Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie最新文献

Huntington's disease (HD) is a progressive, autosomal dominant neurodegenerative disorder characterized by cognitive decline, motor dysfunction, and psychiatric disturbances. A common feature of neurodegenerative disorders is mitochondrial dysfunction, which affects the brain's sensitivity to oxidative damage and its high oxygen demand. This dysfunction may plays a significant role in the pathogenesis of Huntington's disease. HD is caused by a CAG repeat expansion in the huntingtin gene, which leads to the production of a toxic mutant huntingtin (mHTT) protein. This disruption in mitochondrial function compromises energy metabolism and increases oxidative stress, resulting in mitochondrial DNA abnormalities, impaired calcium homeostasis, and altered mitochondrial dynamics. These effects ultimately may contribute to neuronal dysfunction and cell death, underscoring the importance of targeting mitochondrial function in developing therapeutic strategies for HD. This review discusses the mechanistic role of mitochondrial dysfunction in Huntington's disease. Mitochondrial dysfunction is a crucial factor in HD, making mitochondrial-targeted therapies a promising approach for treatment. We explore therapies that address bioenergy deficits, antioxidants that reduce reactive oxygen species, calcium modulators that restore calcium homeostasis, and treatments that enhance mitochondrial dynamics to rejuvenate mitochondrial function. We also highlight innovative treatment approaches such as gene editing and stem cell therapy, which offer hope for more personalized strategies. In conclusion, understanding mitochondrial dysfunction in Huntington's disease may guide potential treatment strategies. Targeting this dysfunction may help to slow disease progression and enhance the quality of life for individuals affected by Huntington's disease.

Asthma, a chronic inflammatory disease, remains a global health challenge due to its complex pathophysiology and the limited treatment efficacy. This study explored the effect of Inula japonica Thunb. water extract (IJW) on asthma and its protective mechanisms. To assess the effects of IJW, we established an experimental asthma model in BALB/c mice using ovalbumin (OVA). Airway hyper-responsiveness (AHR) in response to methacholine was measured. We quantified inflammatory cell infiltration and cytokine and chemokine levels in bronchoalveolar lavage fluid (BALF), as well as total IgE levels in serum. Staining with hematoxylin and eosin and periodic acid-Schiff was used to examine the impact of IJW on lung pathology. We performed RNA sequencing to identify differentially expressed genes, which were subjected to Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses. We used interleukin (IL)-4/IL-13-treated human bronchial epithelial (HBE) cells to explore the associated mechanisms. IJW showed therapeutic effects against OVA-induced asthma by alleviating AHR, peribronchial inflammation, mucus hypersecretion, and collagen fiber deposition. It reduced total IgE levels in the serum and IL-4, IL-5, IL-13, eotaxin, macrophage-derived chemokines, and periostin levels in BALF. In IL-4/IL-13-treated HBE cells, IJW and its components suppressed the Janus kinase-signal transducer and activator of the transcription (JAK-STAT) signaling. These findings support IJW's potential as a pharmacological agent for allergic airway inflammation and asthma.

Purpose: Targeting mitochondrial ferroptosis presents a promising strategy for mitigating myocardial ischemia-reperfusion (I/R) injury. This study aims to evaluate the efficacy of the mitochondrial-targeted ferroptosis inhibitor SS-31@Fer-1 (elamipretide@ferrostatin1) in reducing myocardial I/R injury.

Methods: SS-31@Fer-1 was synthesized and applied to H9C2 cells subjected to hypoxia/reoxygenation (H/R) to assess its protective effects. Cytotoxicity was evaluated using a cell counting kit-8 (CCK-8) assay, with lactate dehydrogenase (LDH) and creatine kinase isoenzyme (CK-MB) levels measured. Mitochondrial reactive oxygen species (ROS) and mitochondrial membrane potential (MMP) were assessed using Mito-SOX and JC-1 fluorescent dyes, respectively. Lipid peroxidation products, malondialdehyde (MDA) and glutathione (GSH), were quantified. Mitochondrial structure, mt-cytochrome b (mt-Cytb), and mt-ATP synthase membrane subunit 6 (mt-ATP6) were analyzed. Additionally, iron homeostasis and ferroptosis markers were evaluated.

Results: SS-31@Fer-1 significantly improved H/R-induced cardiomyocyte viability and reduced LDH and CK-MB levels. Compared to the Fer-1 group, SS-31@Fer-1 reduced GSH and increased MDA levels, enhancing mitochondrial integrity and function. Notably, it increased mitochondrial ROS and decreased MMP, indicating a mitigation of H/R-induced cardiomyocyte cytotoxicity. Furthermore, SS-31@Fer-1 maintained cellular iron homeostasis, as evidenced by increased expression of FTH, FTMT, FPN, and ABCB8. Elevated levels of GPX4 and Nrf2 were observed, while ACSL4 and PTGS2 levels were reduced in the SS-31@Fer-1 group.

Conclusions: SS-31@Fer-1 effectively suppressed ferroptosis in H/R-induced cardiomyocytes by maintaining cellular iron homeostasis, improving mitochondrial function, and inhibiting oxidative stress. These findings provide novel insights and opportunities for alleviating myocardial I/R injury.

Immunoglobulin (Ig) E is a key mediator in the induction and maintenance of allergic inflammation, characterized by a Th2-dominated immune response. Recently epidemiological studies have showed that elevated serum total IgE levels or an increased abundance of mast cells (MCs) at the lesion site are observed in psoriatic patients with cardiovascular diseases (CVD), such as atherosclerosis. Although the underlying mechanisms by which IgE synergizing with MCs in promoting these chronic immune-inflammatory diseases remain unclear, the interleukin (IL)-23/IL-17 axis appears to play a crucial role in comorbidity of psoriasis and atherosclerosis. High IgE production may result from IL-17A response, further exacerbating inflammatory pathways involved in both psoriasis and atherosclerosis. This review explores the possible mechanisms of IgE in these comorbid conditions, reinforcing the rationale for IL-17A targeted biologics in the treatment of psoriasis and atherosclerosis comorbidity. Additionally, IgE is proposed as a potential therapeutic target for alleviating patients suffering from these comorbidity conditions.

The strategy of drug repositioning has historically played a significant role in the identification of new treatments for Parkinson's disease. Still today, numerous clinical and preclinical studies are investigating drug classes, already marketed for the treatment of metabolic disorders, for their potential use in Parkinson's disease patients. While drug repurposing offers a promising, fast, and cost-effective path to new treatments, these drugs still require thorough preclinical evaluation to assess their efficacy, addressing the specific neurodegenerative mechanisms of the disease. This review explores the state-of-the-art approaches to drug repurposing for Parkinson's disease, highlighting particularly relevant aspects. Preclinical studies still predominantly rely on traditional neurotoxin-based animal models, which fail to effectively replicate disease progression and are characterized by significant variability in model severity and timing of drug treatment. Importantly, for almost all the drugs analyzed here, there is insufficient data regarding the mechanism of action responsible for the therapeutic effect. Regarding drug efficacy, these factors may obviously render results less reliable or comparable. Accordingly, future preclinical drug repurposing studies in the Parkinson's disease field should be carried out using next-generation animal models like α-synuclein-based models that, unfortunately, have to date been used mostly for studies of disease pathogenesis and only rarely in pharmacological studies.

Loss of pancreatic islet cell mass and function is one of the most important factors in the development of type 2 diabetes mellitus, and hyperglycemia-induced lesions in other organs are also associated with apoptosis or hyperproliferation of the corresponding tissue cells. The Hippo signaling pathway is a key signal in the regulation of cell growth, proliferation and apoptosis, which has been shown to play an important role in the regulation of diabetes mellitus and its complications. Excessive activation of the Hippo signaling pathway under high glucose conditions triggered apoptosis and decreased insulin secretion in pancreatic islet cells, while dysregulation of the Hippo signaling pathway in the cells of other organ tissues led to proliferation or apoptosis and promoted tissue fibrosis, which aggravated the progression of diabetes mellitus and its complications. This article reviews the mechanisms of Hippo signaling, its individual and reciprocal regulation in diabetic pancreatic pathology, and its emerging role in the pathophysiology of diabetic complications. Potential therapeutics for diabetes mellitus that have been shown to target the Hippo signaling pathway are also summarized to provide information for the clinical management of type 2 diabetes mellitus.

Stroke is globally recognized as the second leading cause of death, significantly impairing both motor and cognitive functions. Enhancing regeneration after stroke is crucial for restoring these functions and necessitates strategies to promote neuroregeneration to achieve better post-stroke outcomes. Brain-derived neurotrophic factor (BDNF) plays a key role in neuroregeneration by influencing motor ability, learning, memory, and rehabilitation after stroke. However, challenges such as the substantial protein size, short half-life of BDNF, and blood-brain barrier hinder its efficient delivery to the brain. In this study, LM22A-4, a BDNF mimetic, was utilized and delivered through a Smart Mesoporous Ball (SMB-3) system to target the ischemic injured brain and explore its potential therapeutic effects in a mouse ischemic stroke model. Treatment with LM22A-4-loaded SMB-3 (LM22A-4-SMB-3) markedly restored neurological, motor, and cognitive deficits following ischemic stroke compared to LM22A-4 alone. Additionally, administration of LM22A-4-SMB-3 reduced apoptotic cell death and glial activation, as evidenced by the TUNEL assay results, and decreased GFAP and Iba-1 expression levels. Furthermore, the phosphorylation of TrkB and Akt, but not that of Erk, was considerably increased in the LM22A-4-SMB-3-treated group. Treatment also enhanced the number of BrdU+/NeuN+ cells, with a marked reduction in post-stroke brain atrophy. These findings suggest that LM22A-4-SMB-3 can attenuate ischemic damage and recover neurological, motor, and cognitive functions by increasing p-TrkB and p-Akt levels and promoting neurogenesis. Therefore, SMB-3-mediated delivery of LM22A-4 presents a potentially applicable delivery system, and LM22A-4-SMB-3 use could be considered a novel therapeutic strategy to improve post-stroke outcomes.

Sechium spp., is a vegetable species renowned for its pharmacological properties, including hepatoprotective activity. This species can crossbreed with its wild relatives, leading to the creation of an HD-Victor hybrid with higher levels of flavonoids, cucurbitacins, and phenolic acids compared to the Sechium edule. However, the antioxidant and hepatoprotective properties of this hybrid are not well-known. We investigated the hepatoprotective effect of HD-Victor hybrid extract on a hepatic-damage mouse model induced by carbon tetrachloride (CCl₄). We conducted a phytochemical characterization and quantified its antioxidant activity. Subsequently, we evaluated the extract at different concentrations, testing the potential to mitigate liver damage induced by CCl₄. After, we performed tests to assess liver function through AST, ALT, ALP and albumin, antioxidant levels, and histopathological examination. Our findings reveal that HD-Victor hybrid extract is rich in flavonoids, phenolic acids, and cucurbitacins and shows DPPH-free radical inhibition, protection in liver function, and increased antioxidant levels. Therefore, the Sechium HD-Victor hybrid extract exerts a protective effect against hepatic damage induced by oxidative stress, showing its potential as a hepatoprotective agent.

Platelet inhibition is a fundamental objective to prevent and treat thrombus formation. Platelet activation depends on mitochondrial function. This study aims to identify a new mitochondria-targeting compound with antiplatelet activity at safe concentrations in vitro. Cytotoxicity and viability tests were performed on human platelets from volunteer donors, together with experiments on aggregation, platelet activation, mitochondrial function, mitochondrial respiration, and thioredoxin reductase 2 (TrxR2) enzymatic activity in isolated platelet mitochondria. The compound MitoCDNB, corresponding to the molecule 5-chloro-2,4-dinitrophenylamino linked with triphenylphosphonium cation (TPP+) by a butyl chain and methanesulfonate as the counterion, was evaluated. MitoCDNB demonstrates potent, high mitochondria-selective antiplatelet effects that provide a novel approach to platelet inhibition with potentially minimized systemic risks. Here, we describe the first compound that inhibits platelet activation by decreasing TrxR2 enzymatic activity and collagen-stimulated maximal mitochondrial respiration, preventing aggregation and platelet activation. These results can be used to develop new antiplatelet drugs targeting mitochondria.

A hypertonic solution of Ibuprofen (Ibu) was designed to nebulize, associating a low concentration of Ibu with L-Arginine (AR), to increase solubility and serve as a nitric oxide donor. To provide preclinical research human bronchial epithelial cells derived from a cystic fibrosis patient homozygous for the ΔF508 CFTR mutation (CFBE41o-) and mouse RAW 264.7 macrophages were pre-treated with Ibu (10-100 μM), AR (20 and 200 μM), or the combination Ibu-AR (10-100 μM). After Angiotensin II (AngII) or LPS/Interferon ϒ (IFN) stimulation, Reactive Oxygen Species (ROS) generation, Nitric Oxide (NO) formation, and the expression of inflammatory markers were determined. Ibu-AR (10/20 μM) significantly reduced ROS generation stimulated by AngII (p < 0.01) in CFBE41o- cells preserved the NO pathway and inhibited LPS-stimulated nitrite generation (p < 0.001). In macrophages, the combination Ibu-Ar, in a ratio of 1:2-1:6, efficiently scavenged excessive ROS generated by LPS, and significantly induced NO generation (p < 0.001), but inhibited nitrite formation. In LPS/IFNϒ-activated Raw, gene signature of M1polarization including tumor necrosis factor (TNF-α), NADPH Oxidase 2 (NOX-2), MCP-1, and inducible nitric oxide synthase (iNOS) were significantly downregulated by Ibu-AR, as well TNF-α, IL-6, and iNOS protein expressions. The inhibitory effect produced by Ibu-AR on M1 macrophages was associated with the inhibition of p-ERK1/2 and p-STAT3. Ibu-AR represents an effective therapeutic strategy for reducing oxidative stress, preserving NO bioavailability, and modulating inflammation in chronic inflammatory diseases.