Treatment of Mycobacterium tuberculosis infected macrophages with rifabutin loaded β-glucan microparticles induces macroautophagy mediated bacillary killing

Article

作者: Sharma, Rolee ; Ahmad, Firoz ; Khubaib, Mohd ; Jain, Parul ; Fatima, Nida ; Ahmad, Shad ; Al-Keridis, Lamya Ahmed ; Saeed, Mohd ; Upadhyay, Tarun Kumar ; Ahmad, Irfan

Tuberculosis (TB), attributable to Mycobacterium tuberculosis (M.tb), constitutes a formidable global health challenge, particularly with the proliferation of multidrug-resistant (MDR) strains. The efficacious clearance of M.tb from host cells is imperative for mitigating infection and averting disease progression. Autophagy, an intricate cellular mechanism for degrading and recycling biomolecules, plays a pivotal role in the immune response to M.tb by facilitating the degradation of intracellular pathogens through the formation of autophagosomes and their subsequent fusion with lysosomes. This study elucidates the therapeutic efficacy of DYDGP microparticles in M.tb-infected macrophages. DCFHDA staining elucidated that DYDGP significantly enhances macrophage membrane integrity and amplifies reactive oxygen species (ROS) production compared to YDGP, even in the presence of NOX-2 inhibitors. Furthermore, DYDGP promotes the biogenesis of acidic vesicular organelles and phago-lysosomal maturation, as corroborated by acridine orange and Lysotracker Red staining. Immunofluorescence and dansylcadaverine staining evidenced that DYDGP enhances autophagy induction and LC3 puncta formation in infected macrophages at both 30 min and 24 h. Protein expression analyses demonstrated elevated levels of NOX-2 and LC3, confirming autophagy induction. Antimycobacterial efficacy assessments revealed that DYDGP treatment engendered significant reductions in colony-forming units (CFUs) for H37Rv (64, 40, 19), MDR32420 (44, 35, 18), MDR32422 (44, 39, 21), and MDR32521 (38, 22, 18) at 30 min, 24 h, and 48 h, respectively. These findings accentuate DYDGP's potential to substantially attenuate M.tb burden, including in MDR strains, thereby positioning it as a promising adjunctive therapy for augmenting tuberculosis treatment.

2024-11-01·Biomedicine & Pharmacotherapy

The potential role of transcription factor sterol regulatory element binding proteins (SREBPs) in Alzheimer's disease

Review

作者: Fan, Panpan ; Zhao, Qingchun ; Chen, Huanhua ; Lin, Junjie ; Gu, Yujia ; Xu, Zihua ; Zhou, Lijun ; Li, Xinzhu ; Wang, Weiyi ; Zheng, Fangyuan ; Liu, Siyuan ; Yang, Aizhu

Sterol regulatory element binding proteins (SREBPs) are a series of cholesterol-related transcription factors. Their role in regulating brain cholesterol biosynthesis, amyloid accumulation, and tau tangles formation has been intensively studied in protein-protein interaction analysis based on genes in clinical databases. SREBPs play an important role in maintaining cholesterol homeostasis in the brain. There are three subtypes of SREBPs, SREBP-1a stimulates the expression of genes related to cholesterol and fatty acid synthesis, SREBP-1c stimulates adipogenesis, and SREBP-2 stimulates cholesterol synthase and LDL receptors. SREBP-2 is activated in response to cholesterol depletion and stimulates a compensatory upregulation of cholesterol uptake and synthesis. Previous studies have shown that inhibition of SREBP-2 reduces cholesterol and amyloid accumulation, and new research suggests that SREBPs play a multifaceted role in Alzheimer's disease. Here, we highlight the importance of SREBPs in AD, in terms of multiple pathways regulating cholesterol in the brain, and primarily demonstrate the potential of SREBP-2 inhibitors. There was a trend towards a significant increase in the expression levels of different SREBP isoforms in AD patients compared to healthy controls. Therefore, there is a close link between SREBPs and AD, and this review analyses the potential role of SREBPs in the treatment of AD. In addition, we systematically reviewed the research progress of SREBPs in AD, and this review will provide more innovative insights into the pathogenesis and treatment of AD and new strategies for drug development in AD.

2023-07-03·Expert Opinion on Investigational Drugs

Psoriasis: a focus on upcoming oral formulations

Review

作者: Puig, Lluís ; Carmona-Rocha, Elena ; Rusiñol, Lluís

INTRODUCTIONTargeted therapies have greatly improved the quality of life of patients with psoriasis. Despite the extensive list of treatments available, multiple new drugs are being developed, especially oral therapies with potential advantages as regards comfort of administration. However, the efficacy and safety of these new oral therapies need to be improved to match those of novel biologics.AREAS COVEREDWe provide a narrative review of the oral therapies for psoriasis that are currently under development, from Jak inhibitors to oral IL-17 and IL-23 inhibitors, among others. A literature search was performed for articles published from 1 January 2020, to 6 June 2023.EXPERT OPINIONThe approval of deucravacitinib, the first Jak inhibitor for the treatment of moderate-to-severe plaque psoriasis, heralds a bright therapeutic future with multiple new oral formulations. A great number of oral treatments with singular mechanism of action, like A3AR agonists, HSP90 inhibitors, ROCK-2 inhibitors, oral TNF inhibitors, oral IL-23 inhibitors, oral IL-17 inhibitors, PD4 inhibitors (orismilast) and several Tyk2 inhibitors, are currently being evaluated in clinical trials and could be suitable for approval in the future. Growing variation in treatment modes of administration will allow dermatologists to better integrate patient preferences in the therapeutic decision process.

100 项与 Caspase-2抑制剂(Elgia) 相关的药物交易

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