Current molecular medicine最新文献

Most chronic respiratory diseases often lead to the clinical manifestation of pulmonary fibrosis. Inflammation and immune disorders are widely recognized as primary contributors to the onset of pulmonary fibrosis. Given that macrophages are predominantly responsible for inflammation and immune disorders, in this review, we first focused on the role of different subpopulations of macrophages in the lung and discussed the crosstalk between macrophages and other immune cells, such as neutrophils, regulatory T cells, NKT cells, and B lymphocytes during pulmonary fibrogenesis. Subsequently, we analyzed the interaction between macrophages and fibroblasts as a possible new research direction. Finally, we proposed that exosomes, which function as a means of communication between macrophages and target cells to maintain cellular homeostasis, are a strategy for targeting lung drugs in the future. By comprehending the mechanisms underlying the interplay between macrophages and other lung cells, we aim to enhance our understanding of pulmonary fibrosis, leading to improved diagnostics, preventative measures, and the potential development of macrophage-based therapeutics.

Hypoxia, characterized by insufficient oxygen supply to tissues, is a significant factor in tumor growth and resistance to treatment. The hypoxia-inducible factor (HIF) signaling pathway is activated when oxygen levels decline, influencing cell activities and promoting tumor progression. HIF-1α and HIF-2α are the main targets for therapeutic intervention in tumors. Nevertheless, the significance of HIF-2α is often overlooked. This review examines the physiological role of HIF-2α in tumor growth and its involvement in tumor growth. HIFs, composed of hypoxia-responsive α and oxygeninsensitive β subunits, play a crucial role in controlling gene expression in both normal and solid tumor tissues under low oxygen levels. HIF-3α, formerly considered a detrimental modulator of HIF-regulated genes, exerts a transcriptional regulatory role by inhibiting gene expression through competition with HIF-1α and HIF-2α for binding to transcriptional sites in target genes under hypoxia. Recent research indicates that various HIF-3 variants exhibit distinct and potentially contrasting functionalities. Hypoxia often occurs during the initiation and progression of cancer formation. Recent research has discovered that HIF-2α, also known as endothelial PAS domain protein 1, has a significant impact on tumors. HIF-2α is a significant cancer-causing gene and a crucial predictor of prognosis in non-small cell lung cancer. However, due to limited research investigating the relationship between HIF-2α and small-cell lung cancer, it is not possible to reach a definitive conclusion. HIF-2α plays a vital function in cancer by preserving the stemness of cancer cells. This review provides a comprehensive overview of HIF-2 and the role of HIF-3 in various cancer-related processes, as well as its potential as a targeted therapeutic approach.

Background: Gastric Cancer (GC) has become one of the most important causes of cancer-related deaths worldwide due to its intractability. Studying the mechanisms of gastric carcinogenesis, recurrence, and metastasis, and searching for new therapeutic targets have become the main directions of today's gastric cancer research. Lactate is considered a metabolic by-product of tumor aerobic glycolysis, which can regulate tumor development through various mechanisms, including cell cycle regulation, immunosuppression, and energy metabolism. However, the effects of genes related to lactate metabolism on the prognosis and tumor microenvironmental characteristics of GC patients are unknown.

Methods: In this study, we have collected gene expression data of gastric cancer from The Cancer Genome Atlas (TCGA) and identified differentially expressed genes in gastric cancer using the "Limma" software package.

Results: 76 differentially expressed lactate metabolism-related genes were screened, and then the Least Absolute Shrinkage and Selection Operator (LASSO) and Cox regression analysis were employed that identified 8 genes, constructed Lactate Metabolism-related gene signals (LMRs), and verified the reliability of the prognostic risk mapping by using TCGA training set and TCGA internal test set. Finally, the functional enrichment analysis was employed to identify the molecular mechanism.

Conclusion: Eight lactate metabolism-related genes were constructed into a new predictive signal that better predicted the overall survival of gastric cancer patients and can guide clinical decisions for more precise and personalized treatment.

miRNA-21 is regarded as both an abundant and highly conserved member of the microRNA (miRNA) family. It is expressed in virtually every cell and is responsible for critical regulatory actions that are important in health and disease. This microRNA has been shown to potentially have a role in the pathogenesis of several immune-related disorders, including autoimmune diseases, such as Multiple sclerosis and systemic lupus erythematosus, as two prominent examples of diseases that might be involved. In the current research, we looked at the role of miRNA-21, regarded as one of the most significant pathogenic miRNAs with a role in the development of autoimmune illness.

Background: A biocompatible polymeric nanoparticle, TQ-PLGA-PF68, was developed through the interaction of the phytochemical thymoquinone (TQ) encapsulated in poly(L-lactide-co-glycolide)-b-poly(ethylene glycol) (PLGA-PEG) with Pluronics F68. So far, this combination has not been assessed on breast cancer cells resistant to anti-cancer drugs. Therefore, this study aimed to assess the cell death caused by TQ-PLGA-PF68 nanoparticles, particularly in resistant breast cancer cell lines expressing estrogen receptor (ER) positivity, such as TamR MCF-7.

Methods: The antiproliferative activity of TQ-PLGA-PF68 nanoparticles was measured using the MTS assay. The cytotoxic effects were further evaluated through colony formation assay and scratch-wound healing assay. Terminal deoxynucleotidyl transferase dUTP Nick End Labeling (TUNEL) assay was performed to determine the characteristics of the apoptosis as well as cell cycle arrest induced by TQ-PLGA-PF68 nanoparticles. The localization of these nanoparticles in the cells was examined using Transmission Electron Microscopy (TEM).

Results: With a TQ concentration of 58.5 μM encapsulated within the nanoparticles, cytotoxicity analysis revealed a significant inhibition of cell proliferation (p<0.05). This finding was corroborated by the results of the colony formation assay. Treatment with TQ-PLGA-PF68 nanoparticles significantly decreased the number of surviving TamR MCF-7 cells by 35% (p<0.001) compared to untreated TamR MCF-7 cells. Concurrently, the scratch-wound healing assay indicated a closure rate of 50% versus >80% (p<0.05) in untreated TamR MCF-7 cells at 12 hours post-wounding. The TUNEL assay successfully confirmed the apoptosis characteristics associated with cell cycle arrest. TEM observation confirmed the cellular internalization of these nanoparticles, suggesting the in vitro therapeutic potential of the formulation.

Conclusion: In this study, a significant functional change in TamR MCF-7 cells induced by the TQ nanoparticles was observed. The unique incorporation of TQ into the PLGA-PEG and Pluronics F68 formulation preserved its bioactivity, thereby reducing the migratory and proliferative traits of drug-resistant cells. This discovery may pave the way for exploring the application of biocompatible polymeric TQ nanoparticles as a novel therapeutic approach in future studies pertaining to resistant breast cancer.

Background: Inflammation, infection, autoimmune diseases, or malignancy can cause the abnormal proliferation of lymphocytes; therefore, clinicians should always take detailed history and physical examination to screen the patient for lymphadenopathy.

Objectives: The aim and objective of the current study was to assess the pattern of diseases causing lymphadenopathies in the Pakistani Population.

Methodology: The current study was a cross-sectional study. Data were obtained from existing patient records from Dow Diagnostic Research and Reference Laboratory [DDRRL]-Dow University of Health Sciences [DUHS] from Jan 2020 to Dec 2022. Patients undergoing chemotherapy and biopsies with poor preservation and inconclusive diagnosis were excluded from the study, while patients of any age, gender, and various sites of lymphadenopathy were included in this study. Ethical approval was obtained from the ethical Review Board [IRB] of Dow University of Health Sciences [DUHS].

Results: A total of 675 FNAC and lymph node biopsies of lymph nodes were obtained. Age, location, and gender were taken into consideration when analyzing the lymph node biopsy materials of these patients. There were 200 [29.62%] males and 475 [70.37%] females. The age range of the patients was 1 year to 80 years, and the mean [SD] age of the patients was 33.76 ± 17.54 years.

Conclusion: In the current study, we aim to provide guidance to the clinician on initial diagnostic laboratory testing, imaging, and the potential need for biopsy by evaluating the pattern of diseases causing lymphadenopathy in our population.

Vitamin C plays a significant role in various physiological functions. Humans depend on external sources of vitamin C due to the loss of the L-gulono-γ-lactone oxidase (GULO) gene that contributes to the synthesis of vitamin C. During the evolutionary loss of the GULO gene, physical, chemical, and biological factors were different from the present environmental settings. Besides the evolutionary genetic loss of the GULO gene, there is a gap in the insightful discussion on the potential implications of the non-functional GULO gene towards the predisposition of humans to cancer that faces hostile and carcinogenic environments. Various methods by which vitamin C modulates cellular processes related to cancer, including DNA repair, epigenetic changes, and redox balance, are discussed. Furthermore, we present experimental and clinical evidence indicating that vitamin C deficiency promotes tumor growth, metastasis, and therapy resistance, emphasizing its potential as a cancer phenotypic modulator. Therapeutic implications of restoring vitamin C levels in cancer treatment range from improving the efficacy of conventional medicines to exploiting metabolic vulnerabilities in tumors. The relevance of assessing vitamin C status in cancer patients and the basis for additional research into vitamin C supplementation as an adjuvant therapy is emphasized. This paper presents a comprehensive overview of the implications associated with the functional deficiency of the GULO gene in human subjects exhibiting diverse tumor hallmarks, encompassing ECM remodeling, hypoxia, epigenetic reprogramming, oxidative stress, and drug responsiveness.

Background: Hippo signaling regulates the behavior and fate of mesenchymal stem cells (MSCs), which are crucial for the repair and cure of acute respiratory distress syndrome (ARDS). However, whether 2-deoxy-D-glucose (2-DG), a specific activator of Hippo signaling, would further enhance the reparative effect of MSCs in ARDS remains unclarified.

Objective: This study aimed to determine whether 2-DG could promote the proliferation, differentiation, migration, and resistance to oxidative stress of mouse bone marrow-derived MSCs (mBMSCs).

Methods: mBMSCs were isolated from C57BL/6 mice and differentiated into alveolar type II epithelial (ATII) cells by noncontact coculture. The specific activator and inhibitor 2-DG and 4-[(5,10-dimethyl-6-Oxo-6,10-dihydro-5h-pyrimido[5,4-B]thieno[3,2- E][1,4]diazepin-2-Yl)amino]benzenesulfonamide (XMU-MP-1) were used to activate and inhibit Hippo signaling, respectively. Oxidative stress-induced injuries were induced by H₂O₂ treatment.

Results: We observed that 2-DG activated Hippo signaling and promoted mBMSC proliferation in a dose-dependent manner. 2-DG also promoted the differentiation of mBMSCs into ATII cells and enhanced not only the horizontal and vertical migration of mBMSCs but also mBMSC homing to injured lung tissue. H₂O₂ treatment inhibited Hippo signaling and reduced the viability of mBMSCs by decreasing the Bcl-2/Bax ratio, but 2-DG activated Hippo signaling and conferred mBMSCs with resistance to oxidative stress by increasing the Bcl-2/Bax ratio. However, XMU-MP-1 suppressed these effects to some extent.

Conclusion: Through Hippo signaling, 2-DG promoted the proliferation, migration, differentiation, and resistance to oxidative stress of mBMSCs, suggesting a novel strategy for enhancing the reparative effects of MSCs in ARDS.

Background: The transcription factor AP1 plays a crucial role in the proliferation, apoptosis, and terminal differentiation of epidermal keratinocytes.

Objective: This study aimed to clarify whether the subunit of AP1, FOSL1 protein, can be used to assess the exacerbation of psoriasis by evaluating its changes in protein and mRNA levels in cultured epidermal keratinocytes and skin specimens of the patients prescribed with bathwater PUVA (Psoralen and UVA) therapy. This study aimed to investigate FOSL1, a subunit of the transcription factor AP-1, as a potential biomarker for psoriasis by examining its protein and mRNA expression in skin specimens from patients undergoing bathwater PUVA (Psoralen and UVA) therapy and cultured epidermal keratinocytes.

Methods: The distribution of FOSL1 in patients' skin was explored by immunohistochemistry. Changes in gene and protein expression were quantitatively assessed by qPCR and ELISA, respectively.

Results: Immunohistochemistry analysis revealed that FOSL1 accumulated in lesional skin. The expression of FOSL1 significantly increased during disease flare-ups but decreased following the treatment with bathwater PUVA therapy. Furthermore, silencing FOSL1 led to a marked reduction in the expression of ten FOSL1 target genes associated with the disease.

Conclusion: Our study suggests that FOSL1 shows potential as a biomarker for psoriasis. This is supported by two key findings: first, the expression of FOSL1 correlates with disease activity, and second, its expression is linked to changes in the expression of genes previously implicated in the pathogenesis of psoriasis, namely MMP1, MMP9, IVL, CCNA2, CCL2, HMOX1, PLAU, PLAUR, and THBD.