Frontiers in bioscience (Landmark edition)最新文献

Sulfatides or 3-O-sulfogalactosylceramide are negatively charged sulfated glycosphingolipids abundant in the brain and kidneys and play crucial roles in nerve impulse conduction and urinary pH regulation. Sulfatides are present in the liver, specifically in the biliary tract. Sulfatides are self-lipid antigens presented by cholangiocytes to activate cluster of differentiation 1d (CD1d)-restricted type II natural killer T (NKT) cells. These cells are involved in alcohol-related liver disease (ArLD) and ischemic liver injury and exert anti-inflammatory effects by regulating the activity of pro-inflammatory type I NKT cells. Loss of sulfatides has been implicated in the chronic inflammatory disorder of the liver known as primary sclerosing cholangitis (PSC); bile ducts deficient in sulfatides increase their permeability, resulting in the spread of bile into the liver parenchyma. Previous studies have shown elevated levels of sulfatides in hepatocellular carcinoma (HCC), where sulfatides could act as adhesive molecules that contribute to cancer metastasis. We have recently demonstrated how loss of function of GAL3ST1, a limiting enzyme involved in sulfatide synthesis, reduces tumorigenic capacity in cholangiocarcinoma (CCA) cells. The biological function of sulfatides in the liver is still unclear; however, this review aims to summarize the existing findings on the topic.

Background: It has been reported the therapeutic effects of mesenchymal stem cells (MSCs) on hearing loss. This study explored the therapeutic effects of growth differentiation factor 6 (GDF6) overexpression-induced MSCs (MSCs-GDF6) on age-related hearing loss (ARHL) and its underlying mechanisms.

Methods: Reverse transcription-quantitative PCR and western blotting were used to evaluate gene expression. Flow cytometry and immunofluorescence assays were performed for the detection of apoptosis and autophagy, respectively. Hearing function and loss of outer hair cells (HCs) in ARHL rats were measured using the auditory brainstem response and cochlear silver nitrate staining, respectively. MSC proliferation was evaluated with the Cell Counting Kit-8 assay.

Results: Growth differentiation factor 15 (GDF15) and sirtuin 1 (SIRT1) expression was significantly decreased in hydrogen peroxide (H₂O₂)-induced House Ear Institute-Organ of Corti 1 (HEI-OC1) cells and the cochlea of ARHL rats. Elevated apoptosis and blocked autophagic flux were uncovered in H₂O₂-induced HEI-OC1 cells and ARHL rats. GDF15 overexpression inhibited apoptosis and restored autophagic flux in vitro and in vivo. Meanwhile, GDF15 positively regulated SIRT1 protein expression. MSCs-GDF6 not only upregulated GDF15 and SIRT1 expression but also suppressed apoptosis and restored autophagic flux to reduce loss of HCs and hearing loss in ARHL rats.

Conclusions: MSCs-GDF6 prevented loss of HCs to relieve ARHL by inhibiting apoptosis and restoring autophagic flux, likely in association with upregulation of the GDF15/SIRT1 axis.

The use of biological control agents is one of the best strategies available to combat the plant diseases in an ecofriendly manner. Biocontrol bacteria capable of providing beneficial effect in crop plant growth and health, have been developed for several decades. It highlights the need for a deeper understanding of the colonization mechanisms employed by biocontrol bacteria to enhance their efficacy in plant pathogen control. The present review deals with the in-depth understanding of steps involved in host colonization by biocontrol bacteria. The colonization process starts from the root zone, where biocontrol bacteria establish initial interactions with the plant's root system. Moving beyond the roots, biocontrol bacteria migrate and colonize other plant organs, including stems, leaves, and even flowers. Also, the present review attempts to explore the mechanisms facilitating bacterial movement within the plant such as migrating through interconnected spaces such as vessels or in the apoplast, and applying quorum sensing or extracellular enzymes during colonization and what is needed to establish a long-term association within a plant. The impacts on microbial community dynamics, nutrient cycling, and overall plant health are discussed, emphasizing the intricate relationships between biocontrol bacteria and the plant's microbiome and the benefits to the plant's above-ground parts, the biocontrol 40 bacteria confer. By unraveling these mechanisms, researchers can develop targeted strategies for enhancing the colonization efficiency and overall effectiveness of biocontrol bacteria, leading to more sustainability and resilience.

Immunology advances have increased our understanding of autoimmune, auto-inflammatory, immunodeficiency, infectious, and other immune-mediated inflammatory diseases (IMIDs). Furthermore, evidence is growing for the immune involvement in aging, metabolic and neurodegenerative diseases, and different cancers. However, further research has indicated sex/gender-based immune differences, which further increase higher incidences of various autoimmune diseases (AIDs), such as systemic lupus erythematosus (SLE), myasthenia gravis, and rheumatoid arthritis (RA) in females. On the other hand, reproductive-age females also show a more potent immune response against infections and vaccines than their age-matched males-furthermore, some immune-based therapies, including immune checkpoint inhibitors (ICIs), show gender-based efficacy and adverse events. Metabolic demands are different in males and females. Immune cell function and polarization are also governed by their metabolic reprogramming, called immunometabolism and immunometabolic reprogramming (IR). Therefore, sex/gender-associated immune differences and their involvement in immune-mediated diseases and immune-based therapeutics indicate the demand for gender-based IR studies to increase the efficacy of immune-based precision medicine.

Cardiovascular complications claim the lives of up to 70% of patients with diabetes mellitus (DM). The mechanisms increasing cardiovascular risk in DM remain to be fully understood and successfully addressed. Nonetheless, there is increasing evidence in the scientific literature of the participation of platelets in the cardiovascular complications of DM. Multiple reports describe the hyperactivity of platelets in DM and their participation in inflammatory responses. The understanding of the mechanisms underlying the contribution of platelets to cardiovascular pathologies in DM will help the development of targeted therapeutic strategies able to reduce cardiovascular risk in these patients. In this literature review, we summarise our current understanding of the molecular mechanisms leading to the contribution of platelets to cardiovascular risk in DM. Both platelet haemostatic activity leading to thrombus formation and their participation to inflammatory processes are stimulated by the biochemical conditions associated with DM. We also present evidence on how DM affect the efficacy of existing therapeutic treatments for thrombosis and, by converse, how antidiabetic drugs may affect platelet function and the haemostasis/thrombosis balance. Taken together, the growing evidence of the different and unexpected roles of platelets in the progression of DM provides a strong rationale for the design of cardiovascular drugs targeting specifically platelets, their pro-inflammatory activity and their activation mechanisms in this disease. Overall, this article provides an important up-to-date overview of the pathophysiological alterations of platelets in DM, which need to be taken into account for the effective management of cardiovascular health in this disease.

Cardiovascular disease (CVD) is the most prevalent cause of mortality and morbidity in the Western world. A common underlying hallmark of CVD is the plaque-associated arterial thickening, termed atherosclerosis. Although the molecular mechanisms underlying the aetiology of atherosclerosis remain unknown, it is clear that both its development and progression are associated with significant changes in the pattern of DNA methylation within the vascular cell wall. The endothelium is the major regulator of vascular homeostasis, and endothelial cell dysfunction (ED) is considered an early marker for atherosclerosis. Thus, it is speculated that changes in DNA methylation within endothelial cells may, in part, be causal in ED, leading to atherosclerosis and CVD generally. This review will evaluate the extensive evidence that environmental risk factors, known to be associated with atherosclerosis, such as diabetes, metabolic disorder, smoking, hypertension and hypercholesterolaemia etc. can affect the methylome of the endothelium and consequently act to alter gene transcription and function. Further, the potential mechanisms whereby such risk factors might impact upon the activities and/or specificities of the epigenetic writers and erasers which determine the methylome [the DNA methyl transferases (DNMTs) and Ten Eleven translocases (TETs)] are considered here. Notably, the TET proteins are members of the 2-oxoglutarate-dependent dioxygenase superfamily which require molecular oxygen (O₂) and α-ketoglutarate (α-KG) as substrates and iron-2⁺ (Fe II) as a cofactor. This renders their activities subject to modulation by hypoxia, metabolic flux and cellular redox. The potential significance of this, with respect to the impact of modifiable risk factors upon the activities of the TETs and the methylome of the endothelium is discussed.

Background: Rheumatic heart disease (RHD), which is caused mainly by Group A Streptococcus, leads to fibrotic damage to heart valves. Recently, endothelial‒mesenchymal transition (EndMT), in which activin plays an important role, has been shown to be an important factor in RHD valvular injury. However, the mechanism of activin activity and EndMT in RHD valvular injury is not clear.

Methods: Our study was divided into two parts: in vivo and in vitro. We constructed a small interfering RNA (ACVR2A-siRNA) by silencing activin receptor type IIA (ACVR2A) and an adeno-associated virus (AAV-ACVR2A) containing a sequence that silenced ACVR2A. The EndMT cell model was established via human umbilical vein endothelial cells (HUVECs), and the RHD animal model was established via female Lewis rats. ACVR2A-siRNA and AAV-ACVR2A were used in the above experiments.

Results: EndMT occurred in the valvular tissues of RHD rats, and activin and its associated intranuclear transcription factors were also activated during this process, with inflammatory infiltration and fibrotic damage also occurring in the valvular tissues. After inhibition of ACVR2A, EndMT in valvular tissues was also inhibited, and inflammatory infiltration and fibrosis were reduced. Endothelial cell experiments suggested that mesenchymal transition could be stimulated by activin and that inhibition of ACVR2A attenuated mesenchymal transition.

Conclusions: Activin plays an important role in signal transduction during EndMT after activation, and inhibition of ACVR2A may attenuate RHD valvular damage by mediating EndMT. Targeting ACVR2A may be a therapeutic strategy to alleviate RHD valvular injury.

Background: We investigated chitosan's protective effects against tertiary butylhydroquinone (TBHQ)-induced toxicity in adult male rats, focusing on cognitive functions and oxidative stress in the brain, liver, and kidneys.

Methods: Rats were divided into four groups (n = 8/group): (1) Control, (2) Chitosan only, (3) TBHQ only, and (4) Chitosan + TBHQ.

Results: TBHQ exposure led to significant cognitive impairments and increased oxidative stress, marked by elevated malondialdehyde (MDA) and decreased superoxide dismutase (SOD) and glutathione (GSH) levels. Behavioral tests, including the Morris Water Maze (MWM) as well as Passive Avoidance Learning (PAL) tasks, confirmed memory and learning deficits in the TBHQ group. Histopathological analysis showed damage in the brain, liver, and kidney tissues of TBHQ-exposed rats. Chitosan treatment significantly mitigated these effects, reducing oxidative stress markers and preserving tissue integrity. These findings suggest that chitosan's antioxidant properties may provide a therapeutic benefit against TBHQ-induced neurotoxicity and organ damage.

Conclusions: These findings suggest that chitosan exerts potent neuroprotective effects, potentially through its antioxidant and anti-inflammatory properties, and could serve as a therapeutic agent against TBHQ-induced toxicity.

Multiple sclerosis (MS) is a chronic autoimmune disorder marked by neuroinflammation, demyelination, and neuronal damage. Recent advancements highlight a novel interaction between iron-dependent cell death, known as ferroptosis, and gut microbiota, which may significantly influences the pathophysiology of MS. Ferroptosis, driven by lipid peroxidation and tightly linked to iron metabolism, is a pivotal contributor to the oxidative stress observed in MS. Concurrently, the gut microbiota, known to affect systemic immunity and neurological health, emerges as an important regulator of iron homeostasis and inflammatory responses, thereby influencing ferroptotic pathways. This review investigates how gut microbiota dysbiosis and ferroptosis impact MS, emphasizing their potential as therapeutic targets. Through an integrated examination of mechanistic pathways and clinical evidence, we discuss how targeting these interactions could lead to novel interventions that not only modulate disease progression but also offer personalized treatment strategies based on gut microbiota profiling. This synthesis aims at deepening insights into the microbial contributions to ferroptosis and their implications in MS, setting the stage for future research and therapeutic exploration.