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Endothelial dysfunction and inflammation are clinically significant risk factors for cardiovascular diseases in hypertension. Although immune cells play a role in hypertension, the impact of plasmacytoid dendritic cells in established renovascular hypertension-induced cardiovascular complications is not fully understood. We investigated plasmacytoid dendritic cells' contribution to arterial endothelial dysfunction and inflammation in renovascular hypertension. A two-kidney one-clip (2K1C) model for four weeks in both male and female mice was used to induce renovascular hypertension. We treated mice with or without anti-PDCA-1 antibodies for one week to deplete the plasmacytoid dendritic cells. Renovascular hypertension causes cardiac hypertrophy, lung edema, and microvascular endothelial dysfunction associated with inflammation induction in mice. Moreover, renovascular hypertension affects the profile of immune cells, including dendritic cells and macrophages, with variations between male and female mice. Interestingly, the depletion of plasmacytoid dendritic cells significantly reduces blood pressure, cardiac hypertrophy, lung edema, inflammation, and oxidative stress and improves microvascular endothelial function via the endoplasmic reticulum (ER) stress, autophagy, and mTOR-dependent mechanisms. Plasmacytoid dendritic cells significantly contribute to the development of cardiovascular complications in renovascular hypertension by modulating immune cells, inflammation, oxidative stress, and ER stress.

RESUMEN

Monocytes and muscles demonstrate functionally contrasting behavior under conditions of zinc deficiency with relation to zinc storage system (muscle retain zinc in contrast to monocytes). We aimed to understand the effects of zinc status and HIV-1 Tat mediated inflammation on expression of zinc transporters in these types of cells. Expression of zinc transporters [ZnTs, ZIPs, and metallothionein (MT)] was quantified by qRT-PCR in RD, THP-1 cells separately and in co-cultured THP-1-RD cells. ZnT1 protein expression levels were confirmed by Western blot. Significant increase of MT and ZnT1 mRNA in response to zinc supplementation and decrease during zinc deficiency indicates significance of the genes encoding transporters in maintaining zinc homeostasis in these tissues. In the RD cells ZIP10 exhibited inverse relation to zinc status whereas no correlation was found in the THP-1 cells. Tat-induced inflammation resulted in the significant elevation of MT, IL6, ZIP7, ZIP8, ZIP9 transcripts in the co-cultured RD cells, whereas THP-1 cells demonstrated increased IL-1ß levels and reduced levels of ZIP7 and ZIP14. Zinc status and HIV-1Tat induced inflammation appear to influence differential expression of MT, ZnTs, and ZIPs in the muscle and monocyte cells.

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RESUMEN

Bone is a passive storage organ for zinc, which contains about 30% of the total body zinc. However, during extreme zinc deficiency, only a small fraction of zinc is released in contrast to other tissues where zinc is released like monocytes or conserved, e.g., skeletal muscle. Zinc plays an important role in bone tissue remodeling. Zinc homeostasis is regulated by several zinc transporters (ZnTs) and importers (ZIPs), but their expression dynamics concerning zinc status of bone cells is not well understood. The study aimed to elucidate the effects of zinc supplementation and depletion on the transcript levels of various zinc transporters. Saos-2, a human osteoblastic cell line, was used as representative bone tissue. Zinc sulfate was used for simulating sufficient zinc status whereas TPEN, a zinc chelator, was used to simulate zinc-deficient state. Expression of various transcripts was measured by qRT-PCR. Subcellular localization of ZnT-1 was carried out by immunofluorescent microscopy, and Western Blotting was carried out to measure the expression of ZnT-1 at the protein level. Among the export transporters the transcript levels of MT, ZnT-1 showed higher levels in zinc sufficient and lower levels in TPEN treated cells. Expression of ZnT-4 was decreased under both the conditions. ZIP-6 and ZIP-13 were downregulated in zinc sufficiency, and ZIP-10 upregulated probably to prevent an excess zinc accumulation in bone cells. Further, ZnT-1 was found to be localized in the nuclear region of SaOS-2 cells. ZnT-1, ZnT-4, ZIP-6, ZIP-11, ZIP-10, and ZIP-13 along with MT may be responsible for maintaining bone zinc homeostasis.

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Zinc homeostasis is maintained by 24 tissue-specific zinc transporters which include ZnTs (ZnT1-10), ZIPs (ZIP1-14), in addition to metallothionein (MT). Current study aimed the role of zinc transporters in maintaining the basal levels of zinc in functionally contrasting tissue specific THP-1 (monocyte), RD (muscle), and Saos-2 (bone) cells. Zinc transporters expression was assessed by qRT-PCR. The mRNA levels of ZnTs (ZnT5-7 & ZnT9), ZIPs (ZIP6-10, ZIP13-14), and MT were significantly (p < 0.05) higher in Saos-2 compared to THP-1 and RD. The present study suggests that distinct expression pattern of zinc transporters and metallothionein might be responsible for the differential zinc assimilation.

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Need for new drugs to fight against tuberculosis (TB) is increasing day by day. In the present work we have taken a spiro compound (GSK 2200150A) reported by GSK as a lead and we modified the structure of the lead to study the antitubercular activity. For structure activity profiling twenty-one molecules have been synthesized, characterized and evaluated for their antimycobacterial potency against both active and dormant TB. Compound 06, 1-((4-methoxyphenyl)sulfonyl)-4',5'-dihydrospiro[piperidine-4,7'-thieno[2,3-c]pyran] was found to be the most potent compound (MIC: 8.23 µM) in active TB and was less effective than the lead but more potent than standard first line drug ethambutol. It was also found to be more efficacious than Isoniazid and Rifampicin and equipotent as Moxifloxacin against dormant Mycobacterium tuberculosis (MTB). Compound 06 also showed good inhibitory potential against over expressed latent MTB enzyme lysine ε-amino transferase with an IC50 of 1.04 ±â€¯0.32 µM. This compound is a good candidate for drug development owing to potential against both active and dormant stages of MTB.

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