Angiotensin II (Ang II) is a pleuripotential hormone that is important in the pathophysiology of multiple conditions including aging, cardiovascular and renal diseases, and insulin resistance. Reactive oxygen species (ROS) are important mediators of Ang II-induced signaling generally and have a well defined role in vascular hypertrophy, which is inhibited by overexpression of catalase, inferring a specific role of H2O2. The molecular mechanisms are understood incompletely. The transcriptional coactivator peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) is a key regulator of energy metabolism and ROS-scavenging enzymes including catalase. We show that Ang II stimulates Akt-dependent PGC-1α serine 570 phosphorylation, which is required for the binding of the histone acetyltransferase GCN5 (general control nonderepressible 5) to PGC-1α and for its lysine acetylation. These sequential post-translational modifications suppress PGC-1α activity and prevent its binding to the catalase promoter through the forkhead box O1 transcription factor, thus decreasing catalase expression. We demonstrate that overexpression of the phosphorylation-defective mutant PGC-1α (S570A) prevents Ang II-induced increases in H2O2 levels and hypertrophy ([3H]leucine incorporation). Knockdown of PGC-1α by small interfering RNA promotes basal and Ang II-stimulated ROS and hypertrophy, which is reversed by polyethylene glycol-conjugated catalase. Thus, endogenous PGC-1α is a negative regulator of vascular hypertrophy by up-regulating catalase expression and thus reducing ROS levels. We provide novel mechanistic insights by which Ang II may mediate its ROS-dependent pathophysiologic effects on multiple cardiometabolic diseases.
In vascular endothelial cells, cytokines induce genes that are expressed in inflammatory lesions partly through the activation of transcription factor NF-κB (nuclear factor-κB). Among the members of the NF-κB/rel protein family, homodimers of the RelA subunit of NF-κB can also function as strong transactivators when expressed in cells. However, the functional role of endogenous RelA homodimers has not been clearly elucidated. We investigated whether RelA homodimers are induced in cytokine-treated vascular endothelial cells. Gel mobility-shift and supershift assays revealed that a cytokine TNFα (tumour necrosis factor α) activated both NF-κB1/RelA heterodimers and RelA homodimers that bound to a canonical κB sequence, IgκB (immunoglobulin κB), in SV40 (simian virus 40) immortalized HMEC-1 (human dermal microvascular endothelial cell line 1). In HMEC-1 and HUVEC (human umbilical-vein endothelial cells), TNFα also induced RelA homodimers that bound to the sequence 65-2κB, which specifically binds to RelA homodimers but not to NF-κB1/RelA heterodimers in vitro. Deoxycholic acid, a detergent that can dissociate the NF-κB–IκB complex (where IκB stands for inhibitory κB), induced the binding of the RelA homodimers to 65-2κB from the cytosolic fraction of resting HMEC-1. Furthermore, TNFα induced the transcriptional activity of a reporter gene that was driven by 65-2κB in HMEC-1. These results suggest that in addition to NF-κB1/RelA heterodimers, TNFα also induces RelA homodimers that are functionally active. Thus RelA homodimers may actively participate in cytokine regulation of gene expression in human vascular endothelial cells.
Background
Ethnoveterinary knowledge is highly significant for persistence of traditional community-based approaches to veterinary care. This is of particular importance in the context of developing and emerging countries, where animal health (that of livestock, especially) is crucial to local economies and food security. The current survey documents the traditional veterinary uses of medicinal plants in the Lesser Himalayas-Pakistan.
Methods
Data were collected through interviews, focus groups, participant observation, and by administering questionnaires. A total of 105 informants aged between 20–75 years old who were familiar with livestock health issues (i.e. farmers, shepherds, housewives and herbalists) participated in the study.
Results
A total of 89 botanical taxa, belonging to 46 families, were reported to have ethnoveterinary applications. The most quoted families were Poaceae (6 taxa), Fabaceae (6), Asteraceae (5), and Polygonaceae (5). Adhatoda vasica was the most cited species (43%), followed by Trachyspermum ammi (37%), and Zanthoxylum armatum var. armatum (36%). About 126 medications were recorded against more than 50 veterinary conditions grouped into seven categories. The highest cultural index values were recorded for Trachyspermum ammi, Curcuma longa, Melia azedarach, Zanthoxylum armatum var. armatum and Adhatoda vasica. The highest informant consensus factor was found for pathologies related to respiratory and reproductive disorders. Comparison with the local plant-based remedies used in human folk medicine revealed that many of remedies were used in similar ways in local human phytotherapy. Comparison with other field surveys conducted in surrounding areas demonstrated that approximately one-half of the recorded plants uses are novel to the ethnoveterinary literature of the Himalayas.
Conclusion
The current survey shows a remarkable resilience of ethnoveterinary botanical knowledge in the study area. Most of the species reported for ethnoveterinary applications are wild and under threat. Thus, not only is it imperative to conserve traditional local knowledge of folk veterinary therapies for bio-cultural conservation motives, but also to assist with in-situ and ex-situ environmental conservation initiatives, which are urgently needed. Future studies that focus on the validation of efficacy of these ethnoveterinary remedies can help to substantiate emic concepts regarding the management of animal health care and for rural development programs.
Keywords: Medicinal plants; Ethnobotany; Ethnoveterinary; Lesser Himalayas; Pakistan