Life sciences最新文献

An increase in life expectancy comes with a higher risk for age-related neurological and cognitive dysfunctions. Given the psycho-socioeconomic burden due to unhealthy aging in the coming decades, the United Nations has declared 2021–2030 as a decade of healthy aging. In this line, multipotent mesenchymal stromal cell-based therapeutics received special interest from the research community. Based on decades of research on cell therapy, a consensus has emerged that the therapeutic effects of cell therapy are due to the paracrine mechanisms rather than cell replacement. Exosomes, a constituent of the secretome, are nano-sized vesicles that have been a focus of intense research in recent years as a possible therapeutic agent or as a cargo to deliver drugs of interest into the central nervous system to induce neurogenesis, reduce neuroinflammation, confer neuroregeneration/neuroprotection, and improve cognitive and motor functions. In this review, we have discussed the neuroprotective properties of exosomes derived from adult mesenchymal stem cells, with a special focus on the role of exosomal miRNAs. We also reviewed various strategies to improve exosome production and their content for better therapeutic effects. Further, we discussed the utilization of ectomesenchymal stem cells like dental pulp stem cells and their exosomes in treating neurodegenerative diseases.

Chronic caloric restriction triggers unfavorable alterations in cardiac function albeit responsible scenarios remain unclear. This work evaluated the possible involvement of Akt2 in caloric restriction-evoked cardiac geometric and functional changes and responsible processes focusing on autophagy and mitophagy. Akt2 knockout and WT mice were subjected to caloric restriction for 30 weeks prior to assessment of myocardial homeostasis. Caloric restriction compromised echocardiographic parameters (decreased LV wall thickness, LVEDD, stroke volume, cardiac output, ejection fraction, fractional shortening, and LV mass), cardiomyocyte contractile and intracellular Ca²⁺ capacity, myocardial atrophy, interstitial fibrosis and mitochondrial injury associated with elevated blood glucocorticoids, autophagy (LC3B, p62, Atg7, Beclin-1), and mitophagy (Pink1, Parkin, TOM20), dampened cardiac ATP levels, mitochondrial protein PGC1α and UCP2, anti-apoptotic protein Bcl2, intracellular Ca²⁺ governing components Na⁺-Ca²⁺ exchanger, phosphorylation of SERCA2a, mTOR (Ser²⁴⁸¹) and ULK1 (Ser⁷⁵⁷), and upregulated Bax, phospholamban, phosphorylation of Akt2, AMPK, and ULK1 (Ser⁵⁵⁵), the responses except autophagy markers (Beclin-1, Atg7), phosphorylation of AMPK, mTOR and ULK1 were negated by Akt2 ablation. Levels of CDK1 and DRP1 phosphorylation were overtly upregulated with caloric restriction, the response was reversed by Akt2 knockout. Caloric restriction-evoked changes in cardiac remodeling and cardiomyocyte function were alleviated by glucocorticoid receptor antagonism, Parkin ablation and Mdivi-1. In vitro experiment indicated that serum deprivation or glucocorticoids evoked GFP-LC3B accumulation and cardiomyocyte dysfunction, which was negated by inhibition of Akt2, CDK1 or DRP1, whereas mitophagy induction reversed Akt2 ablation-evoked cardioprotection. These observations favor a protective role of Akt2 ablation in sustained caloric restriction-evoked cardiac pathological changes via correction of glucocorticoid-induced mitophagy defect in a CDK1-DRP1-dependent manner.

Aims

This review explores the mechanisms, diagnostic approaches, and management strategies for COVID-19-induced liver injury, with a focus on its impact on patients with pre-existing liver conditions, liver cancer, and those undergoing liver transplantation.

Materials and methods

A comprehensive literature review included studies on clinical manifestations of liver injury due to COVID-19. Key areas examined were direct viral effects, drug-induced liver injury, cytokine storms, and impacts on individuals with chronic liver diseases, liver transplants, and the role of vaccination. Data were collected from clinical trials, observational studies, case reports, and review literature.

Key findings

COVID-19 can cause a spectrum of liver injuries, from mild enzyme elevations to severe hepatic dysfunction. Injury mechanisms include direct viral invasion, immune response alterations, drug toxicity, and hypoxia-reperfusion injury. Patients with chronic liver conditions (such as alcohol-related liver disease, nonalcoholic fatty liver disease, cirrhosis, and hepatocellular carcinoma) face increased risks of severe outcomes. The pandemic has worsened pre-existing liver conditions, disrupted cancer treatments, and complicated liver transplantation. Vaccination remains crucial for reducing severe disease, particularly in chronic liver patients and transplant recipients. Telemedicine has been beneficial in managing patients and reducing cross-infection risks.

Significance

This review discusses the importance of improved diagnostic methods and management strategies for liver injury caused by COVID-19. It emphasizes the need for close monitoring and customized treatment for high-risk groups, advocating for future research to explore long-term effects, novel therapies, and evidence-based approaches to improve liver health during and after the pandemic.

GBM is the most common, aggressive, and intracranial primary brain tumor; it originates from the glial progenitor cells, has poor overall survival (OS), and has limited treatment options. In this decade, GBM immunotherapy is in trend and preferred over several conventional therapies, due to their better patient survival outcome. This review explores the clinical trials of several immunotherapeutic approaches (immune checkpoint blockers (ICBs), CAR T-cell therapy, cancer vaccines, and adoptive cell therapy) with their efficacy and safety. Despite significant progress, several challenges (viz., immunosuppressive microenvironment, heterogeneity, and blood-brain barrier (BBB)) were experienced that hamper their immunotherapeutic potential. Furthermore, these challenges were clinically studied to be resolved by multiple combinatorial approaches, discussed in the later part of the review. Thus, this review suggests the clinical use and potential of immunotherapy in GBM and provides the holistic recent knowledge and future perspectives.

Aim

Transcriptional regulation of gene expression plays a crucial role in orchestrating complex morphogenetic and molecular events during heart development and function. Mediator complex is an essential multi-subunit protein complex that governs gene expression in eukaryotic cells. Although Mediator subunits (MEDs) work integrally in the complex, individual MED component displays specialized functions. MED27, categorized as an Upper Tail subunit, possesses an as-yet-uncharacterized function. In this study, we aimed to investigate the physiological role of MED27 in cardiomyocytes.

Materials and methods

we generated a Med27 floxed mouse line, which was further used to generate constitutive (cKO) and inducible (icKO) cardiomyocyte-specific Med27 knockout mouse models. Morphological, histological analysis and cardiac physiological studies were performed in Med27 cKO and icKO mutants. Transcriptional profiles were determined by RNA sequencing (RNAseq) analysis.

Key fundings

Ablation of MED27 in developing mouse cardiomyocytes results in embryonic lethality, while its deletion in adult cardiomyocytes leads to heart failure and mortality. Similar to the ablation of another Upper Tail subunit, MED30 in cardiomyocytes, deletion of MED27 leads to decreased protein levels of most MEDs in cardiomyocytes. Interestingly, overexpression of MED30 fails to restore the protein levels of Mediator subunits in MED27-deficient cardiomyocytes, demonstrating that the role of MED27 in maintaining the integrity and stability of the Mediator complex is independent of MED30.

Significance

Our results revealed an essential role of MED27 in cardiac development and function by maintaining the stability of the Mediator core.

Multiple myeloma, the second most common hematological malignancy, remains incurable with a 5-year survival rate of approximately 50 % and recurrence rates near 100 %, despite significant attempts to develop effective medicines. Therefore, there is a pressing demand in the medical field for innovative and more efficient treatments for MM. Currently, the standard approach for treating MM involves administering high-dose chemotherapy, which frequently correlates with improved results; however, one major limiting factor is the significant side effects of these medications. Furthermore, the strategies used to deliver medications to tumors limit their efficacy, whether by rapid clearance from circulation or an insufficient concentration in cancer cells. Cancer treatment has shifted from cytotoxic, nonspecific chemotherapy regimens to molecularly targeted, rationally developed drugs with improved efficacy and fewer side effects. Nanomedicines may provide an effective alternative way to avoid these limits by delivering drugs into the complicated bone marrow microenvironment and efficiently reaching myeloma cells. Putting drugs into nanoparticles can make their pharmacokinetic and pharmacodynamic profiles much better. This can increase the drug's effectiveness in tumors, extend its time in circulation in the blood, and lower its off-target toxicity. In this review, we introduce several criteria for the rational design of nanomedicine to achieve the best anti-tumoral therapeutic results. Next, we discuss recent advances in nanomedicine for MM therapy.

Adipose tissue dysfunction is a key feature of metabolic syndrome, which increases the risk of periodontitis, an inflammatory disease induced by bacteria that affects the gingiva and other components of periodontal tissue. Recent studies indicate that molecules from inflamed periodontal tissue contribute to adipose tissue dysfunction. However, the cellular mechanisms and interactions between adipose tissue and gingiva driving the progression of metabolic and periodontal conditions remain unclear. To address this, we developed a chimeric (mouse/human) co-culture tissue model (which identifies the origins of species-specific cytokines) to investigate these interactions. Using tissue-specific functional cells and immunocytes, we constructed equivalents of adipose tissue (ATE) and gingiva (GTE), co-cultivating them under inflammatory conditions induced by bacterial endotoxin, lipopolysaccharide (LPS). Our findings showed that exposure to LPS resulted in a notable reduction in lipid accumulation, GLUT4 expression, and adiponectin secretion in ATE, along with increased macrophage colonies forming around lipid droplets, as well as elevated levels of triglyceride, leptin, and IL-6. In GTE, LPS triggered significant inflammatory responses, characterized by increased macrophage accumulation, elevated COX-2 expression, and heightened secretion of inflammatory cytokines. LPS also reduced epithelial thickness and the expression of keratin 19 and collagen IV, indicating impaired barrier function and gingival integrity. Co-culturing ATE with GTE exacerbated these LPS-induced harmful effects in both tissues. In conclusion, our findings suggest that interplay between gingiva and adipose tissue can intensify the inflammatory and dysfunctional changes caused by LPS. This co-culture tissue model offers a valuable tool for future studies on periodontitis and metabolic syndrome.

Heading aims

Based on the current knowledge of the molecular mechanisms by which m6A influences ferroptosis, our objective is to underscore the intricate and interdependent relationships between m6A and the principal regulatory pathways of ferroptosis, as well as other molecules, emphasizing its relevance to diseases associated with this cell death mode.

Materials and methods

We conducted a literature search using the keywords “m6A and ferroptosis” across PubMed, Web of Science, and Medline. The search was limited to English-language publications from 2017 to 2024. Retrieved articles were managed using Endnote software. Two authors independently screened the search results and reviewed the full texts of selected articles.

Key findings

Abnormal m6A levels are often identified as critical regulators of ferroptosis. Specifically, “writers”, “readers” and “erasers” that dynamically modulate m6A function regulate various pathways in ferroptosis including iron metabolism, lipid metabolism and antioxidant system. Additionally, we provide an overview of the role of m6A-mediated ferroptosis in multiple diseases and summarize the potential applications of m6A-mediated ferroptosis, including its use as a therapeutic target for diseases and as diagnostic as well as prognostic biomarkers.

Significance

N6-methyladenosine (m6A) modification, a prevalent RNA modification in eukaryotic cells, is crucial in regulating various aspects of RNA metabolism. Notably, accumulating evidence has implicated m6A modification in ferroptosis, a form of iron-dependent cell death characterized by elevated iron levels and lipid peroxide accumulation. Overall, this review sheds light on the potential diagnostic and therapeutic applications of m6A regulators in addressing conditions associated with ferroptosis.

Aims

Parkinson's disease (PD) is a common neurodegenerative disease that has received widespread attention; however, current clinical treatments can only relieve its symptoms, and do not effectively protect dopaminergic neurons. The purpose of the present study was to investigate the therapeutic effects of human umbilical cord mesenchymal stem cell-derived exosomes loaded with brain-derived neurotrophic factor (BDNF-EXO) on PD models and to explore the underlying mechanisms of these effects.

Main methods

6-Hydroxydopamine was used to establish in vivo and in vitro PD models. Western blotting, flow cytometry, and immunofluorescence were used to detect the effects of BDNF-EXO on apoptosis and ferroptosis in SH-SY5Y cells. The in vivo biological distribution of BDNF-EXO was detected using a small animal imaging system, and dopaminergic neuron improvements in brain tissue were detected using western blotting, immunofluorescence, immunohistochemistry, and Nissl and Prussian blue staining.

Key findings

BDNF-EXO effectively suppressed 6-hydroxydopamine-induced apoptosis and ferroptosis in SH-SY5Y cells. Following intravenous administration, BDNF-EXO crossed the blood–brain barrier to reach afflicted brain regions in mice, leading to a notable enhancement in neuronal survival. Furthermore, BDNF-EXO modulated microtubule-associated protein 2 and phosphorylated tau expression, thereby promoting neuronal cytoskeletal stability. Additionally, BDNF-EXO bolstered cellular antioxidant defense mechanisms through the activation of the nuclear factor erythroid 2-related factor 2 signaling pathway, thereby conferring neuroprotection against damage.

Significance

The novel drug delivery system, BDNF-EXO, had substantial therapeutic effects in both in vivo and in vitro PD models, and may represent a new treatment strategy for PD.