Sidt2 is a key protein in the autophagy-lysosomal degradation pathway and is essential for the maintenance of kidney structure and filtration function

The regulation and homeostasis of autophagy are essential for maintaining organ morphology and function. As a lysosomal membrane protein, the effect of Sidt2 on kidney structure and renal autophagy is still unknown. In this study, we found that the kidneys of Sidt2−/− mice showed changes in basement membrane thickening, foot process fusion, and mitochondrial swelling, suggesting that the structure of the kidney was damaged. Increased urine protein at 24 h indicated that the kidney function was also damaged. At the same time, the absence of Sidt2 caused a decrease in the number of acidic lysosomes, a decrease in acid hydrolase activity and expression in the lysosome, and an increase of pH in the lysosome, suggesting that lysosomal function was impaired after Sidt2 deletion. The accumulation of autophagolysosomes, increased LC3-II and P62 protein levels, and decreased P62 mRNA levels indicated that the absence of the Sidt2 gene caused abnormal autophagy pathway flow. Chloroquine experiment, immunofluorescence autophagosome, and lysosome fusion assay, and Ad-mcherry-GFP-LC3B further indicated that, after Sidt2 deletion, the production of autophagosomes did not increase, but the fusion of autophagosomes and lysosomes and the degradation of autophagolysosomes were impaired. When incubating Sidt2−/− cells with the autophagy activator rapamycin, we found that it could activate autophagy, which manifested as an increase in autophagosomes, but it could not improve autophagolysosome degradation. Meanwhile, it further illustrated that the Sidt2 gene plays an important role in the smooth progress of autophagolysosome processes. In summary, the absence of the Sidt2 gene caused impaired lysosome function and a decreased number of acidic lysosomes, leading to formation and degradation disorders of the autophagolysosomes, which eventually manifested as abnormal kidney structure and function. Sidt2 is essential in maintaining the normal function of the lysosomes and the physiological stability of the kidneys.

Protective Effects of PACAP in a Rat Model of Diabetic Neuropathy

Pituitary adenylate cyclase-activating peptide (PACAP) is a neuropeptide with a widespread occurrence and diverse effects. PACAP has well-documented neuro- and cytoprotective effects, proven in numerous studies. Among others, PACAP is protective in models of diabetes-associated diseases, such as diabetic nephropathy and retinopathy. As the neuropeptide has strong neurotrophic and neuroprotective actions, we aimed at investigating the effects of PACAP in a rat model of streptozotocin-induced diabetic neuropathy, another common complication of diabetes. Rats were treated with PACAP1-38 every second day for 8 weeks starting simultaneously with the streptozotocin injection. Nerve fiber morphology was examined with electron microscopy, chronic neuronal activation in pain processing centers was studied with FosB immunohistochemistry, and functionality was assessed by determining the mechanical nociceptive threshold. PACAP treatment did not alter body weight or blood glucose levels during the 8-week observation period. However, PACAP attenuated the mechanical hyperalgesia, compared to vehicle-treated diabetic animals, and it markedly reduced the morphological signs characteristic for neuropathy: axon–myelin separation, mitochondrial fission, unmyelinated fiber atrophy, and basement membrane thickening of endoneurial vessels. Furthermore, PACAP attenuated the increase in FosB immunoreactivity in the dorsal spinal horn and periaqueductal grey matter. Our results show that PACAP is a promising therapeutic agent in diabetes-associated complications, including diabetic neuropathy.

Sinonasal Tissue Remodelling during Chronic Rhinosinusitis

The purpose of this review is to summarise contemporary knowledge of sinonasal tissue remodelling during chronic rhinosinusitis (CRS), a chronic disease involving long-term inflammation of the paranasal sinuses and nasal passage. The concept of tissue remodelling has significant clinical relevance because of its potential to cause irreversibility in chronic airway tissues. Recent studies have indicated that early surgical treatment of CRS may improve clinical outcome. Tissue remodelling has been described in the literature extensively with no consensus on how remodelling is defined. This review describes various factors implicated in establishing remodelling in sinonasal tissues with a special mention of asthma as a comorbid condition. Some of the main histological features of remodelling include basement membrane thickening and collagen modulation. This may be an avenue of research with regard to targeted therapy against remodelling in CRS.

Transforming growth factor β3 deficiency promotes defective lipid metabolism and fibrosis in kidney

Glomerulosclerosis and tubulointerstitial fibrosis are pathological features of chronic kidney disease. Transforming growth factor β (TGFβ) is a key player in the development of fibrosis. However, of the three known TGFβ isoforms, only TGFβ1 has an established role in fibrosis, and the pathophysiological relevance of TGFβ2 and TGFβ3 is unknown. Because Tgfβ3 deficiency in mice results in early postnatal lethality, we analyzed the kidney phenotype of heterozygous Tgfβ3-knockout mice (Tgfβ3+/-) and compared it with that of matched wild-type mice. Four-month-old Tgfβ3+/- mice exhibited incipient renal fibrosis with epithelial-to-mesenchymal transition, in addition to glomerular basement membrane thickening and podocyte foot process effacement associated with albuminuria. Also evident was insulin resistance and oxidative stress at the renal level together with aberrant renal lipid metabolism and mitochondrial function. Omics analysis showed toxic species such as diacylglycerides and ceramides in Tgfβ3+/- mice, and dysregulated mitochondrial metabolism. Kidney of Tgfβ3+/- mice showed morphological alterations of mitochondria and overactivation of non-canonical MAPK ERK1/2 and JNK cascades. Our study shows that renal TGFβ3 might have antifibrotic and renoprotective properties, opposing or counteracting the activity of TGFβ1.

Pathophysiological mechanisms of diabetic retinopathy

Aim. To evaluate pathophysiological mechanisms in diabetic retinopathy.Material and methods. Factors of diabetic retinopathy pathogenesis, scientific reviews.Results. The evaluation of pathophysiological mechanisms in diabetic retinopathy found that early stages are characterized by histopathological changes, which include loss of pericytes, basement membrane thickening, haemodynamic alterations leading to reduced vascular integrity. The later stages of diabetic retinopathy are characterized by complications, which include visual impairment, primarily due to macular edema and proliferative diabetic retinopathy. Also, the severity of retinopathy was associated with poorer metabolic control, demonstrated by elevated HbA1c. Diabetic complications accompany the accumulation of advanced glycation end products in diabetic tissues. Increased accumulation of these products has been reported in epiretinal membranes by the use of the immunohistochemical technique. The binding of advanced glycation end products to a high-affinity receptor in pericytes exerts selective toxicity resulting in their death. Vascular endothelial growth factor exerts an important role in intraocular neovascularization due to ischemic retinopathy.Conclusions. Early stages of diabetic retinopathy are characterized by his topathological changes which include loss of pericytes, basement membrane thickening, haemodynamic alterations leading to reduced vascular integrity. The later stages of diabetic retinopathy are characterized by complications, which include visual impairment, primarily due to macular edema and proliferative diabetic retinopathy. The binding of advanced glycation end products to a high-affinity receptor in pericytes exerts selective toxicity resulting in their death.

Comparative Histological study of Normal human placentae with Hypertensive placentae in Western part of Tamilnadu state (Kongunadu region)

Background: Placenta forms an intimate bonding between the mother and the foetus. Apart from gaseous exchange, transport of nutrients from mother to the foetus, any disease or disorder affecting the mother also reflects the foetus. Hypertension during antenatal period produces maternal vasospasm and vascular damage due to luminal constriction of uterine spiral arterioles causing histological changes in the placenta and ultimately leads to foetal hypoxia and death. Aim of the study: To compare the histological features between the normal and hypertensive placenta. Materials and Methods: 30 normal and 30 hypertensive placentae were collected, processed in the Department of Anatomy, Karpagam Faculty of Medical Sciences and Research, Coimbatore, Tamilnadu, and visualised under light microscope and their histological features are noted. Results: Various histological features obtained are Syncytial knots, Fibrinoid necrosis, Calcification of Placenta, Placental infarction, Stromal fibrosis, Hypovascularity of Villous, Intervillous fibrin deposition and Basement membrane thickening. Conclusion: In our study, the histological features are more prominent and their areas in microscopic field is noted more in hypertensive placentae than normal placentae.Histtological features are mainly due to maternal vasospasm and vascular endothelial injury.The statistical analysis calculated for the histological features was found to be significant. KEY WORDS: Placenta, Hypertension, Histology, Syncytial knots, Calcification.

Increased Expression of Type-I Collagen in Malignant Colorectal Lesion and Positive Correlations with Clinical Factors

Objective Type-I collagen (Col-I) is one of the main macromolecules of the extracellular matrix, and it is involved in the desmoplastic stromal reaction, an indicator of worse prognosis in cases of colorectal cancer (CRC). The purpose of the present study was to investigate Col-I expression in cases of CRC and adenoma and to correlate with the clinical data and the data regarding the lifestyle of the patients. Methods A retrospective study including 22 patients with adenoma and 15 with CRC treated at a coloproctology service. The clinical and lifestyle data were obtained through medical records, and Col-I expression was investigated by immunohistochemistry. Results Women represented most cases of adenoma (63.64%), whereas CRC was found mainly in men (73.33%) (p = 0.0448). Immunoexpression of Col-I showed a basement membrane thickening in areas of lining of epithelium and around the glands in both lesions. The cases of CRC had a quite evident fibrosis process in the stroma. The quantitative analysis demonstrated a higher protein expression in CRCs compared to adenomas (p = 0.0109), as well as in female patients (p = 0.0214), patients aged ≥ 50 years (p = 0.0400), and in those with a positive family history of colorectal disease (p = 0.0292). These results suggested a remodeling of the microenvironment of the tumor in CRC carcinogenesis. Importantly, the clinicopathologic positive correlations showed a plausible link between the patient's profile and the immunohistochemical findings, which indicate a possible form of patient stratification. Conclusion The immunohistochemical analysis encourages the performance of more comprehensive studies to ascertain if our results could be a tool for the diagnosis and monitoring of the patients.

Inter-pathologist Agreement on Structured Histopathology Reporting in Chronic Rhinosinusitis

Background: Structured histopathology reporting is increasingly being utilized in rhinology to characterize endotypes in chronic rhinosinusitis and guide management decisions after sinus surgery. Objective: The goal of this investigation is to evaluate inter-observer agreement in structured histopathology reporting. Methods: Two experienced head and neck pathologists independently compiled structured histopathology reports for tissue samples collected during functional endoscopic sinus surgery. Cohen’s standard kappa (κ) coefficients were calculated for each histopathologic variable to assess inter-pathologist agreement. Results: A total of 92 cases were analyzed. Substantial inter-pathologist agreement was reached on tissue eosinophil count (κ = 0.64, P < .001), the presence of eosinophil aggregates (κ = 0.62, P < .001), and the presence of fungal elements (κ = 0.74, P < .001). There was moderate agreement on the degree of inflammation (κ = 0.56, P < .001) and the presence of squamous metaplasia (κ = 0.46, P < .001). There was fair agreement on the presence of neutrophil infiltrates (κ = 0.33, P < .001), the presence of hyperplastic changes (κ = 0.40, P < .001), and the presence of fibrosis (κ = 0.24, P = .022). There was only slight agreement on the degree of subepithelial edema (κ = 0.20, P = .008). The κ coefficients for basement membrane thickening and mucosal ulceration were not statistically significant. Conclusion: High inter-pathologist agreement was demonstrated for several salient histopathologic variables, including tissue eosinophil count and the presence of eosinophil aggregates. However, refining the definitions of certain histopathologic variables may improve the reproducibility of structured histopathology reporting.

Renal Alterations Induced by Chronic Exposure to Therapeutic Doses of Antihypercholestremic Atorvastatin

Background: Atorvastatin (ATOR) is widely used for the treatment and prevention of hypercholesterolemia and various diseases, such as cardiovascular complication, with little data about the histopathological and ultrastructural renal alterations that might be induced by this drug. Objectives: The present study was undertaken to investigate the potential toxicity of therapeutic doses of atorvastatin on the microanatomy and ultrastructure of renal tissues from Wistar albino rats. Methods: Adult male Wistar albino rats received an oral daily dose of 5 mg/kg body weight for 90 consecutive days. Biopsies from both kidneys of each study rat were taken for histopathological and ultrastructural examination. Results: ATOR-treated rats exhibited glomerular, tubular, and interstitial histological alterations, including degeneration, necrosis, hyaline droplets, edema, cortical hemorrhages, mesangial hypercellularity, and blood capillary dilation and congestion. In addition, ATOR exposure increased the activity of glucose-6-phosphate dehydrogenase and alkaline phosphatase with a concurrent reduction in proteins and neutral mucosubstances content of the glomeruli and renal cells. Moreover, ATOR-treated animals demonstrated glomerular ultrastructural alterations, consisting mainly of capillary tuft dilatation, glomerular basement membrane thickening, and mesangial cell proliferation. The renal cells of the proximal tubules demonstrated damaged mitochondria, degenerative cellular changes, endoplasmic reticulum dilatation, lysosomal and autophagosome activation, nuclear alteration, myelin figure formation, and microvilli disorganization. Conclusion: The findings of the present work may indicate that ATOR can induce renal histological, histochemical, and ultrastructural alterations that may affect kidney and other vital organ function.