METHAMPHETAMINE [BSA]

Constant research into the pharmaceutical properties of marine natural products has led to the discovery of many potentially active agents considered worthy of medical applications. Genus Conus, which approximately comprises 700 species, is currently under every researcher's interest because of the conopeptides in their crude venom. Conopeptides have a wide range of pharmacological classes and properties. This research focused on the crude venom of Conus striatus to assess its analgesic activity, mutagenicity, nephrotoxicity, and hepatotoxicity in mice. The crude venom was extracted from the conus snails and the protein concentration was determined using Bradford's method. The analgesic activity of the venom was determined using the hot-plate method and standard IFCC method was used to determine the alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Evaluation of mutagenicity was done using micronucleus assay and the nephrotoxicity of the venom was determined using Kidney Coefficient and serum creatinine concentration. The maximum tolerable dose (MTD) of the crude venom was found to be 75 ppm. The venom exhibited potent analgesic activity even higher than the positive control (Ibuprofen). Most of the analgesic drugs can usually impact damage in the liver and kidneys. However, AST and ALT results revealed that the venom has no adverse effects on the liver. Although the venom increased the incidence of micronucleated polychromatic erythrocytes, making it mutagenic, with MTD concentration's mutagenicity comparable to the positive control methyl methanesulfonate (MMS). The kidney coefficients, on the other hand, showed no significant difference between the treated groups and that of the untreated group. The serum creatinine also showed a concentration-dependent increase; with MTD treated mice got the highest creatinine concentration. However, MTD/2 and MTD/4 showed no significant difference in creatinine levels with respect to the untreated groups. Hence, the nephrotoxicity of the venom was only evident when used at higher concentration. The venom exhibited potent analgesic activity indicated that the C. striatus crude venom extract could have a potential therapeutic component as analgesic drugs that displayed no hepatic damage. This study also suggests that for this venom to be utilized for future medical applications, their usage must be regulated and properly monitored to avoid nephrotoxic effect.

We report an early-onset autosomal-recessive neurological disease with cerebellar atrophy and lysosomal dysfunction. We identified biallelic loss-of-function (LoF) variants in Oxidative Resistance 1 (OXR1) in five individuals from three families; these individuals presented with a history of severe global developmental delay, current intellectual disability, language delay, cerebellar atrophy, and seizures. While OXR1 is known to play a role in oxidative stress resistance, its molecular functions are not well established. OXR1 contains three conserved domains: LysM, GRAM, and TLDc. The gene encodes at least six transcripts, including some that only consist of the C-terminal TLDc domain. We utilized Drosophila to assess the phenotypes associated with loss of mustard (mtd), the fly homolog of OXR1. Strong LoF mutants exhibit late pupal lethality or pupal eclosion defects. Interestingly, although mtd encodes 26 transcripts, severe LoF and null mutations can be rescued by a single short human OXR1 cDNA that only contains the TLDc domain. Similar rescue is observed with the TLDc domain of NCOA7, another human homolog of mtd. Loss of mtd in neurons leads to massive cell loss, early death, and an accumulation of aberrant lysosomal structures, similar to what we observe in fibroblasts of affected individuals. Our data indicate that mtd and OXR1 are required for proper lysosomal function; this is consistent with observations that NCOA7 is required for lysosomal acidification.