Life sciences最新文献

Cancer Stem Cells (CSCs) are highly tumorigenic, chemoresistant, and immune evasive. They emerge as a central driver that gives rise to the bulk of tumoral mass, modifies the tumor microenvironment (TME), and exploits it, leading to poor clinical outcomes for patients with cancer. The existence of CSCs thus accounts for the failure of conventional therapies and immune surveillance. Identifying CSCs in solid tumors remains a significant challenge in modern oncology, with the use of cell surface markers being the primary strategy for studying, isolating, and enriching these cells. In this review, we explore CSC markers, focusing on the underlying signaling pathways that drive CSC self-renewal, which simultaneously makes them intrinsically chemoresistant and immune system evaders. We comprehensively discuss the autonomous and non-autonomous functions of CSCs, with particular emphasis on their interactions with the tumor microenvironment, especially immune cells. This reciprocal network enhances CSCs malignancy while compromising the surrounding niche, ultimately defining therapeutic vulnerabilities associated with each CSC marker. The most common CSCs surface markers addressed in this review—CD44, CD133, ICAM1/CD54, and LGR5—provide insights into the interplay between chemoresistance and immune evasion, two critically important phenomena in disease eradication. This new perspective on the state-of-the-art of CSCs will undoubtedly open new avenues for therapy.

Parkinson's disease (PD) is a common and progressively worsening neurodegenerative disorder characterized by abnormal protein homeostasis and the degeneration of dopaminergic neurons, particularly in the substantia nigra pars compacta. The prevalence of PD has doubled in the past 25 years, now affecting over 8.5 million individuals worldwide, underscoring the need for effective management strategies. While current pharmacological therapies provide symptom relief, they face challenges in treating advanced PD stages.

Recent research highlights the therapeutic benefits of retinoic acid (RA) in PD, demonstrating its potential to mitigate neuroinflammation and oxidative stress, regulate brain aging, promote neuronal plasticity, and influence circadian rhythm gene expression and retinoid X receptor heterodimerization. Additionally, RA helps maintain intestinal homeostasis and modulates the enteric nervous system, presenting significant therapeutic potential for managing PD.

This review explores RA as a promising alternative to conventional therapies by summarizing the molecular mechanisms underlying its role in PD pathophysiology and presenting up-to-date insights into both preclinical and clinical studies of RA in PD treatment. It also delves into cutting-edge formulations incorporating RA, highlighting ongoing efforts to refine therapeutic strategies by integrating RA into novel treatments.

This comprehensive overview aims to advance progress in the field, contribute to the development of effective, targeted treatments for PD, and enhance patient well-being. Further research is essential to fully explore RA's therapeutic potential and validate its efficacy in PD treatment.

Phosphocreatine (PCr), a naturally occurring creatine phosphorylated molecule, is a high-energy phosphate compound that is one of the most important substances involved in cell energy metabolism, and also has anti-apoptosis and anti-oxidative stress effects. It is precisely because of its role in maintaining energy homeostasis that PCr is widely used in diseases related to energy damage. In the regulation of cell signal, PCr mainly plays a role through MAPK, NF-κB, PI3K/AKT, ERK/Nrf2/HO-1 and JAK2/STAT3. In clinical applications, PCr is commonly used as a cardioprotective drug, such as ischemic heart disease, myocardial fibrosis, myocardial infarction, arrhythmia, and myocarditis. In recent years, further research on PCr has found that PCr also has a positive role in the treatment of other diseases, including diabetes-induced liver injury, kidney injury, cerebral ischemia-reperfusion injury, and neurodegenerative diseases. In this paper, the literature on PCr in three databases, Web of Sciences, SciFinder, and PubMed, was summarized and analyzed, and the research progress of PCr in recent years was reviewed, hoping to provide help for the expansion of its application in clinical therapy.

Aims

The RNA-binding protein LSM7 is essential for RNA splicing, acting as a key component of the spliceosome complex; however, its specific role in breast cancer (BC) has not been extensively investigated.

Materials and methods

LSM7 expression in BC samples was evaluated through bioinformatics analysis and immunohistochemistry. The impact of LSM7 on promoting metastatic tumor characteristics was examined using transwell and wound healing assays, as well as an orthotopic xenograft model. Additionally, the involvement of LSM7 in alternative splicing of CD44 was explored via RNA immunoprecipitation and third-generation sequencing. The regulatory role of TCF3 in modulating LSM7 gene expression was further elucidated using luciferase reporter assays and chromatin immunoprecipitation.

Key findings

Our findings demonstrate that LSM7 was significantly overexpressed in metastatic BC tissues and was associated with poor prognostic outcomes in patients with BC. LSM7 overexpression markedly increased the migratory and invasive capabilities of BC cells in vitro and significantly promoted spontaneous lung metastasis in vivo. Furthermore, RIP-seq analysis revealed that LSM7 binded to CD44 RNA, enhancing the expression of its alternatively spliced isoform CD44s, thereby driving BC metastasis and invasion. Additionally, the transcription factor TCF3 was found to activate LSM7 transcription by directly binding to its promoter.

Significance

In summary, this study highlights the pivotal role of LSM7 in the production of the CD44s isoform and the promotion of breast cancer metastasis. Targeting the TCF3/LSM7/CD44s axis may offer a promising therapeutic strategy for breast cancer treatment.

Aims

Cognitive dysfunction and systemic disease activity are common manifestations of neuropsychiatric systemic lupus erythematosus (NPSLE), a condition that affects a patient's health and quality of life. Clinical and preclinical studies have demonstrated that intermittent fasting (IF) improves health conditions and quality of life. Therefore, we aimed to test whether IF improves cognitive dysfunction and systemic disease activities in mice with NPSLE and to examine the underlying mechanisms.

Main methods

NPSLE-prone MRL/lpr mice underwent 8 weeks of alternate-day fasting or ad libitum feeding, followed by behavioral tests to assess cognitive manifestations and biochemical tests to evaluate systemic disease activities.

Key findings

IF significantly improved cognitive functionality, decreased blood-brain barrier permeability, and reduced the activation of astrocytes and microglia in the hippocampi of MRL/lpr mice. IF also improved systemic disease activities, including reduced kidney glomerular injury and interstitial inflammation, peripheral blood autoantibody titer, and splenic T lymphocyte contents. Mechanistic studies demonstrated that IF attenuates cognitive dysfunction by facilitating the microglial transition to the M2-like phenotype via the AMPK/PPARγ/NF-κB pathway.

Significance

Together, observations from this study suggest a potential therapeutic benefit of IF in the treatment of cognitive dysfunction in patients with NPSLE.

Repurposing antidiabetic drugs for the treatment of Alzheimer's disease (AD) has emerged as a promising therapeutic strategy. This review examines the potential of repurposing antidiabetic drugs for AD treatment, focusing on preclinical evidence, clinical trials, and observational studies. In addition, the review aims to explore challenges and opportunities in repurposing antidiabetic drugs for AD, emphasizing the importance of well-designed clinical trials that consider patient selection criteria, refined outcome measures, adverse effects, and combination therapies to enhance therapeutic efficacy. Preclinical evidence suggests that glucagon-like peptide-1 (GLP-1) analogs, dipeptidyl peptidase-4 (DPP4) inhibitors, metformin, thiazolidinediones, and sodium-glucose co-transporter-2 (SGLT2) inhibitors exhibit neuroprotective effects in AD preclinical models. In preclinical studies, antidiabetic drugs have demonstrated neuroprotective effects by reducing amyloid beta (Aβ) plaques, tau hyperphosphorylation, neuroinflammation, and cognitive impairment. Antidiabetic drug classes, notably GLP-1 analogs and SGLT2 inhibitors, and a reduced risk of dementia in patients with diabetes mellitus. While the evidence for DPP4 inhibitors is mixed, some studies suggest a potential protective effect. On the other hand, alpha-glucosidase inhibitors (AGIs) and sulfonylureas may potentially increase the risk, especially in those experiencing recurrent hypoglycemic events. Repurposing antidiabetic drugs for AD is a promising therapeutic strategy, but challenges such as disease heterogeneity, limited biomarkers, and benefits versus risk evaluation need to be addressed. Ongoing clinical trials in mild cognitive impairment (MCI) and early AD patients without diabetes will be crucial in determining the clinical efficacy and safety of the antidiabetic drugs, paving the way for potential treatments for AD.

Background

Lung ischemia-reperfusion injury (LIRI) poses a significant challenge in various clinical scenarios. Despite extensive research on the pathogenesis and potential treatments of LIRI, there is a notable absence of bibliometric analysis.

Materials and methods

We summarized the results of LIRI research through two searches on the Web of Science, covering data from 1979 to 2023 with topic words “lung” and “reperfusion injury”. The collected data were analyzed and visualized based on country, author(s), and keywords by bibliometric software. The keyword “programmed cell death” was further added to explore the hotspot of the LIRI research field.

Results

The initial analysis of 1648 research articles showed a total of 40 countries and 7031 researchers were involved in the publications, with America being the most productive country in the research field of LIRI. Keyword analysis revealed that the evolving focus of LIRI research has progressively transitioned from, lung transplantation, primary graft dysfunction, inflammation, oxidative stress, and ex vivo lung perfusion to cell death. Subsequently, 212 publications specifically addressing programmed cell death (PCD) in LIRI were identified, which clarified the recent hotspot of the LIRI field.

Conclusion

With closer international cooperation and increasing research scale, the LIRI research focused mainly on the pathogenesis and potential therapeutic interventions for LIRI. PCD in LIRI is becoming a trending topic and will continue to be a hotspot in this field. Our study may offer valuable guidance for future research endeavors concerning LIRI.

It is known that the cannabinoid type 2 (CB2) receptor has an anti-inflammatory role. Therefore, animals without CB2 receptors show enhanced inflammation and pain in the model of chronic pain, e.g., neuropathic pain. We previously proposed the upregulated leptin signaling at the peripheral nerve as one of the underlying molecular mechanisms of pain exacerbation in nerve-injured CB2 knockouts, as they displayed robust upregulation of leptin receptors and leptin signaling in the peripheral nerve. Due to these past results, we hypothesized that CB2 receptor deficiency might also modify the peripheral neuroinflammation led by chronic exposure to a high-fat diet (HFD). Interestingly, CB2 knockout animals showed significant resistance to HFD-induced neuroinflammation. Namely, 5-week feeding of HFD induced substantial hypersensitivity in WT animals, while tactile sensitivity of HFD-fed CB2 knockouts remained intact. HFD-fed WT animals also displayed the robust upregulation of chemokine CXCR4 expression with increased macrophage infiltration, which was never observed in HFD-fed CB2 knockout mice. Moreover, 5-week HFD exposure led significant increase of CD11b⁺Ly6G⁻Ly6C^high cells and a decrease of CD11b⁺Ly6G⁺Ly6C^low cells in the spleen of WT animals, which was also not found in either HFD-fed CB2 knockouts or standard diet-fed WT and CB2 animals. Together with past reports, these results suggest that CB2 receptors might have a double-sided regulatory role in the context of inflammation development or, more widely, immune system regulation. We propose that CB2 signaling is not always anti-inflammatory and could take a pro-inflammatory role depending on the cause of the inflammation.

Myocardial ischemia-reperfusion injury (MIRI) is an injury to cardiomyocytes due to restoration of blood flow after myocardial infarction (MI). It has recently gained much attention in clinical research with special emphasis on the roles of mitochondrial autophagy and inflammation. A mild inflammatory response promotes recovery of post-ischemic cardiomyocyte function and vascular regeneration, but a severe inflammatory response can cause irreversible and substantial cellular damage. Similarly, moderate mitochondrial autophagy can help inhibit excessive inflammation and protect cardiomyocytes. However, MIRI is aggravated when mitochondrial function is disrupted, such as inadequate clearance of damaged mitochondria or excessive activation of mitophagy. How to moderately control mitochondrial autophagy while promoting its balance with nucleotide-binding oligomerization structural domain receptor protein 3 (NLRP3) inflammasome activation is critical. In this paper, we reviewed the molecular mechanisms of mitochondrial autophagy and NLRP3 inflammasome, described the interaction between NLRP3 inflammasome and mitochondrial autophagy, and the effects of different signaling pathways and molecular proteins on MIRI, to provide a reference for future research.