Rv0547c, a functional oxidoreductase, supports Mycobacterium tuberculosis persistence by reprogramming host mitochondrial fatty acid metabolism.

Mycobacterium tuberculosis (Mtb) successfully thrives in the host by adjusting its metabolism and manipulating the host environment. In this study, we investigated the role of Rv0547c, a protein that carries mitochondria-targeting sequence (MTS), in mycobacterial persistence. We show that Rv0547c is a functional oxidoreductase that targets host-cell mitochondria. Interestingly, the localization of Rv0547c to mitochondria was independent of the predicted MTS but depended on specific arginine residues at the N- and C-terminals. As compared to the mitochondria-localization defective mutant, Rv0547c-2SDM, wild-type Rv0547c increased mitochondrial membrane fluidity and spare respiratory capacity. To comprehend the possible reason, comparative lipidomics was performed that revealed a reduced variability of long-chain and very long-chain fatty acids as well as altered levels of phosphatidylcholine and phosphatidylinositol class of lipids upon expression of Rv0547c, explaining the increased membrane fluidity. Additionally, the over representation of propionate metabolism and ß-oxidation intermediates in Rv0547c-targeted mitochondrial fractions indicated altered fatty acid metabolism, which corroborated with changes in oxygen consumption rate (OCR) upon etomoxir treatment in HEK293T cells transiently expressing Rv0547c, resulting in enhanced mitochondrial fatty acid oxidation capacity. Furthermore, Mycobacterium smegmatis over expressing Rv0547c showed increased persistence during infection of THP-1 macrophages, which correlated with its increased expression in Mtb during oxidative and nutrient starvation stresses. This study identified for the first time an Mtb protein that alters mitochondrial metabolism and aids in survival in host macrophages by altering fatty acid metabolism to its benefit and, at the same time increases mitochondrial spare respiratory capacity to mitigate infection stresses and maintain cell viability.

Aza-Flavanone Diminishes Parkinsonism in the Drosophila melanogasterParkin Mutant.

Parkinson's disease is a chronic and progressive neurodegenerative disease, induced by slow and progressive death of the dopaminergic (DA) neurons from the midbrain region called substantia nigra (SNc) leading to difficulty in locomotion. At present, very few potential therapeutic drugs are available for treatment, necessitating an urgent need for development. In the current study, the parkin transgenic Drosophila melanogaster model that induces selective loss in dopaminergic neurons and impairment of locomotory functions has been used to see the effect of the aza-flavanone molecule. D. melanogaster serves as an amazing in vivo model making valuable contribution in the development of promising treatment strategies. Our in-silico study showed spontaneous binding of this molecule to the D2 receptor making it a potential dopamine agonist. PARKIN protein is well conserved, and it has been reported that Drosophila PARKIN is 42% identical to human PARKIN. Interestingly, this molecule enhances the motor coordination and survivability rate of the transgenic flies along with an increase in expression of the master regulator of Dopamine synthesis, that is, tyrosine hydroxylase (TH), in the substantia nigra region of the fly brain. Moreover, it plays a significant effect on mitochondrial health and biogenesis via modulation of a conserved mitochondrial protein PHB2. Therefore, this molecule could lead to the development of an effective therapeutic approach for the treatment of PD.

Inhibitory role of oleanolic acid and esculetin in HeLa cells involve multiple signaling pathways.

The global burden of cervical cancer from low and middle-income groups is increasing at alarming rates with more than half a million women being diagnosed every year. Although the disease is largely preventable when screened and diagnosed in earlier stages, the development of resistance and relapse had resulted in a poor prognosis. Therefore, a comprehensive approach needs to be put forward to understand and develop new preventive and therapeutic strategies to effectively combat cancer. Recently, much attention has been diverted to plant-derivatives for the treatment as they exhibit potent anti-cancer properties and side-effects caused by chemotherapeutic agents can also be prevented. Oleanolic acid and Esculetin are natural compounds known for their anti-cancer properties. Hence, the present study investigates the effect and mechanism of these compounds on cervical carcinoma, using HeLa cells. Posttreatment, it was observed that these compounds inhibited proliferation by both arresting the cells in the sub G1 phase and inducing senescence. Also, a marked reduction in the migration and cell survival was observed, as evidenced by results obtained from wound healing assay and Annexin V-FITC/PI staining. Furthermore, studies on the expression pattern of genes involved in major signaling pathways demonstrated a profound effect of these compounds. Taken together, the results of our study suggest that both Oleanolic acid and esculetin serve as a plausible therapeutic agent.