TP53 and its Regulatory Genes as Prognosis of Cutaneous Melanoma.

The present study was the first comprehensive investigation of genetic mutation and expression levels of the p53 signaling genes in cutaneous melanoma through various genetic databases providing large datasets. The mutational landscape of p53 and its signaling genes was higher than expected, with TP53 followed by CDKN2A being the most mutated gene in cutaneous melanoma. Furthermore, the expression analysis showed that TP53, MDM2, CDKN2A, and TP53BP1 were overexpressed, while MDM4 and CDKN2B were under-expressed in cutaneous melanoma. Overall, TCGA data revealed that among all the other p53 signaling proteins, CDKN2A was significantly higher in both sun and non-sun-exposed healthy tissues than in melanoma. Likewise, MDM4 and TP53BP1 expressions were markedly greater in non-sun-exposed healthy tissues compared to other groups. However, CDKN2B expression was higher in the sun-exposed healthy tissues than in other tissues. In addition, various genes were expressed significantly differently among males and females. In addition, CDKN2A was highly expressed in the SK-MEL-30 skin cancer cell line, whereas, Immune cell type expression analysis revealed that the MDM4 was highly expressed in naïve B-cells. Furthermore, all six genes were significantly overexpressed in extraordinarily overweight or obese tumor tissues compared to healthy tissues. MDM2 expression and tumor stage were closely related. There were differences in gene expression across patient age groups and positive nodal status. TP53 showed a positive correlation with B cells, MDM2 with CD8+T cells, macrophages and neutrophils, and MDM4 with neutrophils. CDKN2A/B had a non-significant correlation with all six types of immune cells. However, TP53BP1 was positively correlated with all five types of immune cells except B cells. Only TP53, MDM2, and CDKN2A had a role in cutaneous melanoma-specific tumor immunity. All TP53 and its regulating genes may be predictive for prognosis. The results of the present study need to be validated through future screening, in vivo, and in vitro studies.

The mutational analysis of mitochondrial DNA in maternal inheritance of polycystic ovarian syndrome.

Introduction: Polycystic Ovarian Syndrome (PCOS) is a globally prevalent condition that leads to infertility in women. While environmental factors contribute to PCOS, maternal genetics also play a significant role. Currently, there is no definitive test for identifying predisposition to PCOS. Hence, our objective is to discover novel maternal genetic risk factors for PCOS by investigating the genomes of patients from Pakistan. Methods: We utilized Next-Generation Sequencing (NGS) to sequence the complete mitochondrial DNA of three PCOS patients. Subsequently, we employed MitoTIP (Mitochondrial tRNA Informatics Predictor) and PON-mt-tRNA tools to identify variations in the mitochondrial DNA. Our analysis focused on the genes MT-RNR1, MT-RNR2, MT-ATP6, MT-TL2, and MT-CYTB, which displayed common variations in all three genomes. Additionally, we observed individual variations. The D-loop region exhibited the highest frequency of mutations, followed by the non-coding regions of RNR1 and RNR2 genes. Moreover, we detected frameshift mutations in the mitochondrially encoded NADH Dehydrogenase 2 (MT-ND2) and mitochondrially encoded NADH Dehydrogenase 5 (ND5) genes within individual genomes. Results: Our analysis unveiled six regions with common variations in the mitochondrial DNA of all three PCOS patients. Notably, the MT-RNR1, MT-RNR2, MT-ATP6, MT-TL2, and MT-CYTB genes exhibited these variations. Additionally, we identified individual variations in the mitochondrial DNA. The D-loop region displayed the highest mutation frequency, followed by the non-coding regions of RNR1 and RNR2 genes. Furthermore, frameshift mutations were detected in the MT-ND2 and ND5 genes within individual genomes. Conclusion: Through our study, we have identified variations in mitochondrial DNA that may be associated with the development of PCOS and have the potential to serve as predisposition tests. Our findings highlight the presence of novel mutations in the MT-RNR1, MT-RNR2, MT-ATP6, MT-TL2, and MT-CYTB genes, as well as frameshift mutations in the MT-ND2 and ND5 genes. Pathogenicity analysis indicated that most variants were likely to result in benign cysts. However, the frameshift mutations in the ND2 gene were associated with a high risk of complications and pathogenicity in PCOS. This is the first report identifying these mutations and their association with PCOS, contributing to our understanding of the genetic factors underlying the condition.

Natural Polyphyllins (I, II, D, VI, VII) Reverses Cancer Through Apoptosis, Autophagy, Mitophagy, Inflammation, and Necroptosis.

Cancer is the second leading cause of mortality worldwide. Conventional therapies, including surgery, radiation, and chemotherapy, have limited success because of secondary resistance. Therefore, safe, non-resistant, less toxic, and convenient drugs are urgently required. Natural products (NPs), primarily sourced from medicinal plants, are ideal for cancer treatment because of their low toxicity and high success. NPs cure cancer by regulating different pathways, such as PI3K/AKT/mTOR, ER stress, JNK, Wnt, STAT3, MAPKs, NF-kB, MEK-ERK, inflammation, oxidative stress, apoptosis, autophagy, mitophagy, and necroptosis. Among the NPs, steroid saponins, including polyphyllins (I, II, D, VI, and VII), have potent pharmacological, analgesic, and anticancer activities for the induction of cytotoxicity. Recent research has demonstrated that polyphyllins (PPs) possess potent effects against different cancers through apoptosis, autophagy, inflammation, and necroptosis. This review summarizes the available studies on PPs against cancer to provide a basis for future research.

A comparative study on the effects of selected pesticides on hemato-biochemistry and tissue histology of freshwater fish Cirrhinus mrigala (Hamilton, 1822).

The aim of the present study was to investigate the comparative effects of pesticides Chlorfenapyr, Dimethoate and Acetamiprid on the health of Cirrhinus mrigala under long term exposure. Eighty C. mrigala were divided in four equal groups; one control and three treated groups. The blood was collected from both control and treated groups at intervals of 10th, 20th and 30th days for hemato-biochemistry and histopathological alterations. The result indicates significant difference (P < 0.05) in RBCs, Hb, PCV and MCHC whereas elevation in WBCs and Platelets counts were recorded. In 10th day sampling, MCV value of Dimethoate and Acetamiprid treatment had no difference in comparison with the control group, however it is significantly increased (P < 0.05) in rest of sampling. The MCH value of exposed fish showed significant increased (P < 0.05) after 20th and 30th days for Chlorfenapyr and after 30th days for Acetamiprid exposure while insignificantly increased for rest of sampling. It was also found that these pesticides significantly decrease (p < 0.05) the T3 and T4 levels while increase in the TSH, cortical, ALP, AST, ALT and LDH levels in the serum of the treated fishes in contrast to control group. Similarly, histopathological analysis of gills and liver showed significant alterations in all the treated groups. Toxicity trends of these pesticides was ranked as Chlorfenapyr > Acetamiprid > Dimethoate. It is concluded that indiscriminate use of such pesticides poses a noxious threat to non-target organisms, harm the ecosystems and jeopardizes human health.

Molecular mechanisms of anticancer activities of polyphyllin VII.

Cancer is the leading cause of mortality in the world. The major therapies for cancer treatment are chemotherapy, surgery, and radiation therapy. All these therapies expensive, toxic and show resistance. The plant-derived compounds are considered safe, cost-effective and target cancer through different pathways. In these pathways include oxidative stress, mitochondrial dependent and independent, STAT3, NF-kB, MAPKs, cell cycle, and autophagy pathways. One of the new plants derived compounds is Polyphyllin VII (PPVII), which target cancer through different molecular mechanisms. In literature, there is a review gap of studies on PPVII; therefore in the current review, we summarized the available studies on PPVII to provide a base for future research.

Antileishmanial activity and cytotoxicity of ZnO-based nano-formulations.

INTRODUCTION: Nanoparticles (NPs) can be toxic due to their nano-range sizes. Zinc oxide (ZnO) has good biocompatibility and is commercially used in cosmetics. Moreover, ZnO NPs have potential biomedical uses, but their safety remains unclear. METHODS: A range of doped ZnO NPs was evaluated for antileishmanial activity and in vitro toxicity in brine shrimp and human macrophages, and N-doped ZnO NPs were evaluated for in vivo toxicity in male BALB/C mice. N-doped ZnO NPs were administered via two routes: intra-peritoneal injection and topically as a paste. The dosages were 10, 50, and 100 mg/kg/day for 14 days. RESULTS: Topical administration was safe at all dosages, but intra-peritoneal injection displayed toxicity at higher doses, namely, 50 and 100 mg/kg/day. The pathological results for the i.p. dose groups were mild to severe degenerative changes in parenchyma cells, increases in Kupffer cells, disappearance of hepatic plates, increases in cell size, ballooning, cytoplasmic changes, and nuclear pyknosis in the liver. Kidney histology was also altered in the i.p. administration group (dose 100 mg/kg/day), with inflammatory changes in the focal area. We associate pathological abnormalities with the presence of doped ZnO NPs at the diseased site, which was verified by PIXE analysis of the liver and kidney samples of the treated and untreated mice groups. CONCLUSION: The toxicity of the doped ZnO NPs can serve as an essential determinant for the effects of ZnO NPs on environmental toxicity and can be used for guidelines for safer use of ZnO-based nanomaterials in topical treatment of leishmaniasis and other biomedical applications.

Epidemiological and clinical correlates of oral squamous cell carcinoma in patients from north-west Pakistan.

OBJECTIVE: To investigate the association of oral squamous cell carcinoma with demographic variables and oral health indicators. . METHODS: The observational case-control study was conducted at the Institute of Radiotherapy and Nuclear Medicine, Peshawar, Pakistan, from November, 2015, to August, 2016.Pathologically confirmed patients with oral cancer represented the cases, while The controls were ethnically and linguistically-matched subjects without any oral pathology. Demographical, clinical and pathological data was taken down to assess variables, risk factors, and oral health indicators. Descriptive statistics and logistic regression modelling were employed for data analysis. RESULTS: Of the 551 subjects, 341(62%) were males, and 210(38%) were females. Of the total, 276(50.1%) were cases and 275(49.9%) were controls. The mean age of the cases was 55.0}13.4 years and that of the controls was 52.8}14.9 years (p=0.073). Poor oral hygiene, periodontal diseases, material of toothbrush, and no use of mouthwash were significant predictors of oral cancer (p<0.05 each). Smoking and using smokeless tobacco were also significant variables. CONCLUSIONS: Oral health indicators in combination with smoking conferred an increased risk of oral cancer.