Piracetam mitigates nephrotoxicity induced by cisplatin via the AMPK-mediated PI3K/Akt and MAPK/JNK/ERK signaling pathways.

AIMS: Cisplatin (CDDP) is commonly employed as an antineoplastic agent, but its use is significantly limited by the occurrence of dose-dependent nephrotoxicity, the detailed mechanisms of which remain unclear. This research is aimed to explore the molecular mechanisms of Piracetam (PIR)'s protective effects on nephrotoxicity resulting from CDDP exposure and to elucidate the mechanisms responsible for these effects. MAIN METHODS: PIR was given in dosages of 100 and 300 mg/kg body weight for a duration of 15 days; concurrently, on the last day, a single 10 mg/kg dose of CDDP was delivered via intraperitoneal injection. Forty-eight hours post-CDDP injection, the animals were sacrificed to assess nephrotoxicity. Blood samples and renal tissues were taken for biochemical and histopathological investigations. Serum creatinine and blood urea nitrogen (BUN) were measured. AMP-activated protein kinase (AMPK), caspase-9 and nuclear factor kappa b p65 (NF-κB p65) were assessed by immunohistochemistry method. Enzyme-linked immunosorbent assay (ELISA) analysis was employed to determine cytochrome c (Cyt. c), Bcl-2-associated X-protein (BAX), caspase-3, nuclear factor erythroid 2-related factor 2 (Nrf2), Heme oxygenase-1 (HO-1), superoxide dismutase (SOD), tumor necrosis factor alpha (TNF-α), myeloperoxidase (MPO), and interleukin-1ß (IL-1ß) levels in renal tissue homogenates. The mRNA levels of tumor protein P53 (TP53), phosphatidylinositol-3 kinase (PI3K), protein kinase B (Akt), p38 mitogen-activated protein kinase (p38 MAPK), extracellular signal-regulated kinases (ERK), and c-Jun N-terminal kinases (JNK) were tested by quantitative real-time polymerase chain reaction (qRT-PCR). Additionally, histopathological evaluations of the renal tissues and the binding affinity of PIR to AMPK by molecular docking were also performed. KEY FINDINGS: Pre-treatment with PIR enhanced renal function markers such as urea and creatinine, mitigated histological damage, and diminished inflammatory cell presence in renal tubules. PIR demonstrated antioxidant effects by reestablishing the equilibrium between pro-oxidants and antioxidants such as MPO, HO-1, Nrf2, as well as SOD. Furthermore, PIR inhibited the inflammatory pathways through the MAPK/NF-κB pathway. Additionally, PIR counteracted the CDDP-induced decline in PI3K/Akt activity and hindered caspase-dependent apoptotic processes. SIGNIFICANCE: In summary, PIR appears to be an effective therapeutic strategy for reducing CDDP-induced nephrotoxicity, attributed to its antioxidant, anti-inflammatory, and antiapoptotic mechanisms. Consequently, PIR may serve as a complementary treatment alongside CDDP to alleviate nephrotoxicity associated with CDDP.

Glycogen synthase kinase 3 activity enhances liver inflammation in MASH.

Background & Aims: Metabolic dysfunction-associated steatohepatitis (MASH) is characterized by excessive circulating toxic lipids, hepatic steatosis, and liver inflammation. Monocyte adhesion to liver sinusoidal endothelial cells (LSECs) and transendothelial migration (TEM) are crucial in the inflammatory process. Under lipotoxic stress, LSECs develop a proinflammatory phenotype known as endotheliopathy. However, mediators of endotheliopathy remain unclear. Methods: Primary mouse LSECs isolated from C57BL/6J mice fed chow or MASH-inducing diets rich in fat, fructose, and cholesterol (FFC) were subjected to multi-omics profiling. Mice with established MASH resulting from a choline-deficient high-fat diet (CDHFD) or FFC diet were also treated with two structurally distinct GSK3 inhibitors (LY2090314 and elraglusib [9-ING-41]). Results: Integrated pathway analysis of the mouse LSEC proteome and transcriptome indicated that leukocyte TEM and focal adhesion were the major pathways altered in MASH. Kinome profiling of the LSEC phosphoproteome identified glycogen synthase kinase (GSK)-3ß as the major kinase hub in MASH. GSK3ß-activating phosphorylation was increased in primary human LSECs treated with the toxic lipid palmitate and in human MASH. Palmitate upregulated the expression of C-X-C motif chemokine ligand 2, intracellular adhesion molecule 1, and phosphorylated focal adhesion kinase, via a GSK3-dependent mechanism. Congruently, the adhesive and transendothelial migratory capacities of primary human neutrophils and THP-1 monocytes through the LSEC monolayer under lipotoxic stress were reduced by GSK3 inhibition. Treatment with the GSK3 inhibitors LY2090314 and elraglusib ameliorated liver inflammation, injury, and fibrosis in FFC- and CDHFD-fed mice, respectively. Immunophenotyping using cytometry by mass cytometry by time of flight of intrahepatic leukocytes from CDHFD-fed mice treated with elraglusib showed reduced infiltration of proinflammatory monocyte-derived macrophages and monocyte-derived dendritic cells. Conclusion: GSK3 inhibition attenuates lipotoxicity-induced LSEC endotheliopathy and could serve as a potential therapeutic strategy for treating human MASH. Impact and Implications: LSECs under lipotoxic stress in MASH develop a proinflammatory phenotype known as endotheliopathy, with obscure mediators and functional outcomes. The current study identified GSK3 as the major driver of LSEC endotheliopathy, examined its pathogenic role in myeloid cell-associated liver inflammation, and defined the therapeutic efficacy of pharmacological GSK3 inhibitors in murine MASH. This study provides preclinical data for the future investigation of GSK3 pharmacological inhibitors in human MASH. The results of this study are important to hepatologists, vascular biologists, and investigators studying the mechanisms of inflammatory liver disease and MASH, as well as those interested in drug development.

Utilization and perspectives of weight loss medications in pediatric metabolic dysfunction-associated steatotic liver disease.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is increasing globally in pediatric populations. Currently, MASLD management primarily relies on lifestyle interventions, which pose challenges in sustaining long-term weight loss. This study investigated the use of weight loss medications in MASLD care through an international survey of 166 pediatric gastroenterologists and hepatologists. The results indicated a notable interest in weight loss medications, with 38% of practitioners considering or using them, particularly glucagon-like peptide-1 receptor agonists. However, the survey also revealed a tendency among clinicians to refer patients to specialists, emphasizing the potential gap between acknowledgment and prescription practices. Challenges include the lack of guidelines and uncertainty regarding side effects. The study highlights a pressing need for education, with over 90% of the respondents expressing an interest. Our study highlights the current management of MASLD, the potential role of pharmacotherapy, and highlights avenues for improved care and education in this dynamic field.

Recurrent Soft Tissue Rosai Dorfman Disease of Right Medial Thigh Lipoma With Lymph Node Involvement.

Background: Rosai Dorfman disease is a rare non-Langerhans cell histiocytosis that affects lymph nodes, soft tissues, and other organs. The etiology of Rosai Dorfman disease is poorly understood, though it may involve an immunologic processes or infection. Treatment varies according to the disease presentation. Case Presentation: A male aged 56 years was evaluated for a cutaneous mass on his right medial thigh. Initially, the patient received surgical debulking with subsequent observation and no systemic therapy. However, the mass recurred, prompting another surgical removal 9 years after the initial surgery. A mass biopsy showed infiltration of plasma cells, lymphocytes, histiocytes, and occasional neutrophils with noted reactivity of S-100 protein and CD163, but not CD1a. No systemic therapy was initiated, and the patient agreed to a period of watchful waiting. Conclusions: Rosai Dorfman disease of soft tissue occurs in older adults and is often associated with soft tissue abnormalities, and more rarely, in lipomas. Multidisciplinary management of the disease and research for mutations and microenvironment of RDD is needed to better understand its clinicopathological nature and improve novel therapies.

The efficacy of green silica nanoparticles synthesized from rice straw in the management of Callosobruchus maculatus (Col., Bruchidae).

Rice straw, a byproduct of harvesting rice, must be disposed of by farmers in a variety of ways, including burning, which is hazardous for the environment. To address this issue, the straw needs to be utilized and turned into valuable products. One such product is nano-silica (SNPs), which will be synthesized and investigated in our study as a safe alternative to chemical insecticides. Rice straw-derived SNPs were synthesized using the Sol-Gel method. The contact toxicity of SNPs on Callosobruchus maculatus, a major pest of cowpea seeds, has been assessed. The size of synthesized SNPs was determined by transmission electron microscopy to be ~ 4 nm. The SNPs estimated LC50 on C. maculatus adults was 88.170 ppm after 48h exposure. By raising the tested concentration, SNPs treatment increased the mortality%, which reached 100% at 200 ppm exposures. Additionally, SNPs at LC50 treatment decreased adult longevity and the average number of emerged adults. The findings also verified that SNPs had no phytotoxic effects on the cowpea seeds germination. Rather, their application improved seed germination efficacy. This study proposed that rice straw can be utilized to manufacture highly efficient SNPs which can be efficiently employed to preserve stored grains from C. maculatus infestation.

Digital pathology and spatial omics in steatohepatitis: Clinical applications and discovery potentials.

Steatohepatitis with diverse etiologies is the most common histological manifestation in patients with liver disease. However, there are currently no specific histopathological features pathognomonic for metabolic dysfunction-associated steatotic liver disease, alcohol-associated liver disease, or metabolic dysfunction-associated steatotic liver disease with increased alcohol intake. Digitizing traditional pathology slides has created an emerging field of digital pathology, allowing for easier access, storage, sharing, and analysis of whole-slide images. Artificial intelligence (AI) algorithms have been developed for whole-slide images to enhance the accuracy and speed of the histological interpretation of steatohepatitis and are currently employed in biomarker development. Spatial biology is a novel field that enables investigators to map gene and protein expression within a specific region of interest on liver histological sections, examine disease heterogeneity within tissues, and understand the relationship between molecular changes and distinct tissue morphology. Here, we review the utility of digital pathology (using linear and nonlinear microscopy) augmented with AI analysis to improve the accuracy of histological interpretation. We will also discuss the spatial omics landscape with special emphasis on the strengths and limitations of established spatial transcriptomics and proteomics technologies and their application in steatohepatitis. We then highlight the power of multimodal integration of digital pathology augmented by machine learning (ML)algorithms with spatial biology. The review concludes with a discussion of the current gaps in knowledge, the limitations and premises of these tools and technologies, and the areas of future research.

Potential fumigant toxicity of essential oils against Sitotroga cerealella (Olivier) (Lepidoptera: Gelechiidae) and its egg parasitoid Trichogramma evanescens (Hymenoptera: Trichogrammatidae).

Sitotroga cerealella is a serious pest of a wide range of stored cereal grains. An essential element of an integrated pest control approach is the application of plant oils as a substitute for chemical insecticides. This study aimed to investigate the fumigant toxicity of Allium sativum and Mentha piperita essential oils against S. cerealella adult moths and the egg parasitoid Trichogramma evanescens. Gas chromatography-mass spectrometry analyses detected that Diallyl trisulfide (37.97%) and DL-Menthol (47.67%) as main compounds in A. sativum and M. piperita, respectively. The results showed that, A. sativum at 10.0, 5.0, and 2.5 µL/L air resulted in 100% insect mortality after 24 h exposure. The concentrations of 10.0 and 5.0 µL/L air of M. piperita oil resulted in 100 and 96% insect mortality, respectively. The parasitoid adult emergence in the F1 reduced when exposed to LC99 of A. sativum and M. piperita oils by 10.89 and 9.67%, respectively. Also, the parasitism of emerged parasitoid decreased by 9.25 and 5.84% (class I-harmless), respectively. Therefore A. sativum and M. piperita have the potential to be used as bio-fumigant for the management of S. cerealella and can be used alongside the T. evanescens in integrated pest management.

Rho-associated protein kinase 1 inhibition in hepatocytes attenuates nonalcoholic steatohepatitis.

BACKGROUND: NASH is the progressive form of NAFLD characterized by lipotoxicity, hepatocyte injury, tissue inflammation, and fibrosis. Previously, Rho-associated protein kinase (ROCK) 1 has been implicated in lipotoxic signaling in hepatocytes in vitro and high-fat diet-induced lipogenesis in vivo. However, whether ROCK1 plays a role in liver inflammation and fibrosis during NASH is unclear. Here, we hypothesized that pathogenic activation of ROCK1 promotes murine NASH pathogenesis. METHODS AND RESULTS: Patients with NASH had increased hepatic ROCK1 expression compared with patients with fatty liver. Similarly, hepatic ROCK1 levels and activity were increased in mice with NASH induced by a western-like diet that is high in fat, fructose, and cholesterol (FFC). Hepatocyte-specific ROCK1 knockout mice on the FFC diet displayed a decrease in liver steatosis, hepatic cell death, liver inflammation, and fibrosis compared with littermate FFC-fed controls. Mechanistically, these effects were associated with a significant attenuation of myeloid cell recruitment. Interestingly, myeloid cell-specific ROCK1 deletion did not affect NASH development in FFC-fed mice. To explore the therapeutic opportunities, mice with established NASH received ROCKi, a novel small molecule kinase inhibitor of ROCK1/2, which preferentially accumulates in liver tissue. ROCK inhibitor treatment ameliorated insulin resistance and decreased liver injury, inflammation, and fibrosis. CONCLUSIONS: Genetic or pharmacologic inhibition of ROCK1 activity attenuates murine NASH, suggesting that ROCK1 may be a therapeutic target for treating human NASH.

Extracellular Vesicles in Hepatobiliary Health and Disease.

Extracellular vesicles (EVs) are membrane-bound nanoparticles released by cells and are an important means of intercellular communication in physiological and pathological states. We provide an overview of recent advances in the understanding of EV biogenesis, cargo selection, recipient cell effects, and key considerations in isolation and characterization techniques. Studies on the physiological role of EVs have relied on cell-based model systems due to technical limitations of studying endogenous nanoparticles in vivo . Several recent studies have elucidated the mechanistic role of EVs in liver diseases, including nonalcoholic fatty liver disease, viral hepatitis, cholestatic liver disease, alcohol-associated liver disease, acute liver injury, and liver cancers. Employing disease models and human samples, the biogenesis of lipotoxic EVs downstream of endoplasmic reticulum stress and microvesicles via intracellular activation stress signaling are discussed in detail. The diverse cargoes of EVs including proteins, lipids, and nucleic acids can be enriched in a disease-specific manner. By carrying diverse cargo, EVs can directly confer pathogenic potential, for example, recruitment and activation of monocyte-derived macrophages in NASH and tumorigenicity and chemoresistance in hepatocellular carcinoma. We discuss the pathogenic role of EVs cargoes and the signaling pathways activated by EVs in recipient cells. We review the literature that EVs can serve as biomarkers in hepatobiliary diseases. Further, we describe novel approaches to engineer EVs to deliver regulatory signals to specific cell types, and thus use them as therapeutic shuttles in liver diseases. Lastly, we identify key lacunae and future directions in this promising field of discovery and development. © 2023 American Physiological Society. Compr Physiol 13:4631-4658, 2023.

Mirtazapine, an atypical antidepressant, mitigates lung fibrosis by suppressing NLPR3 inflammasome and fibrosis-related mediators in endotracheal bleomycin rat model.

Idiopathic pulmonary fibrosis (IPF) is a progressive and irreversible lung disease with a poor prognosis. There is currently no definitive cure for IPF. The present study establishes a platform for the development of a novel therapeutic approach for the treatment of PF using the atypical antidepressant, mirtazapine. In the endotracheal bleomycin rat model, mirtazapine interfered with the activation of NLRP3 inflammasome via downregulating the NLRP3 on the gene and protein expression levels. Accordingly, the downstream mediators IL-1ß and IL-18 were repressed. Such observation is potentially a direct result of the reported improvement in oxidative stress. Additionally, mirtazapine corrected the bleomycin-induced disparities in the levels of the fibrogenic mediators TGF-ß, PDGF-BB, and TIMP-1, in consequence, the lung content of hydroxyproline and the expression of α-SMA were reduced. Besides, mirtazapine curbed the ICAM-1 and the chemotactic cytokines MCP-1 and CXCL4. This protective property of mirtazapine resulted in improving the BALF total and differential cell counts, diminishing LDH activity, and reducing the BALF total protein. Moreover, the inflammation and fibrosis scores were accordingly lower. To conclude, we reveal for the first time the efficacy of mirtazapine as a potential treatment for PF. The combination of social isolation, sleep problems, breathing difficulties, and fear of death can lead to psychological distress and depression in patients with IPF. Hence, mirtazapine is a promising treatment option that may improve the prognosis for IPF patients due to its antifibrotic effects, as well as its ability to alleviate depressive episodes.

Protective effects of butylated hydroxytoluene on the initiation of N-nitrosodiethylamine-induced hepatocellular carcinoma in albino rats.

Diethylnitrosamine (DEN), a hepatocarcinogen, is found in a variety of smoked and fried foods and was reported to be hepatotoxic in mice. Butylated hydroxytoluene (BHT) is a potent antioxidant used in cosmetic formulations and as a food additive and preservative. As a result, BHT was studied as a potential inhibitor in the early stages of diethylnitrosamine (DEN)-induced HCC. Male Wistar albino rats (n = 24) were equally subdivided. Group 1 was the negative control; Group 2 and 3 administered BHT and DEN, respectively; Group 4 received BHT followed by DEN. Blood samples and rat livers were taken for biochemical and histological investigation. Hepatotoxicity was assessed by increased liver enzymes and HCC indicators, along with reduced antioxidant and pro-apoptotic factors. AFP, AFPL3, GPC3, GSH, SOD, MDA, CASP3 and BAX expression increased significantly after DEN treatment. DEN also reduced GPx, CAT, and CYP2E1 activity, and BCl-2 expression. Moreover, in the hepatic parenchyma, the DEN caused histological alterations. Pretreatment with BHT enhanced antioxidant status while preventing histopathological and most biochemical alterations. BHT pretreatment suppresses DEN-initiated HCC by decreasing oxidative stress, triggering intrinsic mitotic apoptosis, and preventing histopathological changes in liver tissue.

Liver transplantation recovers hepatic N-glycosylation with persistent IgG glycosylation abnormalities: Three-year follow-up in a patient with phosphomannomutase-2-congenital disorder of glycosylation.

Phosphomannomutase-2-congenital disorder of glycosylation (PMM2-CDG) is the most common CDG and presents with highly variable features ranging from isolated neurologic involvement to severe multi-organ dysfunction. Liver abnormalities occur in in almost all patients and frequently include hepatomegaly and elevated aminotransferases, although only a minority of patients develop progressive hepatic fibrosis and liver failure. No curative therapies are currently available for PMM2-CDG, although investigation into several novel therapies is ongoing. We report the first successful liver transplantation in a 4-year-old patient with PMM2-CDG. Over a 3-year follow-up period, she demonstrated improved growth and neurocognitive development and complete normalization of liver enzymes, coagulation parameters, and carbohydrate-deficient transferrin profile, but persistently abnormal IgG glycosylation and recurrent upper airway infections that did not require hospitalization. Liver transplant should be considered as a treatment option for PMM2-CDG patients with end-stage liver disease, however these patients may be at increased risk for recurrent bacterial infections post-transplant.

Endotheliopathy in the metabolic syndrome: Mechanisms and clinical implications.

The increasing prevalence of the metabolic syndrome (MetS) is a threat to global public health due to its lethal complications. Nonalcoholic fatty liver disease (NAFLD) is the hepatic manifestation of the MetS characterized by hepatic steatosis, which is potentially progressive to the inflammatory and fibrotic nonalcoholic steatohepatitis (NASH). The adipose tissue (AT) is also a major metabolic organ responsible for the regulation of whole-body energy homeostasis, and thereby highly involved in the pathogenesis of the MetS. Recent studies suggest that endothelial cells (ECs) in the liver and AT are not just inert conduits but also crucial mediators in various biological processes via the interaction with other cell types in the microenvironment both under physiological and pathological conditions. Herein, we highlight the current knowledge of the role of the specialized liver sinusoidal endothelial cells (LSECs) in NAFLD pathophysiology. Next, we discuss the processes through which AT EC dysfunction leads to MetS progression, with a focus on inflammation and angiogenesis in the AT as well as on endothelial-to-mesenchymal transition of AT-ECs. In addition, we touch upon the function of ECs residing in other metabolic organs including the pancreatic islet and the gut, the dysregulation of which may also contribute to the MetS. Finally, we highlight potential EC-based therapeutic targets for human MetS, and NASH based on recent achievements in basic and clinical research and discuss how to approach unsolved problems in the field.

Eugenol nanoemulsion as bio-fumigant: enhanced insecticidal activity against the rice weevil, Sitophilus oryzae adults.

Nanoemulsion is a promising delivery system for delivering the plant bioactive molecules against insect pests. In this study, we aimed to prepare eugenol based nanoemulsions (EL-NE) by ultrasonication method to investigate its fumigant toxicity against Sitophilus oryzae adults and to analyse the residual characteristics of eugenol bioactive on the treated grains and beetles. In EL-NE preparations, 1:1 ratio of eugenol: Tween 80 combination with 5 min of ultrasonication at frequency of 10 kHz and 12 W power output was determined as optimal. In the optimized nanoemulsions, 19.21 to 42.82 d.nm range of mean droplet size, 0.50 to 0.77 range of polydispersity index and -21.80 to -29.83 mV range of zeta potential values were observed with respect to 2.5 to 10.0% of eugenol concentrations. After 72 h of fumigation, enhanced fumigant toxicities (3.5-11.2 fold) were observed against S. oryzae adults for the optimized EL-NEs compared to eugenol alone. Fumigant toxicity results revealed 14.40 µl/L air of least LC50 value for the 10.0% EL-NE. Persistence of eugenol was more (12.46%) in EL-NE treated wheat grains compared to eugenol alone treatments based on Gas Chromatography-Mass Spectroscopy analysis, which indicates the improved fumigation. This study results suggests EL-NEs as promising nano-biofumigant against the S. oryzae adults for eco-friendly Integrated Pest Management (IPM).

The evolving role of liver sinusoidal endothelial cells in liver health and disease.

LSECs are a unique population of endothelial cells within the liver and are recognized as key regulators of liver homeostasis. LSECs also play a key role in liver disease, as dysregulation of their quiescent phenotype promotes pathological processes within the liver including inflammation, microvascular thrombosis, fibrosis, and portal hypertension. Recent technical advances in single-cell analysis have characterized distinct subpopulations of the LSECs themselves with a high resolution and defined their gene expression profile and phenotype, broadening our understanding of their mechanistic role in liver biology. This article will review 4 broad advances in our understanding of LSEC biology in general: (1) LSEC heterogeneity, (2) LSEC aging and senescence, (3) LSEC role in liver regeneration, and (4) LSEC role in liver inflammation and will then review the role of LSECs in various liver pathologies including fibrosis, DILI, alcohol-associated liver disease, NASH, viral hepatitis, liver transplant rejection, and ischemia reperfusion injury. The review will conclude with a discussion of gaps in knowledge and areas for future research.

Application of Bentonite Clay, Date Pit, and Chitosan Nanoparticles as Promising Adsorbents to Sequester Toxic Lead and Cadmium from Milk.

Evaluating residual lead (Pb) and cadmium (Cd) levels in food products, especially milk, is critical for product safety and quality. In this purview, the current study aims to determine Pb and Cd concentrations in milk using atomic absorption spectrophotometry and compare their values with international standards. In addition, it aims to remove these metals from milk samples using low-cost, naturally occurring materials, such as bentonite, date pit, and chitosan nanoparticles. The ability of potential adsorbents was also investigated using Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), scanning electron microscopy (SEM), energy-dispersive X-ray (EDX), and transmission electron microscope (TEM). Moreover, their impact on milk's nutritional properties was considered. The results revealed that most milk samples contained Pb and Cd, with mean values of 0.237 ± 0.179 and 0.041 ± 0.036 mg/kg, respectively. Furthermore, the three possible adsorbents demonstrated high sequestering ability due to their existing functional groups; the adsorption capacity of bentonite to Pb and Cd was 84 and 88%, date pit was 97 and 93%, and chitosan nanoparticles were 82 and 98%, respectively, with no discernible change in milk nutritional contents. In conclusion, the bentonite, date pit, and chitosan nanoparticles were found to be significantly effective and safe in removing hazardous trace elements (Pb and Cd) from contaminated milk.