Journal of Molecular Histology最新文献

Wound healing is a complex process involving molecular and structural interactions. Transforming growth factor β (TGF-β), the renin-angiotensin system (RAS), and other important mediators play a central role on wound healing process. This study examined the dynamics of healing in healthy, hypertensive, and diabetic rats treated with or without Losartan, focusing on healing rate, scar characteristics, and molecular modulation. Macroscopic and microscopic analyses revealed delayed healing and reduced collagen deposition in diabetic and hypertensive rats compared with normoglycemic controls. Losartan affected healing by regulating TGF-β expression and collagen organization. In the groups of hypertensive and diabetic rats treated with losartan, healing aesthetics improved by less collagen deposition and consequently minor chances to fibrosis development, probably due to lower TGFβ and SMADs expression. Diabetic rats showed reduced skin and collagen fiber thickness, whereas hypertensive rats showed better healing under Losartan treatment (LT). These results demonstrate the complex interactions between LT, diabetes and hypertension on important fibrotic and inflammatory pathways. Although LT successfully reduces TGF-β expression and classical SMAD signaling in hypertensive settings, its minor effect in diabetes conditions indicate the necessity of supplemental treatments that target mechanisms unique to hyperglycemia, such as glycation end products or oxidative stress inhibitors. To improve treatment outcomes for individuals with diabetes and hypertension comorbidities, future studies should investigate the combination of multi-pathway modulators.

A significant correlation between type 2 diabetes mellitus (T2DM) and mood has been reported. However, the specific mechanism of mood’s role in T2DM is unclear. This study aims to discover mood-related biomarkers in T2DM and further elucidate their underlying molecular mechanisms. The GSE81965 and GSE55650 datasets were sourced from public databases, and mood-related genes (MRGs) were retrieved from previous literature. Initially, differentially expressed MRGs (DE-MRGs) were obtained by combining differential expression analysis and weighted gene co-expression network analysis (WGCNA). Subsequently, the DE-MRGs were incorporated into the LASSO and SVM to identify diagnostic biomarkers for T2DM. Four machine learning methods were utilized to construct the diagnostic models in T2DM, and the model with the optimal algorithm was screened. Further, based on biomarkers, functional enrichment, immune infiltration, and regulatory network analyses were conducted to excavate deeper into the pathogenesis of T2DM. In vivo experiments were used to validate the expression of the biomarkers. A total of 23 DE-MRGs were identified by overlapping 723 DEGs and 64 key modules, and there were strong positive correlations between these DE-MRGs. Afterward, KCTD16, SLC8A1, RAB11FIP1, and RASGEF1B were identified as biomarkers associated with mood in T2DM, and they had favorable diagnostic performance. Meanwhile, the RF diagnostic model constructed based on biomarkers was performed optimally and had high diagnostic accuracy for T2DM patients. Animal experiments indicated that expression levels of SLC8A1, RAB11FIP1, and RASGEF1B in T2DM were consistent with the microarray results. In conclusion, KCTD16, SLC8A1, RAB11FIP1, and RASGEF1B were identified as biomarkers related to mood in T2DM.

Neuroblastoma (NB) is a prevalent extracranial malignant neuroendocrine tumor in children, originating from the sympathetic nervous system. This study aims to investigate new therapeutic targets for NB. The differentially expressed genes were screened by analyzing the GSE35133 and GSE90689 datasets. Hub genes were identified by constructing a protein–protein interaction network. The diagnostic value of the hub genes was assessed through the analysis of receiver operating characteristic (ROC) curves and the expression, prognosis, and immune infiltration of IFI27 in pan-cancer were analyzed on the online website Sangerbox. The hub gene expression levels were validated by performing real-time reverse transcriptase-polymerase chain reaction. The functions of IFI27 in NB were investigated by Cell Counting Kit-8, 5-ethynyl-2'-deoxyuridine, wound healing, and Transwell assays. Six candidate genes (IFI27, TNFSF10, IFI44, DDX58, HIST1H1C, and HIST1H1E) were identified as potential diagnostic biomarkers for NB. The expression levels of IFI27, TNFSF10, IFI44, and DDX58 were significantly decreased, while HIST1H1C and HIST1H1E were elevated. Notably, IFI27 displayed correlations with prognosis and immune infiltration in multiple tumors. In vitro, functional assays demonstrated that the knockdown of IFI27 promoted the proliferation, migration, and invasion of U251 cells. Conversely, in SK-N-AS cells, IFI27 overexpression inhibited cell proliferation, migration, and invasion. IFI27 was lowly expressed in NB and participated in the progression of NB, which provides a new insight into the pathogenic mechanism and novel therapeutic strategy for NB.

Alzheimer disease (AD) is a neurodegenerative condition. Thymoquinone (TQ) is a natural compound that possesses beneficial biological effects on the brain. The present study evaluates the protective impact of TQ on the cerebellum in rats with AlCl3-induced Alzheimer's disease. Four groups were utilized. Control: 20 rats that were subdivided into two subgroups. Ia: received distilled water for 4 weeks. Ib: received corn oil via oral gavage (1 ml/kg daily) for 4 weeks. TQ group: 10 rats received TQ in corn oil via oral gavage (20 mg/kg daily) for 4 weeks. AD group:10 rats received AlCl3 in distilled water via oral gavage (300 mg/kg daily) for 4 weeks. AD & TQ group: 10 rats received both AlCl3 & TQ for 4 weeks. The grip period in the rotarod test decreased, escape latency in first three days and the entry latency period to the quadrant with the removed escape platform in the Morris water maze test increased in AD group, but when TQ was administered concurrently, there was a noteworthy improvement. Meanwhile, when compared to AD group, the addition of TQ showed a significant decrease (P < 0.05) in levels of malondialdehyde (MDA) and nitric oxide (NO), associated with a significant increase (P < 0.05) in reduced glutathione (GSH) level. Furthermore, AD & TQ group exhibited substantial preservation of the cerebellum's histological structure, the Purkinje cells number and transverse diameter showed a high significant increase (P < 0.001) and a significant increase (P < 0.05), respectively in comparison to the AD group. Using TQ showed improvement in behavioral tests, biochemical and histological findings. Thus, TQ might have therapeutic effects on Alzheimer’s disease.

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.