Background: Heart failure with preserved ejection fraction (HFpEF) is a significant public health concern with limited treatment options. Dysregulated nitric oxide-mediated signaling has been implicated in HFpEF pathophysiology, however, little is known about the role of endogenous hydrogen sulfide (H2S).
Objectives: This study evaluated H2S bioavailability in patients and two animal models of cardiometabolic HFpEF and assessed the impact of H2S on HFpEF severity through alterations in endogenous H2S production and pharmacological supplementation.
Background And Aims: Acute kidney injury (AKI) due to renal ischemia-reperfusion injury (RIRI) is associated with high morbidity and mortality, with no renoprotective drug available. Previous research focused on single drug targets, yet this approach has not reached translational success. Given the complexity of this condition, we aimed to identify a disease module and apply a multitarget network pharmacology approach.
View Article and Find Full Text PDFUlcerative colitis (UC) is an inflammatory bowel disease that is often resistant to current treatment options, leading to a need for alternative therapies. Herbal products have shown promise in managing various conditions, including UC. However, the potential of branchlets ethanolic extract (CGBRE) in treating UC has not been explored.
View Article and Find Full Text PDFCancer is a leading cause of death globally and has been associated with Mycobacterium tuberculosis (Mtb). The angiogenesis-related VEGFR-2 is a common target between cancer and Mtb. Here, we aimed to synthesize and validate potent dual human VEGFR-2 inhibitors as anticancer and anti-mycobacterial agents.
View Article and Find Full Text PDFBackground: Diabetic foot ulcer (DFU) is a common diabetic complication associated with disability and reduced quality of life. Available therapeutics are not sufficient to combat the spread of DFU. Here we aim to investigate the impact of alagebrium, an advanced glycation end product (AGE)-crosslink breaker, on the healing of DFU.
View Article and Find Full Text PDFAlzheimer's disease (AD) and other forms of dementia are together a leading cause of disability and death in the aging global population, imposing a high personal, societal, and economic burden. They are also among the most prominent examples of failed drug developments. Indeed, after more than 40 AD trials of anti-amyloid interventions, reduction of amyloid-β (Aβ) has never translated into clinically relevant benefits, and in several cases yielded harm.
View Article and Find Full Text PDFOral ulcer is a frequent condition that commonly affects the tongue and in which 75% of the patients experience pain, and 25% report taste changes. The available therapies are not sufficiently effective for rapid and complete healing of tongue ulcers. We previously annotated the metabolites of Thymus satureioides (TS) aerial parts and reported their antioxidant, dermacosmeceutical and hepatoprotective properties.
View Article and Find Full Text PDF() and () are the most common Gram-negative bacteria associated with pneumonia and coinfecting the same patient. Despite their high virulence, there is no effective vaccine against them. In the current study, the screening of several proteins from both pathogens highlighted FepA and OmpK35 for in addition to HasR and OprF from as promising candidates for epitope mapping.
View Article and Find Full Text PDFPinocembrin (5,7-dihydroxyflavone) is a major flavonoid found in many plants, fungi and hive products, mainly honey and propolis. Several in vitro and preclinical studies revealed numerous pharmacological activities of pinocembrin including antioxidant, anti-inflammatory, antimicrobial, neuroprotective, cardioprotective and anticancer activities. Here, we comprehensively review and critically analyze the studies carried out on pinocembrin.
View Article and Find Full Text PDFPharmaceuticals (Basel)
October 2022
Background: Acute kidney injury (AKI) induced by renal ischemia-reperfusion injury (RIRI) is associated with a high incidence of mortality. Existing therapies are mainly supportive, with no available nephroprotective agent. The purpose of this study is to examine the potential protective effect of Bark Extract (ARBE) in RIRI.
View Article and Find Full Text PDFAtherosclerosis and its complications are major causes of cardiovascular morbidity and death. Apart from risk factors such as hypercholesterolemia and inflammation, the causal molecular mechanisms are unknown. One proposed causal mechanism involves elevated levels of reactive oxygen species (ROS).
View Article and Find Full Text PDFBackground: The nicotinamide adenine dinucleotide phosphate oxidase isoform 4 (Nox4) mediates reactive oxygen species (ROS) production and renal fibrosis in diabetic kidney disease (DKD) at the level of the podocyte. However, the mitochondrial localization of Nox4 and its role as a mitochondrial bioenergetic sensor has recently been reported. Whether Nox4 drives pathology in DKD within the proximal tubular compartment, which is densely packed with mitochondria, is not yet known.
View Article and Find Full Text PDFHypertension is the most important cause of death and disability in the elderly. In 9 out of 10 cases, the molecular cause, however, is unknown. One mechanistic hypothesis involves impaired endothelium-dependent vasodilation through reactive oxygen species (ROS) formation.
View Article and Find Full Text PDFThe 1998 Nobel Prize in Medicine and Physiology for the discovery of nitric oxide, a nitrogen containing reactive oxygen species (also termed reactive nitrogen or reactive nitrogen/oxygen species) stirred great hopes. Clinical applications, however, have so far pertained exclusively to the downstream signaling of cGMP enhancing drugs such as phosphodiesterase inhibitors and soluble guanylate cyclase stimulators. All clinical attempts, so far, to inhibit NOS have failed even though preclinical models were strikingly positive and clinical biomarkers correlated perfectly.
View Article and Find Full Text PDFReactive oxygen species (ROS) are ubiquitous metabolic products and important cellular signaling molecules that contribute to several biological functions. Pathophysiology arises when ROS are generated either in excess or in cell types or subcellular locations that normally do not produce ROS or when non-physiological types of ROS (e.g.
View Article and Find Full Text PDFNitric oxide (NO)-cyclic GMP (cGMP) signaling is a vasoprotective pathway therapeutically targeted, for example, in pulmonary hypertension. Its dysregulation in disease is incompletely understood. Here we show in pulmonary artery endothelial cells that feedback inhibition by NO of the NO receptor, the cGMP forming soluble guanylate cyclase (sGC), may contribute to this.
View Article and Find Full Text PDFDysfunctional reactive oxygen species (ROS) signaling is considered an important disease mechanism. Therapeutically, non-selective scavenging of ROS by antioxidants, however, has failed in multiple clinical trials to provide patient benefit. Instead, pharmacological modulation of disease-relevant, enzymatic sources of ROS appears to be an alternative, more promising and meanwhile successfully validated approach.
View Article and Find Full Text PDFReactive oxygen species (ROS) have been mainly viewed as unwanted by-products of cellular metabolism, oxidative stress, a sign of a cellular redox imbalance, and potential disease mechanisms, such as in diabetes mellitus (DM). Antioxidant therapies, however, have failed to provide clinical benefit. This paradox can be explained by recent discoveries that ROS have mainly essential signaling and metabolic functions and evolutionally conserved physiological enzymatic sources.
View Article and Find Full Text PDFProc Natl Acad Sci U S A
April 2019
Drug discovery faces an efficacy crisis to which ineffective mainly single-target and symptom-based rather than mechanistic approaches have contributed. We here explore a mechanism-based disease definition for network pharmacology. Beginning with a primary causal target, we extend this to a second using guilt-by-association analysis.
View Article and Find Full Text PDFToll-like receptors (TLRs) are involved in the progression of ischemic brain injury and hence vascular dementia; however, the underlying mechanisms are largely unknown. Here, we have investigated the interrelationship between stress-responsive heme oxygenase (HO)-1 isoenzyme and TLR4 during chronic brain hypoperfusion. The right unilateral common carotid artery occlusion was performed by ligation of the right common carotid artery in C57BL/6J mice.
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