Journal of Molecular Histology最新文献

Cervical cancer (CC) remains a leading cause of cancer-related mortality in women worldwide, highlighting the urgent need for novel therapeutic strategies. This study investigates the molecular mechanisms and clinical significance of Cell Division Cycle Associated 5 (CDCA5) in cervical cancer progression. We performed comprehensive analyses of CDCA5 expression in cervical cancer and normal tissues, correlating expression levels with clinicopathological features and patient outcomes. Functional studies using CC cell lines (SiHa, HeLa, and CaSki) examined the effects of CDCA5 manipulation on tumor cell behavior. We identified E2F1 as a key transcriptional regulator of CDCA5 and validated our findings using in vivo xenograft models. CDCA5 was significantly upregulated in CC tissues and correlated with advanced disease stages and poor survival outcomes. Mechanistically, CDCA5 depletion in SiHa and HeLa cells suppressed proliferation, migration, and invasion, while its overexpression in CaSki cells enhanced these malignant properties. We identified E2F1 as a transcriptional activator of CDCA5. Importantly, CDCA5 knockdown significantly inhibited tumor growth in nude mouse models. Our findings establish CDCA5 as a critical E2F1-regulated oncogenic factor in cervical cancer progression. The strong correlation between CDCA5 expression and poor clinical outcomes suggests its potential as both a prognostic biomarker and therapeutic target in cervical cancer treatment.

The extracellular matrix guides cell behavior through mechanical properties, which plays a role in determining cell function and can even influence stem cell fate. Compared with adherent culture, the three-dimensional culture environment is closer to the growth conditions in vivo, but is limited by standardization of material properties and observation and measurement methods. Therefore, it is necessary to study the relationship among the three-dimensional morphological characteristics of cells, cytoskeleton, and stem cell differentiation under adherent culture conditions. Here, we control the cell volume by adjusting the cell density, microfilament cytoskeleton tension, and osmotic pressure of the culture environment, and analyze the cell morphological features and differentiation to the osteoblastic and adipogenic lineages. Based on the in vitro and in vivo results, we identify cell volume as the true reflection of the cytoskeleton tension under stress stimuli compared with cell spreading area. By adjusting cell volume, cytoskeletal tension and cell differentiation can be regulated without affecting cell spreading area. Further study shows that the Ras-related small GTPase RAP2 inhibits the activity of mechanical transducers Lamin A/C and YAP1, playing an important role in cell volume regulation of cell differentiation. In summary, our results support the close relationship between cell volume and cytoskeleton tension. The regulatory role of cell volume on cell differentiation is modulated, at least in part, by RAP2-related mechanosensitive pathways. Our insights into how cell volume regulates cell differentiation may build a bridge between two-dimensional and three-dimensional mechanical studies in cell biology.

Malignant tumors are among the major diseases threatening human survival in the world, and advancements in medical technology have led to a steady increase in their detection rates worldwide. Despite unique clinical presentations across the spectrum of malignancies, treatment modalities generally adhere to common strategies, encompassing primarily surgical intervention, radiation therapy, chemotherapy, and targeted treatments. Uncovering the genetic elements contributing to cancer cell proliferation, metastasis, and drug resistance remains a pivotal pursuit in the development of novel targeted therapeutics. Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PPARGC1A/PGC-1α) is a transcriptional coactivator that influences most cellular metabolic pathways. Its aberrant expression is associated with numerous chronic diseases, including diabetes, heart failure, neurodegenerative disorders, and cancer development. This study primarily discusses the structure, physiological functions, regulatory mechanisms, and research advancement concerning the role of PGC-1α in the proliferation and metastasis of malignant tumors. Targeting PGC-1α and its related regulatory pathways for therapeutic interventions holds promise in facilitating precise and individualized oncological treatments. This approach is expected to counteract drug resistance in patients with cancer and offer a novel direction for the treatment of malignant tumors.

Type 2 diabetes mellitus (T2DM) adversely affects various organs, including the brain and its blood barrier. In addition to the brain, hyperglycemia damages the testes. The testes possess blood-tissue barriers that share common characteristics and proteins with the blood-brain barrier (BBB), including breast cancer-resistant protein (BCRP). This study aimed to investigate the impact of uncontrolled DM on the brain and testes, with a specific focus on BCRP. Moreover, it examined the effects of liraglutide (Lira) and denatonium benzoate (DB), a bitter taste receptor agonist, on T2DM. Forty adult male rats were randomized into five groups: normal control, diabetic, diabetic + DB, diabetic + Lira, and diabetic + DB + Lira. T2DM was induced using fructose and streptozotocin (STZ). After eight weeks of treatment, rats were sacrificed, and samples of blood, semen, testes, and brain were collected to evaluate metabolic and semen parameters, oxidative stress, inflammatory markers, histological features of the brain and testes, and BCRP expression. DB and Lira, both individually and in combination, mitigated fructose/STZ-induced hyperglycemia and dyslipidemia. Additionally, they enhanced SOD activity and reduced MDA, TNFα, and IL-6 levels in the brain and testes, alongside improving sperm quality and serum levels of FSH, LH, and testosterone. Rats treated with DB, Lira, or DB + Lira demonstrated improved brain and testicular tissue architecture. BCRP expression was upregulated in the brains and testes of Lira- and DB + Lira-treated rats. These findings indicated that DB positively affects the metabolic profile of T2DM. Furthermore, Lira and DB provided protection against T2DM-induced brain and testicular damage.

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Tumor necrosis factor-α (TNF-α) induces a multitude of actions and consequences in bone and cartilage resorption and immune response augmentation. In this research, we aimed to investigate the effects of TNF-α on osteogenesis parameters in newborn mice. Experimental research was conducted on 42 pregnant mice, dividing into seven groups as follows: control (no injection), vehicle 1 (PBS injection on 7-9th pregnancy days (PD)), vehicle 2 (PBS injection during pregnancy), experimental 1 (injection of 10 ng/kg of TNF-α on 7-9th PD), experimental 2 (injection of 100 ng/kg of TNF-α on 7-9th PD), experimental 3 (injection of 10 ng/kg of TNF-α during pregnancy) and experimental 4 (injection of 100 ng/kg of TNF-α during pregnancy). Immunohistochemical and histomorphologic studies were performed on right lower limb of newborn mice. The expression of osteocalcin and RANK markers and cortical bone thickness showed no significant difference between the groups. There were no significant changes in osteogenesis parameters in this study. Some evidences have demonstrated the dual role of TNF-α on body tissues. However, future investigations should be done to analyze the molecular pathways involved in TNF-α functions and assess the paradoxical effects of TNF-α on osteogenesis.

Although minimal increases in testicular temperature can compromise spermatogenesis and lead to fertility-related problems, the basic mechanism involved in germ cell destruction as a response to heat stress is still unclear. However, necroptosis is known to regulate a number of physiological and pathological events. This study investigated the role of RIPK1/RIPK3 and MLKL, the main regulators of necroptosis, against different heat stresses in testis tissue. Forty-two Wistar albino rats were divided into seven groups: six experimental exposed to heat stress and one control. Heat stress was induced by causing the rats to swim for 30 min daily for 60 days in a water bath at temperatures of 39 °C and 43 °C. Testis tissues were collected while the animals were under anesthesia on the 1st, 7th, and 14th days after 60 days of heat application. The tissues were first fixed in Bouin’s solution. After routine histological procedures, immunohistochemical staining was performed on one-half of the tissues using RIPK1/RIPK3 and MLKL primary antibodies on serially collected 5 μm-thick sections. Immunoblotting analysis was performed on the other half. Analyses revealed an increase in the expression of RIPK1/RIPK3 and MLKL proteins, regulators of necroptosis, in both the 39 °C and 43 °C groups, although this was greater in the tissue exposed to 43 °C heat stress. These molecules were also especially affected by round and elongated spermatids, and reactivity was observed in Leydig cells. In conclusion, exposure to increased temperature may cause RIPK1/RIPK3 and MLKL-mediated cellular changes in the testis.

Persimmon (Diospyros kaki L.) leaves are a traditional medicinal herb used for treating many infectious and inflammatory-related conditions, including wound healing. To validate its traditional use, our study evaluates the acute toxicity and wound-healing effects of methanolic extracts of Persimmon (Diospyros kaki L.) leaves (MEPL) on excisional neck injury in rats. A uniform dorsal neck injury was created for twenty-four Sprague Dawley rats, which were randomly aligned into 4 groups and treated topically twice daily with 0.2 ml of the following: group A, rats treated with 1% CMC; group B, rats received intrasite gel; groups C and D, rats treated with MEPL (0.2 ml of 250 and 500 mg/kg, respectively). The toxicity results showed a lack of physiologic alteration or mortality in rats ingested with an oral dosage of up to 5 g/kg of MEPL. Histological screening of regenerated skin tissues revealed higher deposition of collagen, fibroblast cells, and reduced inflammatory cells in MEPL-treated rats. The topical application of MEPL led to positive modulation of Transforming Growth Factor Beta 1 (angiogenetic factor) in wound tissues, indicating increased tissue regeneration and faster wound contraction. MEPL treatment caused a significant elevation of tissue antioxidants (superoxide dismutase and catalase) and hydroxyproline (collagen) contents while reducing malondialdehyde contents. The inflammatory mediators (TNF-α and IL-6) were lower, and anti-inflammatory cytokines (interleukin 10) were higher in MEPL-treated rats than in the vehicle group. The study outcomes back up the traditional use of MEPL for wound healing, which could be linked with its phytochemicals (flavonoids and terpenoids) that require further isolation and molecular identification.

Long non-coding RNAs (lncRNAs) have emerged as pivotal regulatory molecules in cancer biology. Among these, long intergenic non-protein coding RNA 02418 (LINC02418), a recently identified lncRNA, has been linked to endometrial cancer (EC), although its function and operational mechanisms are largely unclear. The present investigation aims to elucidate the molecular mechanism through which LINC02418 influences EC pathogenesis. We employed Western blotting and quantitative real-time PCR to analyze Ras protein specific guanine nucleotide releasing factor 1 (RASGRF1) and LINC02418 expression profiles in EC tissues and cell lines. Functional analyses, including cell proliferation, migration, and invasion assays, were conducted to evaluate the impact of LINC02418 overexpression on EC cells. Xenograft mouse models were established for in vivo validation. The molecular interactions between LINC02418, miR-494-3p, and RASGRF1 were characterized using luciferase reporter and RNA pull-down assays. LINC02418 expression was significantly downregulated in EC tissues and cell lines compared to their normal counterparts. Forced expression of LINC02418 significantly suppressed EC cell proliferation, migration, and invasion in vitro. In xenograft models, LINC02418 overexpression resulted in reduced tumor burden and enhanced cell death. Mechanistically, LINC02418 enhanced RASGRF1 expression by sequestering miR-494-3p, a finding substantiated by RNA pull-down assays. The tumor-suppressive effects of LINC02418 were partially reversed by RASGRF1 silencing and miR-494-3p overexpression. Clinical analyses revealed that reduced RASGRF1 expression correlated with poor histological differentiation, advanced tumor stages, and decreased overall survival in EC patients. Our findings establish LINC02418 as a tumor suppressor that regulates EC progression through modulation of the miR-494-3p/RASGRF1 axis, highlighting its potential as a therapeutic target in EC treatment.

Genital tract infections are common causes of male infertility, and most of diagnosed men are asymptomatic. This study examined the effect of gallic acid (GA) against lipopolysaccharide (LPS)-induced testicular inflammation. Thirty-two Spraque Dawley, 2.5-3 month-old male rats were separated into four groups (n = 8). Control group; saline at 3 ml/kg, and in the GA group; GA was dissolved in saline, by gavage at 100 mg/kg for 14 days. LPS group; LPS 5 mg/kg as a single dose was given intraperitoneal on the 11th day. LPS + GA group; GA was given for 14 days and LPS 5 mg/kg on the 11th day. After 72 h of LPS injection, all samples were collected. Semen analysis, biochemical assays, histological evaluations, and immunohistochemical or Western blot analyses for nuclear factor-kappa B (NF-κB) and Prokineticin 2/prokineticin receptor 1(PK2/PKR1) pathways were performed. There was a significant decrease in body and testicular weight, sperm parameters, serum testosterone level, mean seminiferous tubule diameter, germinal epithelial thickness, and Johnsen score in the LPS group compared to control and GA groups. However, a significant increase was found in interstitial space width, percentage of abnormal sperm, NF-κB and PK2 immunoreactivities, and expression of PK2 and PKR1 proteins. In the LPS + GA group, GA administration was observed to significantly prevent these adverse effects. In conclusion, the inhibitory effects of GA on the NF-κB and PK2/PKR1 pathways not only suppressed the inflammatory response but also restored impaired sperm parameters and testicular structure. These findings indicate GA’s potential for treating testicular inflammation and protecting male reproductive health.