Current Molecular Medicine - Volume 24, Issue 7, 2024

Bladder cancer (BC) is one of the most common malignant tumors worldwide and poses a significant hazard to human health. During the development of BC, hypoxia plays a crucial role. Hypoxia-inducible factor (HIF) is a key transcription factor for hypoxic adaptation, which regulates the transcription of various genes, including inflammation, angiogenesis, and glycolytic metabolism. Recent studies have shown the precise role of HIF in various biological behaviors of BC. More importantly, a new antitumor medication targeting HIF-2 has been used to treat renal cancer. However, therapies targeting HIF-1 in BC have not yet been developed. In this review, we discussed how HIF-1 is expressed and affects the growth, metastasis, and angiogenesis of BC. At the same time, we investigated several HIF-1 inhibitors that provide new perspectives for targeting HIF-1.

Sepsis is a fatal organ dysfunction caused by the host's uncontrolled response to infection, with high morbidity and mortality. Early diagnosis and intervention are the most effective methods to reduce the mortality due to sepsis. However, there is still a lack of definite biomarkers or intervention targets for the diagnosis, evaluation, prognosis, and treatment of sepsis. Long non-coding RNAs (lncRNAs) are a type of noncoding transcript with a length ranging from 200 to 100,000 nucleotides. LncRNAs mainly locate in the cytoplasm and nucleus and participate in various signaling pathways related to inflammatory reactions and organ dysfunction. Recent studies have reported that lncRNAs are involved in regulating the pathophysiological process of sepsis. Some classical lncRNAs have been confirmed as promising biomarkers to evaluate the severity and prognosis of sepsis. This review summarizes the mechanical studies on lncRNAs in sepsis-induced acute lung, kidney, myocardial, and liver injuries, analyzes the role of lncRNAs in the pathogenesis of sepsis, and explores the possibility of lncRNAs as potential biomarkers and intervention targets for sepsis-induced multiple organ dysfunction.

Extracorporeal membrane oxygenation (ECMO) is identified as a novel therapeutic strategy that offers short-term support to the metabolism of the heart and lungs in humans. Recently, the clinical centers, which provide ECMO has increased rapidly worldwide. The indications for the use of ECMO in daily clinical practice were broadened dynamically. However, even with the widespread adoption of ECMO, it still remains significant morbidity and mortality, and the underlying mechanisms are still not elucidated. Notably, one of the vital complications during ECMO was proposed as the inflammatory progression within the extracorporeal circulation. via the development of inflammatory response, patients with ECMO may further suffer from systemic inflammatory response syndrome (SIRS), posing serious risks to human health. Recently, growing evidence confirmed that through exposure of blood into the ECMO circuit could lead to the stimulation of the immune system which also facilitated the inflammatory response and systemic impaired. In the current review, the pathological development of inflammatory progression in patients with ECMO is well-listed. Furthermore, the relationship between immune-related activation and the development of inflammation is also summarized, which may further help us to decide the therapeutic strategies in daily clinical practice.

Metabolic reprogramming in cancer cells is a strategy to meet high proliferation rates, invasion, and metastasis. Also, several researchers indicated that the cellular metabolism changed during the resistance to chemotherapy. Since glycolytic enzymes play a prominent role in these alterations, the ability to reduce resistance to chemotherapy drugs is promising for cancer patients. Oscillating gene expression of these enzymes was involved in the proliferation, invasion, and metastasis of cancer cells. This review discussed the roles of some glycolytic enzymes associated with cancer progression and resistance to chemotherapy in the various cancer types.

Resveratrol (Res), a polyphenol found in red wine, has been shown to decelerate aging, the progressive loss of physiological integrity and cellular senescence, characterized by the inability to progress through the cell cycle. No successful clinical trials have yet to be completed in humans on dose limitations. Yet, the potent anti-aging and anti-senescence efficacy of Res has been documented in several in vivo animal models. In this review, we highlight the molecular mechanisms of Res efficacy in antiaging disorders, such as diabetes, neurodegenerative disorders, eye diseases, and cardiovascular diseases.

Truly miraculous medications and antibiotics have helped save untold millions of lives. Antibiotic resistance, however, is a significant issue related to health that jeopardizes the effectiveness of antibiotics and could harm everyone's health. Bacteria, not humans or animals, become antibiotic-resistant. Bacteria use quorum-sensing communication routes to manage an assortment of physiological exercises. Quorum sensing is significant for appropriate biofilm development. Antibiotic resistance occurs when bacteria establish a biofilm on a surface, shielding them from the effects of infection-fighting drugs. Acylated homoserine lactones are used as autoinducers by gram-negative microscopic organisms to impart. However, antibiotic resistance among ocular pathogens is increasing worldwide. Bacteria are a significant contributor to ocular infections around the world. Gram-negative microscopic organisms are dangerous to ophthalmic tissues. This review highlights the use of elective drug targets and treatments, for example, combinational treatment, to vanquish antibiotic-resistant bacteria. Also, it briefly portrays anti-biotic resistance brought about by gram-negative bacteria and approaches to overcome resistance with the help of quorum sensing inhibitors and nanotechnology as a promising medication conveyance approach to give insurance of anti-microbials and improve pathways for the administration of inhibitors of quorum sensing with a blend of anti-microbials to explicit target destinations and penetration through biofilms for treatment of ocular infections. It centres on the methodologies to sidestep the confinements of ocular anti-biotic delivery with new visual innovation.

Background: The developmental biology for the nonalcoholic fatty liver disease and coronary heart disease are known but elaborative ideas of triglycerides phenomenon in the embryo-genesis of the liver and the heart are still not clear. Objective: The aim of the study was to relate different triglycerides like LXRα, LPL, LDL R, PPARG-, SREBP-1C expression in the high fat fed mice with the normal fed diet mice in the process of developmental and embryo-genesis biology. Methods: Tissue preparation was done by ripalysis. Different protein content was obtained via western blot for the 6 samples namely a-17.5 days mice embryo heart; b- 0th day or the birthday mice infant heart; c-1 week mice infant heart; d-2 weeks mice infant heart; e-3 weeks mice infant heart; f-Adult mice heart. Protein lysates from the heart tissues of the mice was obtained via homegenization and centrifugation. Hematoxylin and Eosin (H and E) was done to see the fat droplets in the liver tissues at the different developmental stages. Result: LXRα,SREBP-1C expression in 17.5 days mice embryo heart and 0th day or the birthday mice infant heart is highly expressed in the high fat diet. LDL-R in the high fat diet mice is increased in 2 weeks mice infant heart but in17.5 days mice embryo heart and in 0th day or the birthday mice infant heart it is low expression but from 1week mice infant heart to the adult mice heart the expression is in decreasing trend. Similarly LPL is highly expressed in17.5 days mice embryo heart and 1 week mice infant heart and thus low expression in decreasing order until adult mice heart.Thus, these results collectively shows that maternal HF diet increases expression of proteins such as LPL, LDLr in the embryo phase and thus getting normal expressions in the adult phase that facilitate Triglycerides (TAG) hydrolysis across the liver and the heart. Also,maternal high fat diet increases the SREBP1c expression, leading to stimulation of LPL Expression. Conclusion: In summary, using a pregnant mice model, we found that maternal high fat diet increases the fetal fat accumulation. Elevated placental LPL activity and expression of genes that facilitate placental lipid transport suggest that enhanced placental lipid transport may play a key role in maternal nutrition and obesity-induced fetal fat accumulation.

Background: The role of deficiency of vitamin D in a wide range of human cancer, including breast cancer, has been proven, but its role in benign breast diseases remains unknown. This study aimed to determine the prevalence of vitamin D deficiency in patients with fibrocystic breast (FB) disease. Methods: First, the hospital prevalence of fibrocystic breast was determined by a crosssectional study. Then, patients were divided into two groups by a case-control study; women with confirmed fibrocystic breasts based on breast pain, physical examination, and ultrasonography were included as a case group (N=48), and age-matched women without fibrocystic breasts were also included as a control group (N=48). After recording the demographic and gynecological characteristics and exposure to the sun, gynecological records, and family history of fibrocystic breast, the blood sample was taken to determine vitamin D. Data were analyzed by Stata software. Results: The result indicated that the studied groups had significant differences in regards to weight, breast pain, the severity of breast pain, breast heaviness, family history of fibrocystic breast, history of breast disease, caffeine consumption, and exposure to sunlight (p <0.05), but did not show significant differences based on age, occupation, education, gynecological history, diabetes mellitus, hypertension, obesity and hypothyroidism, vegetable, fast food, and dairy products consumption. The frequency of vitamin D deficiency in the case group was 45.8%, and in the control group, it was 20.8%, and there was a statistically significant difference (p <0.05). Conclusion: Vitamin D deficiency is more common in women with fibrocystic breast disease and may play a role in the development of the disease.

Background: Cartilage injuries are currently the most prevalent joint disease. Previous studies have emphasized the use of stem cells as the effective treatment for regenerating cartilage damage. Objective: In this study, considering the difficulties of the cellular therapy method, it was hypothesized that human synovial fluid-derived mesenchymal stem cell (hSFMSC) exosomes as a SC source could be used to treat these injuries as a safer and cell-free therapeutic alternative procedure due to its direct relevance to cartilage regeneration. Moreover, this study aimed to determine the miRNA and target genes required for the formation of SC treatment combined with gene therapy in order to reveal the mechanism of cartilage regeneration and increase its effectiveness. Methods: MSCs were characterized by flow cytometry, and immunocytochemical and differentiation analyses were done. To characterize functionally isolated exosomes, in vitro uptake analysis was performed. RT-qPCR was used to examine in terms of the advantages of cellular and cell-free therapy, mature human chondroblasts derived by differentiation from hSF-MSCs and human chondrocyte profiles were compared in order to demonstrate the above profile of hSF-MSCs and exosomes isolated from them, and the effectiveness of SC therapy in repairing cartilage damage. Results: According to our findings, the expression level of hsa-miR-155-5p was found to be considerably higher in chondrocytes differentiated from human synovial fluid MSCs than in mature human chondrocytes. These findings were also supported by the TGF-signalling pathway and chondrogenesis marker genes. Conclusion: It was concluded that hSF-MSCs and exosomes can be used in the treatment of cartilage damage, and hsa-miR-155-5p can be used as a target miRNA in a new gene therapy approach because it increases the therapeutic effect on cartilage damage.

Background: The identification in breast cancer (BC) of novel genetic biomarkers regulating natural killer (NK) cell function, including the HLA, KIR, and CD16A (FCGR3A), may be still a challenge. Objective: We aimed to evaluate whether the combined effect of these polymorphisms has an impact on BC susceptibility and progression. Methods: 47 BC Italian patients and healthy individuals (39 females and 66 males/ females) were genotyped by Sanger sequencing (HLA-C exon 2-4 and FCGR3A- 158V/F, 48L/R/H) and PCR-SSP typing (KIR genes). Results: HLA-C gene allele analysis showed the group C1, with HLA-C*07:02:01 allele, to be significantly associated with tumor progression (16.7% vs. 4.0%, p=0.04, OR=4.867), and instead, group C2, with HLA-C*05:01:01, was protective against disease susceptibility (0.0% vs. 7.2%, p=0.019, OR=0.087). In addition, we highlighted a significant reduction of the KIR2DS4ins in BC patients (pcorr.=0.022) and an increased combined presence of KIR2DL1 and KIR2DS1 genes in advanced BC patients compared to earlier stages (66.7% vs. 19.2%, p=0.002). The concurrent lack of KIR2DL2 and KIR2DS4 genes in the presence of HLA-C2 alleles was significantly associated with increased susceptibility to BC (p=0.012, OR=5.020) or with lymph node involvement (p=0.008, OR=6.375). Lastly, we identified different combinations of the FCGR3A-48/158 variants and KIR genes in BC patients compared to controls. Conclusion: Our findings suggest that in the development of BC probably exists a disorder of the NK innate immunity influenced by KIR/HLA-C gene content and FCGR3A-158 polymorphisms and that the combined analysis of these biomarkers might help predict genetic risk scores for tailored screening of BC patients in therapy.

Aims and objectives: Semaphorin3A (Sema3a) is lowly expressed in the peripheral blood of gastric cancer patients, suggesting Sema3a may be involved in the progression of gastric cancer. Nevertheless, the specific role and the potential regulatory mechanism of Sema3a in gastric cancer is still obscure. Neuropilin-1 (NRP-1) has been reported to interact with Sema3a; herein, we intended to reveal the role and regulatory mechanism of Sema3a/neuropilin-1 (NRP-1) in gastric cancer progression. Methods: Cell transfection was carried out to regulate gene expression. CCK-8 and colony formation assays were applied to estimate cell proliferation. Scratch assay and transwell assay were conducted to assess the cell migration and invasion abilities. Angiogenesis ability was assessed using a tubule-forming assay. The expression of corresponding genes and proteins were detected by RT-qPCR and western blot, respectively. Results: Data showed that Sema3a was downregulated in gastric cancer cells and NRP-1 was upregulated. Sema3a overexpression repressed NRP-1 level in AGS cells. Overexpression of Sema3a inhibited cell proliferation, migration, and invasion abilities as well as epithelial-mesenchymal transition (EMT) of AGS cells. Overexpression of Sema3a inhibited tube formation and reduced the expression of VEGFA/VEGFR2 in AGS cells. However, the effects of Sema3a overexpression on the malignant behaviors in AGS cells were partly reversed by NRP-1 overexpression. Additionally, Sema3a overexpression enhanced the inhibitory effects of Ramucirumab, an anti-VEGFR2 agent, on the proliferative, migratory, and invasive capabilities as well as EMT in AGS cells. Conclusion: In conclusion, Sema3a alleviates the proliferation, migration, invasion, and angiogenesis capabilities of gastric cancer cells via repressing NRP-1. This finding may provide potential targets for gastric cancer therapy.

Background: Neuropathic pain is chronic and affects the patient’s life. Studies have shown that IRF5 and CXCL13/CXCR5 are involved in neuropathic pain; however, their interactions are unknown. Objective: In this study, a rat neuropathic pain model was constructed by inducing chronic compression injury (CCI). IRF5 recombinant lentiviral vector and CXCL13 neutralizing antibody were administered to investigate their action mechanisms in neuropathic pain. Consequently, the new strategies for disease treatment could be evolved. Methods: The CCI rats were intrathecally injected with recombinant lentivirus plasmid LV-IRF5 (overexpression), LV-SH-IRF5 (silencing), and CXCL13 neutralizing antibody. Mechanical withdrawal threshold (MWT) and thermal withdrawal latency (TWL) were measured. The tumor necrosis factor (TNF)-alpha, interleukin (IL)-1β, and IL-6 levels were recorded via the enzyme-linked immunosorbent assay (ELISA). The spinal cord was stained using hematoxylin–eosin (HE). The binding of IRF5 to CXCL13 was analyzed by chromatin immunoprecipitation (ChIP) and dual luciferase reporter assay. The IRF5, neuronal nuclei (NeuN), CXCL13, and CXCR5 expressions were detected through quantitative real-time polymerase chain reaction and Western blot. Results: The MWT and TWL values in the CCI group were lower than in the Sham group. The expressions of CXCL13, CXCR5, and IRF5 in CCI rats were gradually increased with the modeling time. IRF5 silencing suppressed the expression of NeuN and lumbar enlargement in CCI rats and promoted MWT and TWL. Moreover, IRF5 silencing inhibited the expressions of CXCR5 and CXCL13 genes and down-regulated the expression levels of inflammatory factors. IRF5 was directly and specifically bound with the endogenous CXCL13 promoter and thus regulated it. IRF5 overexpression exacerbated the disease phenotype of CCI-induced neuropathic pain in rats. Administration of CXCL13 neutralizing antibodies reversed the IRF5 overexpression effects. Conclusion: The IRF5 silencing alleviated neuropathic pain in CCI rats by downregulating the pain threshold, inflammatory cytokine levels, and CXCL13/CXCR5 signaling. IRF5 overexpression exacerbated the disease parameters of CCI-induced neuropathic pain in rats; however, they were reversed by neutralizing antibodies against CXCL13.