Heat shock protein 90 (Hsp90) inhibitor and cannabinoid agonists ameliorate dry skin-induced chronic itch. We have recently reported that cannabinoids, hsp90 and nitric oxide (NO) are involved in dry skin-induced itch. Here, we investigated the contribution of the Th2 cell signaling pathway to the antipruritic effect of the hsp90 inhibitor 17-Alilamino-17-demethoxygeldanamycin (17-AAG), nitric oxide synthase (NOS) inhibitor Nω-Nitro-L-arginine methyl ester hydrochloride (L-NAME) and cannabinoid agonist WIN 55,212–2 on a dry skin-induced scratch. Dry skin-induced chronic itching was created by topical application of AEW (acetone/diethyl ether/water). WIN 55,212–2 (1 mg/kg, i.p.), L-NAME (1 mg/kg, i.p.) and increasing doses of 17-AAG (1, 3 and 5 mg/kg,i.p.) were administered to Balb/c mice (for each group, n = 6). After these applications, skin tissues were taken from the nape region of all of the mice. Gene and protein expressions of IL-13 and IL-31 were evaluated in skin tissues by RT-PCR and immunohistochemistry, respectively. IL-13 and IL-31 mRNA expressions and immune positive cell counts were increased in the AEW applied groups. WIN 55,212–2 reduced both of the increased cytokines levels, while L-NAME decreased only the IL-13. 17-AAG dose-dependently reduced the increased cytokine levels. IL-13 and IL-31 levels significantly decreased following the co-administration of these agents. These results show that increased levels of IL-13 and IL-31 are associated with pruritus. Hsp90 inhibition and cannabinoid system activation may induce antipruritic effects through down-regulation of these cytokines.

Background: For centuries, cannabinoids have been known to be effective in pain states. Itch and pain are two sensations sharing a lot in common.Objective: The goal of this research was to observe whether the cannabinoid agonist WIN 55,212-2 reduces serotonin-induced scratching behaviour and whether neurotoxic destruction of descending serotonergic and noradrenergic pathways mediate the antipruritic effect of WIN 55,212-2.Material and methods: Scratching behaviour was induced by intradermal injection of serotonin (50 µg/50 µl/mouse) to Balb/c mice. The neurotoxins 5,7-dihydroxytryptamine (5,7-DHT, 50 μg/mouse) and 6-hydroxydopamine (6-OHDA, 20 μg/mouse) are applied intrathecally to deplete serotonin and noradrenaline in the spinal cord. WIN 55,212-2 (1, 3, 10 mg/kg, i.p.) dose-dependently attenuated serotonin-induced scratches. Neurotoxic destruction of neither the serotonergic nor the noradrenergic systems by 5,7-DHT and 6-OHDA, respectively, had any effect on the antipruritic action of WIN 55,212-2.Conclusion: Our findings indicate that cannabinoids dose-dependently reduce serotonin-induced scratching behaviour and neurotoxic destruction of descending inhibitory pathways does not mediate this antipruritic effect.

HIV, which causes acquired immune deficiency syndrome (AIDS), invades the host cell via the CD4 receptor and CCR5 or CXCR4 co-receptors. Interferons induced early in HIV infection induce an antiviral defense mechanism through IFNAR signaling. Our study aimed to examine the relationship between CCR5, CXCR4, and IFNAR1 gene variations as a risk factor in HIV + patients and their response to their clinical parameters. Targeted next-generation sequencing (tNGS) was used to perform molecular genotyping analysis of the CCR5, CXCR4, and IFNAR1 genes in genomic DNA from 22 HIV + patients and 25 healthy individuals as controls. We detected 13 rare mutations in the study, including 3 missense, 1 synonymous, 2 5′UTR, 4 3′UTR, and 1 frameshift variation. We also analyzed 6 common variants in the IFNAR1 and CXCR4 genes. HIV + patients carrying the homozygous TT genotype of the IFNAR1 intronic rs2856973:T > A variant had higher CD4 + T cell counts compared with patients carrying the TA + AA genotypes of the rs2856973 variant in the naive and first month of the ART (p = 0.001 and p = 0.001, respectively). Similarly, participants receiving ART with a TT genotype of rs2856973:T > A showed a significantly higher CD4 + T cell count in the third month (p = 0.001). Patients carrying the homozygous wild-type genotype of the CXCR4 intronic rs2680880:A > T SNP had lower CD4 + T cell count compared with subjects carrying the AT + TT mutant genotypes of rs2680880:A > T in the naive and first-month period (p = 0.015 and p = 0.025, respectively). Our results demonstrate that intronic variations in the IFNAR1 rs2856973:T > A and CXCR4 rs2680880:A > T genes can contribute to modifications in HIV progression and CD4 + T recovery under ART.

Objective: Voltage-gated potassium channel genes are among the most frequently implicated in epilepsy and antiseizure medication (ASM) response. In this pilot study, we aimed to identify rare and common variants by sequencing voltage-gated potassium channel (Kv) genes in epilepsy patients using ASM, and to reveal the potential drug responses of these variants. Methods: To investigate the role of genetic variants in Kv genes (KCNQ1, KCNQ2, KCNQ3, KCNA1, KCNA2, and KCNV2) in response to ASMs among 31 epilepsy patients, we used targeted next-generation sequencing (tNGS). Patients were classified as responders or persistent based on seizure control status. Selected variants in the genes were annotated, filtered, and analyzed for association with ASM response. Results: We identified 181 variants in the 6 channel genes, including missense, synonymous, intronic, UTR, and stop-gained variants. Six variants of uncertain significance (VUSs) were observed, including KCNA2c.*1314C>T, KCNQ1c.*976G>A, KCNQ2 (c.2613G>T p.Arg871Ser and c.1148+62T>G), and KCNQ3 (c.*6282A>G and c.*2860T>C). Two novel variants were identified in our study group, KCNA2:c.*1314C>T and KCNQ3:c.*2860T>C. Both were located in the 3′ UTR region and classified as VUSs according to ACMG guidelines. In the KCNV2 gene, the CG haplotype comprising rs7029012 and rs10967705 was observed more frequently in patients with drug-persistent epilepsy than in those with drug-responsive epilepsy (18.5% vs. 0.8%; χ² = 6.756, p = 0.009, BH-FDR q = 0.036), suggesting a potential association with pharmacoresistant epilepsy. Conclusions: Our haplotype analysis suggests the potential pharmacogenetic contribution of the KCNV2 gene to ASM response; however, these exploratory findings require validation in larger independent cohorts and functional studies.

Aim: Type 2 diabetes mellitus (T2DM) is commonly managed using metformin and DPP-4 inhibitors (vildagliptin, linagliptin) to improve glycemic control. However, their effects on electrolyte, mineral, and vitamin B12 levels remain unclear. The aim of this research was to evaluate the impact of metformin and DPP-4 inhibitors on electrolyte levels, as well as mineral and vitamin B12 levels. Material and Methods: Electrolyte and mineral levels (including sodium, potassium, calcium, magnesium, and chloride), along with vitamin B12 concentrations, measured through standard laboratory methods in blood samples from T2DM patients receiving metformin and DPP-4 inhibitors, as well as healthy controls, were retrospectively obtained from medical records. The results were analyzed by comparing the control group with the treatment groups and the treatment groups with each other. Results: Sodium levels were decreased significantly in the metformin+DPP-4 inhibitor group compared to the metformin group (p=0.034). Potassium concentrations were considerably elevated in both the metformin group and the DPP-4 inhibitor group than in the control group (p=0.010 and p=0.006, respectively). Vitamin B12 concentrations demonstrated a statistically significant reduction in the metformin+DPP-4 inhibitor group relative to the control group (p=0.006). Conclusion: These findings highlight the potential impact of metformin and DPP-4 inhibitors on mineral and electrolyte homeostasis, emphasizing the importance of regular assessment of electrolyte levels and vitamin B12 status in individuals receiving these treatments.