: NCT0309207

Centipede Venoms and Their Components: Resources for Potential Therapeutic Applications

Venomous animals have evolved with sophisticated bio-chemical strategies to arrest prey and defend themselves from natural predators. In recent years, peptide toxins from venomous animals have drawn considerable attention from researchers due to their surprising chemical, biochemical, and pharmacological diversity. Similar to other venomous animals, centipedes are one of the crucial venomous arthropods that have been used in traditional medicine for hundreds of years in China. Despite signifying pharmacological importance, very little is known about the active components of centipede venoms. More than 500 peptide sequences have been reported in centipede venomous glands by transcriptome analysis, but only a small number of peptide toxins from centipede has been functionally described. Like other venomous animals such as snakes, scorpions, and spiders, the venom of centipedes could be an excellent source of peptides for developing drugs for treatments as well as bio-insecticides for agrochemical applications. Although centipede venoms are yet to be adequately studied, the venom of centipedes as well as their components described to date, should be compiled to help further research. Therefore, based on previous reports, this review focusses on findings and possible therapeutic applications of centipede venoms as well as their components

The first salamander defensin antimicrobial peptide.

Antimicrobial peptides have been widely identified from amphibian skins except salamanders. A novel antimicrobial peptide (CFBD) was isolated and characterized from skin secretions of the salamander, Cynops fudingensis. The cDNA encoding CFBD precursor was cloned from the skin cDNA library of C. fudingensis. The precursor was composed of three domains: signal peptide of 17 residues, mature peptide of 41 residues and intervening propeptide of 3 residues. There are six cysteines in the sequence of mature CFBD peptide, which possibly form three disulfide-bridges. CFBD showed antimicrobial activities against Staphylococcus aureus, Bacillus subtilis, Candida albicans and Escherichia coli. This peptide could be classified into family of β-defensin based on its sequence similarity with β-defensins from other vertebrates. Evolution analysis indicated that CFBD was close to fish β-defensin. As far as we know, CFBD is the first β-defensin antimicrobial peptide from salamanders

A Novel Toxin from Haplopelma lividum Selectively Inhibits the NaV1.8 Channel and Possesses Potent Analgesic Efficacy

Spider venoms are a complex mixture of peptides with a large number of neurotoxins targeting ion channels. Although thousands of peptide toxins have been identified from venoms of numerous species of spiders, many unknown species urgently need to be investigated. In this study, a novel sodium channel inhibitor, µ-TRTX-Hl1a, was identified from the venom of Haplopelma lividum. It contained eight cysteines and formed a conserved cysteine pattern of ICK motif. µ-TRTX-Hl1a inhibited the TTX-resistant (TTX-r) sodium channel current rather than the TTX-sensitive (TTX-s) sodium channel current. Meanwhile, µ-TRTX-Hl1a selectively inhibited NaV1.8 with an IC50 value of 2.19 μM. Intraperitoneal injection of µ-TRTX-Hl1a dose-dependently reduced inflammatory and neuropathic pain in rodent models of formalin-induced paw licking, tail-flicking, acetic acid-induced writhing, and hot plate test. It showed a better analgesic effect than morphine in inflammatory pain and equipotent effect to morphine in neuropathic pain. These findings demonstrate that µ-TRTX-Hl1a might be a valuable tool for physiology studies on NaV1.8 and a promising lead molecule for pain therapeutics

A bimodal activation mechanism underlies scorpion toxin–induced pain

Venomous animals use peptide toxins for hunting and self-defense. To achieve these goals, toxins need to bind to their targets with high affinity due to the small amount that a single bite or sting can deliver. The scorpion toxin BmP01 is linked to sting-induced excruciating pain; however, the reported minimum concentrations for activating TRPV1 channel or inhibiting voltage-gated potassium (Kv) channels (both in the micromolar range) appear too high to be biologically relevant. We show that the effective concentration of BmP01 is highly pH-dependent-it increases by about 10-fold in inhibiting Kv channels upon a 1-U drop in pH but decreases more than 100-fold in activating TRPV1. Mechanistic investigation revealed that BmP01 binds to one of the two proton-binding sites on TRPV1 and, together with a proton, uses a one-two punch approach to strongly activate the nociceptive channel. Because most animal venoms are acidic, proton-facilitated synergistic action may represent a general strategy for maximizing toxin potency

Water extract of sporoderm-broken spores of Ganoderma lucidum elicits dual antitumor effects by inhibiting p-STAT3/PD-L1 and promoting ferroptosis in castration-resistant prostate cancer

Prostate cancer (PCa) is one of the most common malignancies among male patients with cancer pathology worldwide. Owing to the inevitable development of irremediable castration-resistant prostate cancer (CRPC) following intervention with androgen deprivation therapy, new therapeutic strategies are in great demand. Ganoderma lucidum, a medicinal fungus, has recently been reported to be a potential antitumor agent. However, whether the water extract of sporoderm-broken spores of G. lucidum (BSGWE), a special approach to obtain whole wall-broken spore extracts of G. lucidum, can inhibit castration-resistant prostate cancer (CRPC) has not been well characterized. In this study, we found that BSGWE inhibited cell proliferation, caused cell cycle arrest in G2/M phase, and promoted ferroptosis, which resulted in high levels of reactive oxygen species (ROS) in vitro and suppressed the growth of CRPC tumors in xenograft models. In addition, we reported that BSGWE inhibited STAT3 expression, which partly accounted for the inhibition of the transcription of PD-L1 and led to ferroptosis, manifested by the downregulation of SLC7A11 and GPX4 expression. Furthermore, BSGWE exhibited a synergistic effect with 5-fluorouracil (5-Fu) in chemotherapy of CRPC in vitro and in vivo. This study provides biological evidence that BSGWE is a novel STAT3 inhibitor that exerts anti-proliferation, pro-cell death, and pro-immunity effect and indicates a novel utilization of BSGWE in neoadjuvant chemotherapy of CRPC