Journal of Molecular Histology最新文献

An endometrioid carcinogenic pathway of the fallopian tube with possible potential precursors including type II SCOUTs (secretory cell outgrowths) and E-TIN (endometrioid tubal intraepithelial neoplasia) has been recently documented. We report an incidental focus of E-TIN identified in a hysterectomy specimen for Grade 1 endometrioid type endometrial carcinoma. The lesion was present at the fimbriated end of left fallopian tube involving 1 plica. It comprised crowded glandular proliferation with a pseudostratified columnar lining. The cells displayed elongated nuclei with no remarkable nuclear atypia.

Immunohistochemistry showed patchy loss of PAX 2 expression with multifocal aberrant nuclear and cytoplasmic staining for B-catenin. p53 was wild-type and ER was positive.

In view of the co-existing endometrioid type endometrial carcinoma, a possible metastatic spread to the fallopian tube was considered. However, morphologically no obvious nuclear atypia noted, and no associated inflammatory response or desmoplastic stromal reaction identified within the tubal lesion. And on immunostaining, the endometrial tumour was distinct from the tubal lesion. For instance, PTEN was negative/lost in the endometrial tumour but retained in the tubal lesion and B-catenin was membranous in the endometrial tumour but aberrant with multifocal nuclear and cytoplasmic overexpression in the tubal lesion. WT1 was negative in the endometrial tumour but positively expressed by the tubal lesion. All the above findings favoured the possibility of the tubal lesion as being independent of the endometrial primary. In conclusion, we describe an incidental B-catenin aberrant endometrioid type proliferation of the fallopian tube/E-TIN, to raise awareness of such lesions.

Valproic acid (VPA) is a well-known and increasingly documented antiepileptic drug that has been widely used in the treatment of epilepsy and/or epilepsy-related disorders. Prolonged clinical use of VPA has been reported to cause side effects such as nephrotoxicity. Edaravone (EDA) is a powerful free radical scavenger. The aim of the study was to investigate the protective effects of EDA against VPA-induced oxidative renal injury. Four experimental groups were formed by randomly assigning thirty-eight male Sprague Dawley rats. The first group, (Control Group, n = 8), consisted of healthy rats. The second group, (Group II, n = 10), comprised control rats given intraperitoneally EDA (30 mg/kg/day) for seven days. The third group (Group III, n = 10) was administered intraperitoneally only VPA (500 mg/kg/day) for seven days. The last group (Group IV, n = 10) was treated with VPA + EDA for seven days. On the 8th day, kidney tissues were immediately removed from rats. In kidney homogenates, reduced glutathione levels and Na/K⁺-ATPase, paraoxonase1 and prolidase activities were remarkably decreased while catalase, superoxide dismutase, glutathione peroxidase, glutathione reductase, myeloperoxidase, and xanthine oxidase activities and lipid peroxidation, protein carbonyl, advanced oxidized protein products, and hydroxyproline contents were notably elevated in VPA given group. Consistently, administration of EDA decreased renal degenerative changes seen in the kidney tissue of VPA given rats. Treatment with EDA in the VPA group significantly resulted in the recovery of both biochemical and histopathological alterations. As a result, EDA is potentially beneficial to revert oxidative renal damage induced by VPA.

To seek out the targeting of Escherichia coli outer membrane vesicles (E. coli OMVs) in breast tumor-bearing mice and their biosafety in healthy mice. Ultrafiltration in conjunction with ultracentrifugation was utilized to concentrate E. coli OMVs, and characterize them. Subcutaneous breast tumors were induced in BALB/c mice to serve as an experimental model, and the biodistribution of E. coli OMVs in both tumor-bearing and healthy mice was monitored using an in vivo fluorescence imaging system. Utilizing frozen sections, the infiltration of E. coli OMVs in tumor tissues was appraised at the 24-hour post-injection. Healthy BALB/c mice were randomly divided into control group and vesicles group. Following the intravenous injection of E. coli OMVs, monitoring encompassed variations in body weight, blood routine indices, serum levels of AST, ALT, and BUN, organ indices (heart, liver, spleen, lung, and kidney), along with tissue histopathology over a 14-day period. The spherical E. coli OMVs had a diameter of (155.8 ± 3.1) nm and exhibited the expression of outer membrane proteins OmpA and OmpC. Upon assessment, it was evident that the E. coli OMVs persisted in the tumor tissues even 24 h post-injection. An evident decrease in the body weight of the vesicles group, distinct from the control group, was observed on the second day after injection (P < 0.001); in contrast, no considerable differences were noted at subsequent time points (P > 0.05). Following the injection, the vesicles group displayed notable reductions in WBC and PLT as relative to the control group (P < 0.0001) on the initial day, however, there were no noteworthy distinctions as opposed to the control group for other hematological indices; No notable variances in hematological indices between the two groups were observed on the seventh and fourteenth day (P > 0.05). Over the 14 days, no substantial differences were observed in the serum levels of BUN, AST, ALT, and organ indices within the vesicles group as opposed to the control group (P > 0.05). Furthermore, there were no obvious abnormal changes in tissue morphology. 0.5 mg/kg of E. coli OMVs can safely and effectively target 4T1 breast tumor in mice.

Glyphosate-based herbicides are extensively utilized in Neotropical agriculture for weed control. Despite their widespread application, concerns regarding water contamination and its consequential impacts on aquatic organisms persist. Notably, there remains a dearth of studies investigating the effects of glyphosate on Neotropical fish species. This study aimed to address this gap by investigating the morphophysiological effects of this herbicide on the liver, gills, and ovaries of Astyanax altiparanae, an ecological and economically important neotropical fish species. Forty individuals were acclimated for 15 days before being exposed to different concentrations of glyphosate (65, 280, and 1000 µg/L) for 28 days. Histological and histometric analyses were conducted on liver, gill, and ovary samples. The findings revealed significant alterations in fish physiology following exposure to glyphosate. The hepatosomatic index increased markedly across all concentration levels, accompanied by dilation of hepatic sinusoidal capillaries, particularly pronounced at higher concentrations. Gill samples exhibited congestion in the central venous sinus, lamellar fusion, and cell death. Additionally, the exposed fish showed a decrease in gonadosomatic index, and the mature females an increase in pre-vitellogenic follicles and a decrease in vitellogenic follicles. This study detected adverse morphophysiological impacts of glyphosate-based herbicides on A. altiparanae, even at permitted concentrations. These findings emphasize the necessity for further research and improved management strategies to mitigate environmental risks associated with herbicide use in aquatic ecosystems.

Background

Cyclophosphamide (CP)-induced hepatotoxicity is a significant problem in clinical settings. This study aimed to evaluate the protective effect of levocabastine (LEV) on CP-induced hepatotoxicity in Swiss albino mice.

Methods and results

Mice were given CP (toxic drug) 200 mg/kg, i.p., once on the 7th day, and LEV 50 and 100 µg/kg, i.p., and fenofibrate (FF) 80 mg/kg, p.o., daily for 14 days. On the 15th day, blood and liver samples were collected to assess biological parameters. CP 200 mg/kg caused hepatotoxicity due to oxidative stress, inflammation, apoptosis, and fibrosis as manifested by a reduction in catalase, reduced glutathione (GSH), superoxide dismutase (SOD), and an increase in thiobarbituric acid reactive substance (TBARS), nitrite, tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), transforming growth factor-beta 1 (TGF-β1), interleukin-1β (IL-1β), alkaline phosphatase (ALP), alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma-glutamyl transferase (GGT) levels. Cleaved caspase-3 and nuclear factor kappa-B (NF-κB) expression was also increased and nuclear factor erythroid 2-related factor (Nrf2) expression was decreased as confirmed by Immunohistochemical analysis. It also caused histopathological abnormalities and fibrosis as manifested by Hematoxylin-Eosin (H&E) and Masson’s trichrome (MT) staining. These alterations were returned to almost normal when treated with LEV 100 µg/kg and FF 80 mg/kg. Thus, LEV protected CP-induced hepatotoxicity by reversing inflammation, apoptosis, fibrosis, oxidative stress, hepatic injury, and histopathological damages.

Conclusion

LEV can be helpful as an adjuvant in cancer patients who are on CP treatment, to minimize toxicity. However, its role in in-vivo cancer model is further needed to be confirmed.

N-ethyl-N-nitrosourea (ENU) as n-nitrosamine and alkylating agent, ubiquitous within living cells and in the environment can act as a full carcinogen and induce tumor formation in various tissues such as liver. In this study, gallic acid-loaded chitosan nanoparticles (GANPs) were synthesized and evaluated for their chemopreventive effect against ENU-induced hepatotoxicity and mortality in rats. Twenty-four male Wistar rats were divided into four groups including: control, ENU (single doses of 50 mg/kg via intraperitoneal injection), GA + ENU and GANPs + ENU. Animals were orally pretreated with GA (50 mg/kg) and GANPs (50 mg/kg) for 30 days, and liver injuries induced by ENU on the 31st day of study. After ENU administration, weight changes and mortality were monitored during 30 days, and then the animals were sacrificed and alpha-fetoprotein (AFP) as a tumor marker, liver function tests (ALT, AST and ALP), oxidative stress markers (GSH and MDA), mitochondrial toxicity parameters, and histopathological assessment were evaluated. Except for AFP and MDA, ENU caused significant elevation of liver enzymes, mitochondrial ROS formation, collapse of mitochondrial membrane potential depletion of GSH, histopathological abnormalities and mortality in rats. Our data showed that GANPs significantly increased the survival of rats by up to 66%, delayed in death time and prevented weight changes after exposure to ENU. Moreover, GANPs restored liver enzyme levels, ROS formation, mitochondrial dysfunction, GSH levels, and histopathological abnormalities towards normal. Our findings suggest that GANPs revealed a significant protective effect against deadly toxicity induced by ENU as an alkylating full carcinogen agent in liver tissue.

Graphical Abstract

Diabetic nephropathy (DN) is a leading cause of end-stage kidney failure, contributing to elevated morbidity and mortality rates in individuals with diabetes. Despite its potential renoprotective effects, the molecular mechanism by which gastrodin (GSTD) impacts DN remains unclear. To investigate this, mice were initially induced with DN via intraperitoneal streptozotocin (STZ) injection (50 mg/kg) and subsequently treated with varying doses of GSTD (5, 10, 20 mg/kg). Furthermore, the potential molecular mechanism of GSTD in mitigating DN was explored in vivo in conjunction with compound C, an inhibitor of 5’-AMP-activated protein kinase (AMPK). Subsequently, the blood weight, fasting blood glucose levels, and renal injury markers of DN-afflicted mice were assessed. Additionally, renal tissues were subjected to quantitative reverse-transcriptase-polymerase chain reaction (qRT-PCR) and enzyme-linked immunosorbent assay (ELISA) to evaluate inflammatory factor levels, colorimetric assays to measure renal malondialdehyde (MDA) levels, and immunoblotting analysis to examine AMPK/nuclear factor erythroid 2-related factor 2 (Nrf2) pathway. The results demonstrated that a 6-week GSTD regimen effectively improved metabolic manifestations associated with DN, including reductions in fasting blood glucose levels, 24-hour urine output, renal indices, amelioration of glomerular histopathological abnormalities, diminished glycogen accumulation, and fibrosis. Furthermore, DN-afflicted renal tissues exhibited decreased MDA levels and elevated expression of AMPK/Nrf2 pathway-associated proteins. The beneficial effects of GSTD on DN and its protein modulation were reversed upon co-intervention with compound C. Together, our findings imply that GSTD improves DN by activating the AMPK/Nrf2 pathway, thereby mitigating STZ-induced renal damage, inflammatory responses, and oxidative stress.

Claudins (CLDNs) play a crucial role in regulating the permeability of epithelial barriers and can impact tumor behavior through alterations in their expression. However, the precise mechanisms underlying the involvement of CLDNs in breast cancer progression remain unclear. This study aimed to investigate the role of CLDN11 in breast cancer progression. Utilizing the TCGA database and clinical specimens from breast cancer patients, we observed reduced expression of CLDN11 in tumor tissues, which correlated with poor prognosis in breast cancer patients. In vitro, silencing of CLDN11 enhanced the proliferative and migratory characteristics of breast cancer cell lines MCF-7 and MDA-MB-231. Mechanistically, CLDN11 deficiency promoted the upregulation of Forkhead Box M1 (FOXM1) by activating the hedgehog signaling pathway, thereby sustaining tumor progression in breast cancer. In vivo, blockade of hedgehog signaling suppressed the tumor progression induced by CLDN11 silencing. Our study highlights the significance of the CLDN11/FOXM1 axis in breast cancer progression, suggesting CLDN11 as a potential diagnostic indicator and therapeutic target for clinical therapy.

Type 1 diabetes (T1D) is characterized by an autoimmune-mediated destruction of pancreatic beta cells and a chronic inflammatory state, which may influence the progression of colorectal cancer (CRC) through immune system dysregulation and enhanced tumor immune evasion. This study aims to elucidate the role of p65 in modulating the tumor microenvironment in CRC within the context of T1D and to determine how this modulation affects tumor growth, immune cell infiltration, and the expression of immune evasion molecules such as CEACAM5. NOD mice, which model T1D, were inoculated with MC38 colon carcinoma cells engineered to knock down p65. Tumor growth was monitored, and the tumor microenvironment was analyzed using flow cytometry to assess the infiltration of immune cells. The expression of Ki-67 and CEACAM5 in tumor cells was also evaluated. Additionally, in vitro assays were conducted to study the proliferation and activation of T cells co-cultured with tumor cells. Knockdown of p65 in tumor cells significantly inhibited tumor growth in NOD mice. This was accompanied by an increased infiltration of cytotoxic CD8+ T cells and no significant change in CD4+ or Foxp3 + T regulatory cells within the tumor microenvironment. There was a notable reduction in the expression of Ki-67 and CEACAM5, indicating decreased proliferation and potential immune evasion capabilities of the tumor cells. Our findings demonstrate that the NF-κB p65 subunit plays a crucial role in promoting tumor growth and modulating the immune microenvironment in CRC, particularly in the context of T1D. Knocking down p65 not only reduces tumor progression but also enhances the anti-tumor immune response by decreasing immune evasion mechanisms. These results suggest that targeting the NF-κB pathway may be a viable strategy to improve the efficacy of cancer immunotherapy, especially in patients with autoimmune diseases like T1D. Physical activity enhances the effect of immune checkpoint blockade by inhibiting the intratumoral HIF1-α/CEACAM5 axis.

Background

Diabetes mellitus represents a prominent global health concern, characterized by a rising prevalence rate. Type 2 Diabetes Mellitus (T2DM) is purported to be associated with an intricate interplay of genetic, environmental, and lifestyle factors. While some progress have been made in T2DM management, controlling associated complications remains a great challenge in medicine.

Objectives

This study investigated a synthesized Imidazolyl Thiazolidinedione antidiabetic agent (PA9), focusing on serum parameters.

Methods

Streptozotocin-induced diabetic rats (n = 6) were subjected to orally treatment with PA9 (synthesized by Shakour et al. in an equal dose of a standard drug, 0.011 mmol/kg). The study conducted to measure some specific serum factors, including lipid profiles, liver and kidney enzymes, cardiac enzymes, and oxidative stress markers, both before and after treatment.

Results

The study findings indicated that PA9 effectively ameliorates hyperlipidemia by significantly reducing total cholesterol and triglyceride levels in serum. Additionally, PA9 demonstrated hepatoprotective effects against TZD-induced injuries, as evidenced by decreased levels of alanine transaminase and, alkaline phosphatase. In addition, PA9 also exhibited a modulatory effect on a cardiac injury marker, creatine kinase MB. Moreover, PA9 demonstrated antioxidant properties by reducing oxidative stress markers and enhancing the activities of catalase, thiol, and superoxide dismutase.

Conclusions

The synthesized TZD compound (PA9) stands out as a highly promising agent for the management of diabetes. Its significant antihyperlipidemic effects, preventive influences on organ injuries, and demonstrated efficacy in reducing oxidative stress marker (SOD) make it therapeutic agent in diabetes management. This study lays the groundwork for innovative strategies in diabetes management.

Graphical abstract

The impact of imidazolylthiazolidinedione (PA9) on serum parameters in diabetic rats.