Parthenolide ameliorates 3-nitropropionic acid-induced Huntington's disease-like aberrations via modulating NLRP3 inflammasome, reducing microglial activation and inducing astrocyte shifting.

BACKGROUND: Huntington's disease (HD) is a progressive neurodegenerative disease that causes motor, cognitive, and psychiatric abnormalities, with no satisfying disease-modifying therapy so far. 3-nitropropionic acid (3NP) induces behavioural deficits, together with biochemical and histological alterations in animals' striata that mimic HD. The role of nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 (NLRP3) inflammasome in HD pathogenesis remains largely uncharacterized. Parthenolide (PTL), a naturally occurring nuclear factor kappa B (NF-κB) inhibitor, is also known to inhibit NLRP3 inflammasome. Whether PTL is beneficial in HD has not been established yet. AIM: This study evaluated the possible neuroprotective effects of PTL against 3NP-induced behavioural abnormalities, striatal biochemical derangements, and histological aberrations. METHODS: Male Wistar rats received PTL (0.5 mg/kg/day, i.p) for 3 weeks and 3NP (10 mg/kg/day, i.p) was administered alongside for the latter 2 weeks to induce HD. Finally, animals were subjected to open-field, Morris water maze and rotarod tests. Rat striata were examined histologically, striatal protein expression levels of glial fibrillary acidic protein (GFAP), cluster of differentiation 45 (CD45) and neuron-specific enolase (NSE) were evaluated immunohistochemically, while those of interleukin (IL)-1ß, IL-18, ionized calcium-binding adapter molecule-1 (Iba1) and glutamate were determined by ELISA. Striatal nuclear factor erythroid 2-related factor 2 (Nrf2), Kelch-like ECH-associated protein (Keap1), NF-κB, NLRP3, apoptosis-associated speck-like protein containing a CARD (ASC), caspase-1, S100 calcium-binding protein A10 (S100A10) and complement-3 (C3) were assessed by gene expression analysis. RESULTS: PTL improved motor, locomotor, cognitive and anxiety-like behaviours, restored neuronal integrity, upregulated Nrf2, and inhibited NLRP3 inflammasome, NF-κB and microglial activation. Additionally, PTL induced astrocyte shifting towards the neuroprotective A2 phenotype. CONCLUSION: PTL exhibits neuroprotection against 3NP-induced HD, that might be ascribed, at least in part, to its modulatory effects on Keap1/Nrf2 and NF-κB/NLRP3 inflammasome signaling.

The Utilization of Animals as Models for Human Autopsies in Medical Education, Supported by Peer-Assisted Tutoring.

Background: Human autopsy is widely used to investigate and confirm the causes of death. Commonly reported cases involve the cardiovascular and cerebral systems. However, human autopsy practices have been restricted due to ethical and religious implications in many countries. Aim: The study aims to know if using human autopsy techniques on animal models might be an effective way for teaching post-mortem autopsy to medical students and exposing them to clinical pathology involving vital organs in medical education and find out the role of peer-assisted learning in improving the process. Methods: Two pre-lab sessions were conducted to emphasize the embryological and structural similarities and explain the differences between the human brain and heart and animal models: cow brain and sheep heart. Other two sessions of organ dissection were provided to perform human autopsy techniques on animal models practically for educational purposes. Peer-assisted tutoring was implemented. Questionnaires, interviews, and the Delphi technique were used to triangulate the assessment. A year later, participating foreign exchange students were interviewed to evaluate the long-term impacts based on Kirkpatrick models. Results: The questionnaire showed students' satisfaction with the autopsy workshops and peer-assisted tutoring. The last session was attended by foreign exchange students whose feedback proves the implementation can be done in different medical education systems around the globe. Conclusion: This study shows that animal model autopsy provides a valuable alternative in medical education and improves the students' comprehension and clinical skills, and peer-assisted learning has a secondary role in enhancing it. Supplementary Information: The online version contains supplementary material available at 10.1007/s40670-023-01735-w.

Bone marrow embolism: should it result from traumatic bone lesions? A histopathological human autopsy study.

Bone marrow embolism (BME) is likely a consequence of fractures in which pulmonary vessels are the most affected. However, some cases of BME were reported in the absence of trauma. Thus, a traumatic injury might not be necessary for developing BME. This study discusses BME cases in patients without signs of fractures or blunt trauma. The discussion addresses various possible mechanisms for the appearance of BME. Options include cancer in which bone marrow metastasis is a suggestive cause. Another proposal is the chemical theory where bone marrow fats are released via lipoprotein lipase in a pro-inflammatory state, resulting in vascular/pulmonary obstruction. Other cases discussed in this study are hypovolemic shock and drug-abuse related BME. All autopsy cases with BME were included regardless of the cause of death for a period of 2 years. Autopsies involved complete dissection with the macroscopic evaluation of the affected organs, including the heart, lungs, and brain. Tissues were also prepared for microscopic examination. Of the 11 cases, eight showed non-traumatic BME (72%). These findings conflict with theories in the literature that BME most commonly occurs after fractures or trauma. One of the eight cases exhibited mucinous carcinoma; one is presented with hepatocellular carcinoma; and two cases showed severe congestion. Lastly, one case was found to be associated with each of the following conditions: liposuction, drug abuse, pulmonary hypertension, and heart failure. Each case suggests a different pathophysiology for developing BME, yet the exact mechanisms are not fully understood. Further study of non-traumatic associated BME is recommended.

Ameliorating effect of ketogenic diet on acute status epilepticus: Insights into biochemical and histological changes in rat hippocampus.

This study aimed to evaluate the potential neuroprotective effects of ketogenic diet (KD) against the neuronal disruptions induced by SE in lithium-pilocarpine rat model of status epilepticus (SE). Four groups of female rats include; groups I and III received standard diet and groups II and IV received KD for 3 weeks. Groups I and II were left untreated, while groups III and IV were injected with LiCl (127 mg/kg, i.p.) followed by pilocarpine HCl (10 mg/kg, i.p.) 18-24 h later, repeatedly, till induction of SE. 72 h post-SE, KD effectively ameliorated the balance between excitatory (glutamate) and inhibitory (GABA) neurotransmitters and the oxidative stress indices, increased adenine nucleotides and decreased immunoreactivity of iNOS, TNFα, glial fibrillary acidic protein, and synaptophysin. Thiswas in association with improvement in inflammatory response and neuronal tissue characteristics in hippocampus of SE rats. Histological changes showed preservation of neuronal integrity. These findings highlight the protective effects of KD in the acute phase post-SE via ameliorating biochemical and histological changes involved. PRACTICAL APPLICATIONS: Epilepsy is the fourth most common neurological disorder that requires lifelong treatment. It stigmatizes patients and their families. The use of the ketogenic diet (KD) as a therapy for epilepsy developed from observations that fasting could reduce seizures. From 1920s, the KD was a common epilepsy treatment until it was gradually superseded by anticonvulsant drugs so that by the 1980s it was rarely used. However, there has been a resurgence of interest and usage of the KD for epilepsy since the turn of the century. Despite its long history, the mechanisms by which KD exhibits its anti-seizure action are not fully understood. Our study aims to identify the mechanism of KD which may help further studies to achieve the same benefits with a drug or supplement to overcome its unpalatability and gastrointestinal side effects.

Lutein exerts its cardioprotective effect against the experimental model of isoprenaline-induced myocardial infarction via MIAT/miR-200a/Nrf2/TXINP pathway.

Acute myocardial infarction (AMI) remains a leading cause of morbidity and mortality worldwide. Lutein (LU) possesses numerous pharmacological activities, including anti-inflammatory, antioxidant, and antiapoptotic effects. This study aimed to investigate the cardioprotective potential of LU in isoprenaline (ISO)-induced MI and to explore its molecular mechanisms of action. AMI was induced by two consecutive subcutaneous doses of ISO (65 mg/kg; s.c.). The LU group was pretreated with LU (20 mg/kg; p.o.) for 30 days followed by ISO injections on Days 29 and 30. ISO group showed elevated serum creatine kinas-MB (CK-MB) and considerable electrocardiographic changes along with reduced ejection fraction compared to the normal group. LU pretreatment could decrease serum CK-MB activity, normalize QRS and QTc intervals and restore ejection fraction compared to the untreated group. The ISO group demonstrated infarcted-like lesions, which were ameliorated in the LU-pretreated group. Immunohistochemical investigation revealed upregulated cardiac troponin T (cTn T) and desmin expressions in the LU-pretreated group. LU pretreatment also enhanced cardiac thioredoxin (Trx) and glutathione (GSH) contents as well as reduced lipid peroxidation, compared to the untreated group. Importantly, LU pretreatment could downregulate long noncoding MI associated transcript (lncRNA MIAT) and thioredoxin-interacting protein (TXNIP) and augment micro RNA (miR)-200a and nuclear factor erythroid 2-related factor 2 (Nrf2) expressions compared to the ISO group. Moreover, a significant inverse correlation between MIAT and miR-200a was observed. In conclusion, this study revealed that LU could ameliorate ISO-induced MI in rats by modulating MIAT/miR-200a/Nrf2 pathway.

Case item creation and video case presentation as summative assessment tools for distance learning in the pandemic era.

BACKGROUND: There is an urgent need for more diverse methods for student evaluation, given the sudden shift to online learning necessitated by the coronavirus disease 2019 (COVID-19) pandemic. Innovative assessment tools will need to cover the required competencies and should be used to drive self-learning. Self-assessments and peer assessments may be added to the traditional classroom-based evaluations to identify individual insecurities or overconfidence. Identification of these factors is essential to medical education and is a focus of current research. METHODS: A modified operational assessment was introduced for the evaluation of third-year medical students. This intervention has facilitated sustained education and has promoted interactive student learning. Members of the entering class of 2017 participated in an integrated team and a competency-based online project that involved innovative item creation and case presentation methods. RESULTS: The new assessment process has been implemented successfully with positive feedback from all the participants; a usable product has been generated. CONCLUSIONS: We created new assessment tools in response to the COVID-19 pandemic that have been used successfully at our institution. These tools have provided a framework for integrated and interactive evaluations that can be used to facilitate the modification of traditional assessment methods.

Role of a schistosoma haematobium specific microRNA as a predictive and prognostic tool for bilharzial bladder cancer in Egypt.

Urinary bladder cancer is a common malignancy in Egypt, thus reliable methodologies are required for screening and early detection. In this study, we analyzed the gene expression of a Schistosoma hematobium specific microRNA "Sha-miR-71a" and mitogen-associated protein kinase-3 (MAPK-3) in the urine samples of 50 bladder cancer patients and 50 patients with benign bilharzial cystitis. Fifty control subjects were also tested. Indirect hemagglutination test (IHA) diagnosed 70% of studied cancer cases as bilharzial associated bladder cancer (BBC), while histopathological examination detected only 18%. Urinary Sha-miR-71a & MAPK-3 revealed enhanced expression in BBC (p-value = 0.001) compared to non-bilharzial bladder cancer (NBBC) cases. Patients with chronic bilharzial cystitis exhibited a significant increase in gene expression compared to those with acute infection (p-value = 0.001). Sha-miR-71a and MAPK-3 showed good sensitivity and specificity in the diagnosis of BBC when analyzed by the receiver operating characteristic (ROC) curve. They were also prognostic regarding malignancy grade. Both biomarkers showed a positive correlation. Our results revealed that IHA is a reliable test in the diagnosis of bilharziasis associated with bladder cancer, and that Sha-miR-71a and MAPK-3 provide non-invasive specific biomarkers to diagnose BBC, as well as a potential role in testing bilharzial patients for risk to develop cancer.

Immunomodulatory effect of diallyl sulfide on experimentally-induced benign prostate hyperplasia via the suppression of CD4+T/IL-17 and TGF-ß1/ERK pathways.

Benign prostatic hyperplasia (BPH) is a nonmalignant enlargement of the prostate common in older men. Diallyl sulfide (DAS), a major component of garlic, has been reported to possess antioxidant, anti-inflammatory, and antiproliferative effects. However, the underlying protective immunomodulatory mechanism of DAS on BPH remains vague. Herein, experimental BPH was induced in rats by daily subcutaneous injection of testosterone propionate (TP) (3 mg/kg, s.c.) for 4 weeks. In parallel, finasteride (Fin) (5 mg/kg, p.o) or DAS (50 mg/kg, p.o.) was administered orally during BPH induction. TP-induced histological alterations and the immune-inflammatory cascade. On the other hand, DAS or Fin administration alleviated all abnormalities induced testosterone. Fin and DAS administration markedly reduced prostate weight by 53% with Fin, and by 60% with DAS. Moreover, serum testosterone and DHT were reduced by 55% and 52%, respectively, with Fin and by 68% and 75%, respectively, with DAS, in concordance with decreased protein expression of androgen receptor (AR), and prostate-specific antigen (PSA). Furthermore, both regime lessen immune-inflammatory milieu, as evidenced by decrease CD4+ T-cells protein expression and associated inflammatory cytokines. Concomitantly, Fin and DAS exhibited marked mitigation in insulin-like growth factor-1 (IGF-1), transforming growth factor-beta1 (TGF-ß1), and phosphorylated extracellular signal-regulated kinase (ERK1/2) signaling. Besides alleviating oxidative stress by 53% and 68% in prostatic MDA and by 27% and 7% in prostatic iNOS with Fin and DAS, respectively. In conclusion, this work highlighted a potential therapeutic approach of DAS as a dietary preventive agent against BPH via its anti-inflammatory and immunomodulatory effect along with suppression of the ERK pathway.

Hydrogen sulfide enhances the effectiveness of mesenchymal stem cell therapy in rats with heart failure: In vitro preconditioning versus in vivo co-delivery.

Stem cell therapy represents a promising therapeutic avenue for cardiac disorders, including heart failure. Although stem cell transplantation showed encouraging preliminary results, the outcomes of clinical studies are still unsatisfactory. This study aimed to compare the outcomes of two therapeutic approaches, in vivo co-delivery of sodium hydrogen sulfide (NaHS) concomitant with bone marrow-derived mesenchymal stem cell (BMSC) transplantation and in vitro preconditioning of BMSCs with NaHS, both of which are intended to promote the success of stem cell therapy in rats with isoprenaline-induced heart failure. Heart failure developed 4 weeks after the subcutaneous injection of isoprenaline (170 mg/kg) for 4 consecutive days. The in vivo approach involved the co-delivery of intraperitoneally administered NaHS concomitant with BMSC transplantation for a period of 14 days. The in vitro approach involved preconditioning BMSCs with NaHS for 30 min before transplantation. Compared to treatment with BMSCs alone, in vitro preconditioning of BMSCs with NaHS improved left ventricular function as measured by echocardiography and electrocardiography and enhanced stem cell homing, proliferation and differentiation as manifested by higher cardiac expression of GATA-4 and myocyte enhancer factor 2. Moreover, the measurement of cardiac transforming growth factor beta 1 levels and histopathological investigation revealed mitigated fibrosis and myocardial injury scores. Compared with BMSC therapy alone, the in vivo approach enhanced stem cell homing and differentiation, alleviated fibrosis and augmented vascular endothelial growth factor (VEGF) and endothelial nitric oxide synthase (eNOS) expression. In conclusion, NaHS can potentiate the efficiency of BMSC therapy for heart failure by in vitro preconditioning or in vivo co-delivery. The in vitro approach is superior with regard to improving cardiac function in addition to enhancing stem cell proliferation, while the in vivo approach is superior with regard to increasing cardiac VEGF and eNOS expression.

Crosstalk between liver-related microRNAs and Wnt/ß-catenin pathway in hepatocellular carcinoma patients.

BACKGROUND AND STUDY AIMS: Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide with highest incidence in Asia and Africa. MicroRNAs (miRNAs), a class of non-coding single stranded RNA, which not only post transcriptionally regulate gene expression but also respond to signaling molecules to affect cell functions such as Wnt/ß-catenin signaling specifically in HCC. The goal of this study is to investigate the crosstalk between Wnt/ß-catenin signaling proteins and microRNAs expression in HCC patients. PATIENTS AND METHODS: Fresh tissue samples of 30 primary HCC patients and 10 control subjects were included. Expression level of 13 different miRNAs (miR-10a- miR-106b- miR-99a- miR-148a- miR-125b- miR-30e- miR-183- miR-155- miR-199a- miR-199a3p- miR-24- miR-122 and miR-215) were examined using real-time PCR assay. Five proteins involved in the Wnt/ß-catenin pathway (ß-catenin, APC, c-myc, survivin and cyclin D1) were analysed by immunohistochemistry technique. The correlation between miRNAs expression levels with protein expressions was assessed. RESULTS: Up-regulation of miR-155 and miR-183 was reported in HCC patients compared to normal controls and this up-regulation was significantly correlated with liver cirrhosis in the case of miR-155 (p<0.05) referring to their oncogenic activity. Down-regulation was observed for 11 miRNAs in HCC indicating their tumour suppression activity. MiRNA-10a, miR-30e, miR-215, miR-125b and miR-148a were significantly correlated with the expression of important players in Wnt/ß-catenin pathway including ß-catenin, APC and c-myc (p<0.05). Detailed analysis revealed that miR-215 is associated with the grade of the disease and miR-125b is associated with HCV infection. CONCLUSION: Collectively, our data showed potential role of miR-10a, miR-30e, miR-215, miR-125b and miR-148a as important mediators in HCC progression. Furthermore, their association with Wnt/ß-catenin cascade proteins could be exploited to develop new therapeutic target strategies in HCC.

Lymphoepithelioma-Like Carcinoma of the Breast Mimicking Granulomatous Mastitis- Case Report and Review of the Literature

Lymphoepithelioma-like carcinoma (LELC) of the breast is an exceedingly rare variant of mammary cancer. To our knowledge, only twenty - one cases have been reported in the literature. Diagnosis of this type of mammary carcinoma may be challenging, owing to its rarity and the histopathological similarity to common inflammatory and malignant lesions of the breast mainly granulomatous mastitis, medullary carcinoma, pleomorphic lobular carcinoma, lymphoma and other hematological malignancies. Our case is the 22nd case of lymphoepithelioma-like carcinoma reported in the breast, presenting with a palpable tender mass in a post-menopausal female. Her clinical picture had been mistaken for inflammatory disease. We present our case, with its detailed clinical history, radiological findings, histopathological and immune-histochemical findings along with a review of the literature. Highlighting this type of tumors may help in appropriate diagnosis. Moreover, studying the behavior of these rare neoplasms is essential to expedite treatment for this tumor type.

Meloxicam modulates oxidative stress status, inhibits prostaglandin E2, and abrogates apoptosis in carbon tetrachloride-induced rat hepatic injury.

The current study aimed at investigating the potential hepatoprotective property and mechanism of meloxicam (MEL) against carbon tetrachloride (CCl(4))-induced hepatocellular damage in rats. Subcutaneous administration of CCl(4) (2 mL/kg, twice/week for 8 weeks) induced hepatocellular damage substantiated by hematoxylin and eosin staining and significant elevation in serum aspartate transaminase, alanine transaminase, and total bilirubin. In addition, CCL(4) treatment led to elevation in liver contents of lipid peroxidation marker (malondialdehyde), prostaglandin E2, active caspase 3, and Terminal deoxynucleotidyl transferase dUTP nick end labeling-positive cells and reduction in the activities of superoxide dismutase, catalase, glutathione-S-transferase, and reduced glutathione in the liver tissue. Prior oral treatment with MEL (5 mg/kg, twice/week) retained the normal liver histology and significantly restored all of these parameters close to normal values. These results demonstrated the hepatoprotective utility of MEL against the CCl(4)-induced liver injury which might ascribe to its antioxidant, free radical scavenging, antiapoptotic and anti-inflammatory effects.