In vitro evaluation of immunomodulatory, anti-diabetic, and anti-cancer molecular mechanisms of Tribulus terrestris extracts.

Dampened immunity and impaired wound healing in diabetic patients may lead to diabetic foot ulcer disease, which is the leading cause of limb amputations and hospitalization. On the other hand, cancer is the most significant cause of mortality globally, accounting for over 10 million fatalities in 2020, or nearly one in every six deaths. Plants and herbs have been used to treat chronic diseases due to their essential pharmaceutical attributes, such as mitigating drug resistance, ameliorating systemic toxicities, reducing the need for synthetic chemotherapeutic agents,and strengthening the immune system. The present study has been designed to evaluate the effects of Tribulus terrestris on wound healing, cytotoxic and anti-inflammatory responses against HepG-2 liver cancer cell line. Two solvents (methanol and ethanol) were used for root extraction of T. terrestris. The wound healing potential of the extracts was studied on diabetic cell culture line by scratch assay. The anti-oxidant and cytotoxic potentials were evaluated by in vitro assays against HepG2 cell line. The methanolic root extract resulted in the coverage of robust radical scavenging or maximum inhibition of 66.72%,potent cytotoxic activity or reduced cell viability of 40.98%, and anti-diabetic activity having mighty α-glucosidase inhibition of 50.16% at a concentration of 80 µg/ml. Significant reduction in the levels of LDH leakage (56.38%), substantial ROS (48.45%) and SOD (72.13%) activities were recorededMoreover, gene expression analysis demonstrated the down-regulation of inflammatory markers (TNF-α, MMP-9, Bcl-2, and AFP) in HepG-2 cells when treated with T. terresteris methanolic extract as compared to stress. Furthermore, the down-regulation of inflammatory markers was validated through ELISA-mediated protein estimation of IL-1ß and TNF-α. It is expected that this study will lay a foundation and lead to the development of efficient but low-cost, natural herbs extract-based dressing/ointment for diabetic patients and identify potential drug metabolites to treat out-of-whack inflammatory responses involved in cancer onset, progression, and metastasis.

In silico-prediction of chloroquine as a multi-targeted drug against CDKN2A signaling network associated with cutaneous malignant melanoma.

Melanoma is one of the most common skin infections, has triggered significant morbidity and mortality across the globe. Previous studies have reported that mutations in CDKN2A signalling network is associated with cutaneous malignant melanoma. In the present study, initially, the BioGrid database was utilized, and then hierarchical clustering was performed to identify the CDKN2A signature pathways. In addition, a GO Enrichment analysis was investigated using DAVID (n=187 genes) toolkit. Subsequently, the cBioPortal cancer genomic platform was exploited using alteration ranked frequency to determine the role of the CDKN2A signaling network in 363 samples of cutaneous malignant melanoma patients and we find that CDKN2A and its close interactors PTEN and HUWE1 show highest mutations. Further, we systematically employed molecular docking approach via MOE to target PTEN, CDKN2A and HUWE1 with chloroquine which is naturally occurring in medicinal plant Nigella sativa (NS) and observed virtuous interactions between all receptors and ligand molecules with a binding energy of -11.379, -10.324 and -9.06 Kcal/mol, respectively. The outcomes obtained stipulate a vigorous research resource for using chloroquine as a multitargeted anticancer drug. This novel evidence should help the development of effective therapeutic compounds for the treatment of cancer. Our results reveal that chloroquine is a relevant and novel potential therapeutic drug for the treatment of melanoma.

Prevalence of Pyrazinamide Resistance in Khyber Pakhtunkhwa, Pakistan.

AIMS: Pyrazinamide (PZA) is an important component of first-line tuberculosis (TB) treatment because of its distinctive capability to kill subpopulations of persister Mycobacterium tuberculosis (MTB). The significance of PZA can be understood by its inclusion in the most recent World Health Organization-recommended multidrug-resistant (MDR) TB regimen. Very little information is available about the prevalence of PZA-resistant TB from geographically distinct regions of high burden countries, including Khyber Pakhtunkhwa (KPK), Pakistan, because drug susceptibility testing (DST) of PZA is not regularly performed due to the complexity. In this study, we aimed to find the prevalence of PZA resistance in geographically distinct, Pashtun-dominant KPK Province of Pakistan and its correlation with other first- and second-line drug resistance. MATERIALS AND METHODS: In this study, DST of PZA was performed through an automated BACTEC MGIT 960 system (BD Diagnostic Systems). The resistant samples were further subjected to DST of isoniazid (INH), rifampicin (RIF), ethambutol (EMB), streptomycin (SM), moxicillin (MOX), amikacin (AMK), ofloxacin (OFX), kanamycin (KM), and capreomycin (CAP). RESULTS: Out of 1,075 MTB-positive isolates, 83 (7.7%) were found to be resistant to PZA. Among the PZA-resistant isolates, 76 (90-91.6%) and 67 (80-80.7%) were found to be resistant to INH and RIF, respectively, whereas 63 (76%) were resistant to both first-line drugs, INH and RIF (MDR-TB). The resistance level of EMB, OFX, and SM was also significantly high in PZA resistance, 35 (42%), 40 (48%), and 41 (49-50%) respectively. CONCLUSION: PZA resistance is significantly associated with other first- and second-line drug resistance. A significant number of PZA-resistant isolates are MDR cases. Therefore, DST of PZA should regularly be performed along with other drugs for better management of treatment of MDR and extensively drug resistant (XDR), to avoid side effects in patients.