Cirsimaritin Alleviates Dextran Sodium Sulfate-Induced Acute Colitis in Experimental Animals: A Therapeutic Approach for Inflammatory Bowel Disease.

Inflammatory bowel disease (IBD) is a chronic disease that affects the entire digestive tract. IBD can be classified as ulcerative colitis or Crohn's disease. The key symptoms of IBD include the emergence of abscesses or pustules, pronounced abdominal discomfort, diarrhea, fistulas, and intestinal narrowing, all of which can greatly affect a patient's daily well-being. Several factors, including bacterial infections, immune response irregularities, and changes in the intestinal milieu, can contribute to the onset of IBD. The aim of this study was investigating the role of cirsimaritin in reducing the severity of colitis in animal model. To induce colitis in laboratory Swiss albino mice, a 4% dextran sulfate sodium (DSS) concoction was provided in their hydration source for a duration of six days. Before the onset of colitis, mice were treated with cirsimaritin (10 mg/kg) once daily to evaluate its potential treatment effects against DSS-induced inflammation. The results showed that 10 mg/kg of cirsimaritin decreased colitis severity (P<0.05). Moreover, cirsimaritin successfully reversed the detrimental effects induced by DSS, including weight reduction, colon truncation, tissue-related damage, increased levels of inflammatory cells in the affected region, and secretion of proinflammatory cytokines. Our findings suggest that cirsimaritin can effectively alleviate acute colitis triggered by DSS.

Exploring the Global Landscape of Self-Medication Among Students: Trends, Risks, and Recommendations for Safe and Responsible Practices

Objective: This study aimed to provide a comprehensive overview of self-medication practices among students by conducting a bibliometric analysis of the available scientific literature. This research highlights the importance of promoting safe and responsible healthcare behaviors among students. Methods: A systematic search was conducted in the Scopus database to retrieve all peer-reviewed English articles and reviews published from 1968 onwards. The retrieved documents were analyzed to identify publication trends, citation counts, top journals, geographical distribution, and emerging research themes. Results: The findings indicate a significant increase in published literature about student self-medication over the past fifteen years. However, it was observed that the citation count for these documents was lower than expected, suggesting a need for increased attention toward this critical topic. The analysis also identified several hot topics in student self-medication, including the misuse of over-the-counter medications, dietary supplements, and psychoactive substances. The inappropriate use of antibiotics and the self-medication of mental health issues, such as anxiety and depression, were also identified as significant problems. Conclusions and recommendations: Self-medication among students is a complex and critical issue that requires immediate attention. This study highlights the urgent need for greater awareness and education regarding responsible self-medication practices among students. New policies, interventions, and strategies should be developed to address malpractices, misconceptions, and harmful practices related to self-medication. Educational institutions and health authorities should play a crucial role in providing students with mental health resources and support services... (AU)

Association of proton pump inhibitor use with survival and adverse effects outcomes in patients with multiple myeloma: pooled analysis of three clinical trials.

Proton pump inhibitors (PPIs) are commonly used in cancer patients, but their impact on treatment outcomes in multiple myeloma (MM) patients remains unclear. This study investigated the association of PPI use with survival and adverse effects in MM patients across three randomized-control trials initiating daratumumab, lenalidomide, or bortezomib combination treatments. Cox proportional hazard analysis and logistic regression were employed to assess the associations with treatment outcomes, while adjusting for age, sex, weight, MM international staging system stage, ECOG-performance status, comorbidity count, and presence of gastrointestinal disorders. Pooled data involving 1804 patients revealed that 557 (32%) used PPIs at baseline. PPI use was independently associated with worse overall survival (adjusted HR [95% CI] 1.32 [1.08-1.62], P = 0.007) and grade ≥ 3 adverse events (adjusted OR [95% CI] 1.39 [1.03-1.88], P = 0.030). However, the association with progression-free survival did not reach statistical significance (adjusted HR [95% CI] 1.14 [0.97-1.33], P = 0.112). Findings were consistent across trials and treatment arms. PPI use was identified as a negative prognostic factor in MM patients, potentially enhancing clinical decisions regarding its use. Further research is needed to fully comprehend the impacts and safety of PPI use in MM patients.

Giant Armadillo Optimization: A New Bio-Inspired Metaheuristic Algorithm for Solving Optimization Problems.

In this paper, a new bio-inspired metaheuristic algorithm called Giant Armadillo Optimization (GAO) is introduced, which imitates the natural behavior of giant armadillo in the wild. The fundamental inspiration in the design of GAO is derived from the hunting strategy of giant armadillos in moving towards prey positions and digging termite mounds. The theory of GAO is expressed and mathematically modeled in two phases: (i) exploration based on simulating the movement of giant armadillos towards termite mounds, and (ii) exploitation based on simulating giant armadillos' digging skills in order to prey on and rip open termite mounds. The performance of GAO in handling optimization tasks is evaluated in order to solve the CEC 2017 test suite for problem dimensions equal to 10, 30, 50, and 100. The optimization results show that GAO is able to achieve effective solutions for optimization problems by benefiting from its high abilities in exploration, exploitation, and balancing them during the search process. The quality of the results obtained from GAO is compared with the performance of twelve well-known metaheuristic algorithms. The simulation results show that GAO presents superior performance compared to competitor algorithms by providing better results for most of the benchmark functions. The statistical analysis of the Wilcoxon rank sum test confirms that GAO has a significant statistical superiority over competitor algorithms. The implementation of GAO on the CEC 2011 test suite and four engineering design problems show that the proposed approach has effective performance in dealing with real-world applications.

Exploring the Use of YouTube as a Pathology Learning Tool and Its Relationship With Pathology Scores Among Medical Students: Cross-Sectional Study.

BACKGROUND: YouTube is considered one of the most popular sources of information among college students. OBJECTIVE: This study aimed to explore the use of YouTube as a pathology learning tool and its relationship with pathology scores among medical students at Jordanian public universities. METHODS: This cross-sectional, questionnaire-based study included second-year to sixth-year medical students from 6 schools of medicine in Jordan. The questionnaire was distributed among the students using social platforms over a period of 2 months extending from August 2022 to October 2022. The questionnaire included 6 attributes. The first section collected demographic data, and the second section investigated the general use of YouTube and recorded material. The remaining 4 sections targeted the participants who used YouTube to learn pathology including using YouTube for pathology-related content. RESULTS: As of October 2022, 699 students were enrolled in the study. More than 60% (422/699, 60.4%) of the participants were women, and approximately 50% (354/699, 50.6%) were second-year students. The results showed that 96.5% (675/699) of medical students in Jordan were using YouTube in general and 89.1% (623/699) were using it as a source of general information. YouTube use was associated with good and very good scores among the users. In addition, 82.3% (575/699) of medical students in Jordan used YouTube as a learning tool for pathology in particular. These students achieved high scores, with 428 of 699 (61.2%) students scoring above 70%. Most participants (484/699, 69.2%) reported that lectures on YouTube were more interesting than classic teaching and the lectures could enhance the quality of learning (533/699, 76.3%). Studying via YouTube videos was associated with higher odds (odds ratio [OR] 3.86, 95% CI 1.33-11.18) and lower odds (OR 0.27, 95% CI 0.09-0.8) of achieving higher scores in the central nervous system and peripheral nervous system courses, respectively. Watching pathology lectures on YouTube was related to a better chance of attaining higher scores (OR 1.96, 95% CI 1.08-3.57). Surprisingly, spending more time watching pathology videos on YouTube while studying for examinations corresponded with lower performance, with an OR of 0.46 (95% CI 0.26-0.82). CONCLUSIONS: YouTube may play a role in enhancing pathology learning, and aiding in understanding, memorization, recalling information, and obtaining higher scores. Many medical students in Jordan have positive attitudes toward using YouTube as a supplementary pathology learning tool. Based on this, it is recommended that pathology instructors should explore the use of YouTube and other emerging educational tools as potential supplementary learning resources.

Impact of Thermal Maturation of the Upper Cretaceous Bituminous Limestone of Attarat Um Ghudran Central Jordan on Calcareous Nannofossil Preservation.

Oil shale deposits of the Late Cretaceous from three boreholes in central Jordan were examined to assess the impact of thermal maturation on the content of nannofossils. Thermal activity has been shown to have a strong effect on organic matter content and composition but its effect on calcareous nannofossil assemblages remains inconclusive. This study aims to determine the impact of thermal maturation on nannofossil assemblages and to compare this to an estimated maturity level based on bulk geochemical analysis. Micropaleontological and geochemical analyses were conducted on 31 samples from three oil shale wells drilled in Attarat Um Ghudran central Jordan. Several types of nannofossil preservation have been recorded, including dissolution, overgrowth, and breakage. In the Jordan oil shale sections, nannofossils exhibit a variety of preservation types, with intense dissolution in the middle part of the study sections. The vast majority of the samples had high TOC enrichment, with 29 samples exceeding values of >10%. Kerogen recovery and quality from the oil shale are very good, with a predominance of fluorescent amorphous organic matter (AOM) and minor algal components. The low fluorescence preservation index (FPI), which is 1 in most of the samples, indicates that alteration occurred due to intense thermal activities in the study interval. The palynomorph and AOM fluorescence, ranging from a spore coloration index (SCI) of 3 to 5, suggest that the studied samples were approaching the oil window. A correlation between the nannofossil preservation and geochemical parameters shows a predominance of poorly preserved nannofossils along with high total organic carbon contents and an elevated hydrogen index (HI). We show that low FPI values and a higher level of maturity are associated with poor nannofossil preservation, suggesting that nannofossils, in conjunction with petrographic analysis of kerogen, could be used as a rapid screening technique for estimating levels of oil-shale maturity. The nature of the tectonism in the study area, including faulting and a metamorphosed zone, enhanced the maturity, which might explain why the nannofossils were so significantly affected.

Human dispersals out of Africa via the Levant.

Homo sapiens dispersed from Africa into Eurasia multiple times in the Middle and Late Pleistocene. The route, across northeastern Africa into the Levant, is a viable terrestrial corridor, as the present harsh southern Levant would probably have been savannahs and grasslands during the last interglaciation. Here, we document wetland sediments with luminescence ages falling in the last interglaciation in the southern Levant, showing protracted phases of moisture availability. Wetland sediments in Wadi Gharandal containing Levallois artifacts yielded an age of 84 ka. Our findings support the growing consensus for a well-watered Jordan Rift Valley that funneled migrants into western Asia and northern Arabia.

GRP78 is Overexpressed in Non-small Cell Lung Cancer Tissues and is Associated with High VEGF Expression in Squamous Cell Carcinoma: A Pilot Study.

BACKGROUND: Neovascularization is essential for the growth and progression of tumor tissues. GRP78 is frequently overexpressed in various cancers and has been suggested as a proangiogenic factor. PURPOSE: This study aimed to investigate the expression levels of GRP78 and to test for significant relationships with the angiogenic markers, VEGF, and CD31. METHODS: In this study, paraffin-embedded NSCLC tissue samples (71 adenocarcinomas and 23 squamous cell carcinoma) were retrospectively collected from 94 patients with NSCLC. The expressions of VEGF, CD31, and GRP78 were determined by immunohistochemistry. RESULTS: High expression levels of VEGF and GRP78 were observed in 65 and 74 cases, respectively. Thirty-six patients expressed high CD31 levels. Adenocarcinomas expressed higher levels of the three proteins than squamous cell carcinomas (p-value < 0.05). Moreover, a statistically significant association was found between the expression levels of VEGF and CD31 (p-value = 0.001) and VEGF and GRP78 (p-value=0.028). CONCLUSION: GRP78 overexpression was revealed in most of the investigated samples. The positive association between VEGF and GRP78 may indicate the proangiogenic role of GRP78 in lung cancer. Moreover, the positive association between VEGF and CD31 expression levels suggests that VEGF may cooperate with CD31 to promote angiogenesis in NSCLC.

Isolated lateral leg compartment syndrome: A case report.

BACKGROUND: Acute leg compartment syndrome is a well-known orthopedic emergency associated with potentially devastating consequences if not treated immediately. Multiple compartments are usually involved with a clear history of trauma and classic symptoms and signs. However, isolated lateral leg compartment syndrome is relatively rare and is often misdiagnosed due to the atypical presentation of no trauma and the lack of pathognomonic signs. CASE SUMMARY: A 31-year-old male patient presented to our emergency room with excruciating left calf pain and inability to mobilize one-day after participating in a football match despite no clear history of preceding trauma. The patient went to another hospital before presenting to us where he was diagnosed to have a soft tissue injury and was discharged home on simple analgesics. On clinical examination, the left leg showed a tense lateral compartment with severe tenderness. The pain was aggravated by dorsiflexion and ankle inversion. Neurovascular examination of the limb was normal. We suspected a compartment syndrome but as the presentation was atypical and an magnetic resonance imaging (MRI) was readily available in our institution, we immediately performed an MRI and this confirmed a large hematoma in the lateral compartment with a possible partial proximal peroneus longus muscle tear. The patient was taken immediately for an emergency open fasciotomy. The patient is now 18 mo postoperatively having recovered completely and engages fully in sports with no restrictions. CONCLUSION: Atypical presentation due to the lack of pathognomonic signs makes the diagnosis of isolated lateral leg compartment syndrome difficult. Pain on passive inversion and dorsiflexion and weak active eversion may be suggested as sensitive signs.

Prevalence and clinicopathological associations of HER2 expression in non-small cell lung cancer: a retrospective study in Jordanian patients.

BACKGROUND: Human epidermal growth factor receptor 2 (HER2), a promising therapeutic target, can be mutated, amplified, or overexpressed in different malignancies, including non-small cell lung cancer (NSCLC). Although these alterations showed adverse prognostic effects in many cancers, their clinical significance in NSCLC is controversial. This study primarily assessed the prevalence of HER2 protein expression in NSCLC among Jordanian patients. In addition, the possible association between HER2 protein expression and clinicopathological variables was evaluated. METHODS: A total of 100 surgically resected NSCLC cases treated at King Hussein Cancer Center (KHCC) between 2009 and 2021 were examined for HER2 protein expression using immunohistochemistry (IHC). The American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) guidelines for breast cancer were applied to interpret the results with a final score ranging from 0 to 3+, considering a score of 3 + as overexpression. Additionally, a separate subset of patients was tested for HER2 gene mutation. Fisher's exact test was used to assess the association between HER2 scores and the other variables. Kaplan-Meier method was used to calculate survival. RESULTS: Of the 100 cases, Her2 overexpression (score 3+) was detected in 2 cases (2%), score 2 + in 10 cases (10%), score 1 + in 12 cases (12%), and score 0 in 76 cases (76%). The two positive cases were one adenocarcinoma and one squamous cell carcinoma; both patients were elderly male smokers. No significant association was identified between Her2 expression and age, gender, smoking, histological subtype, grade, stage, tumor size, and lymph node status. Our findings also showed no association between Her2 expression and survival; however, advanced tumor stages and positive lymph node metastasis were significantly associated with poor overall survival. All cases tested for the Her2 mutation were negative. CONCLUSIONS: Her2 overexpression is uncommon in NSCLC among the Jordanian population. However, when the same scoring criteria are used, the rates are similar to other results found in Asian cohorts. Due to our study's relatively small sample size, a larger one is required to investigate the prognostic value and the molecular associations between the different Her2 alterations.

Spontaneous idiopathic intratesticular hemorrhage as a differential diagnosis for acute scrotal pain.

BACKGROUND: Spontaneous idiopathic testicular hemorrhage is an extremely rare entity with few published reports in the literature. CASE PRESENTATION: We report a case of a 15-year-old boy who had been experiencing intense, left scrotal pain for the previous twelve hours. No previous history of trauma or bleeding disorders. The left testis was enlarged and tender. Left orchiectomy was performed. The entire testis was dusty and dark grossly. Microscopic sections show diffuse intratesticular bleeding with intact seminiferous tubules and spermatogenesis. CONCLUSIONS: Spontaneous idiopathic testicular hemorrhage should be considered when evaluating patients with acute scrotal pain. Clinical and ultrasonographic findings and histopathologic evaluation are mandatory to diagnose it.

Lysionotin exerts antinociceptive effects in various models of nociception induction.

Background: Lysionotin, a natural flavonoid extracted from Lysionotus pauciflorus Maxim (Gesneriaceae), has several pharmacological effects including anti-bacterial, anti-hypertensive and anti-inflammatory effects. However, its analgesic effect has not been investigated. This study aimed to assess the antinociceptive activity of lysionotin using chemically and thermally induced nociception in a mouse model. Methods: The antinociceptive effects of various lysionotin doses (50, 100, 150, and 200 µg/kg) were assessed in mice using the acetic acid-induced writhing test, hot plate test, and formalin-induced paw licking assay. The effects were compared to those of mice treated with acetylsalicylic acid or morphine in the presence or absence of naloxone (an opioid receptor antagonist). Capsaicin- and glutamate-induced paw licking tests were also used to evaluate the involvement of the vanilloid and glutamatergic systems, respectively. Results: Lysionotin produced significant dose-dependent inhibition of nociceptive behavior in the acetic acid-induced writhing test, showing 60% inhibition at a dose of 200 µg/kg. Lysionotin also caused a significant increase in the latency period in response to the hot plate test (76.4% at 200 µg/kg), and significantly inhibited both the neurogenic and inflammatory phases in the formalin-induced paw licking test. Naloxone significantly reverses the effect of lysionotin in both hot plate test and formalin-induced paw licking test. Moreover, lysionotin significantly inhibited the neurogenic nociception induced by intraplantar injections of glutamate and capsaicin (57% and 67.2%, respectively at a dose of 200 µg/kg). Thus, lysionotin exhibited peripheral and central antinociception through the modulation of vanilloid receptors, opioid receptors, and the glutamatergic system. Conclusion: Lysionotin possesses antinociceptive activity on adult mice that is mediated through both central and peripheral pathways.

Analysis and mapping of global scientific research on human monkeypox over the past 20 years.

Background and Aim: Human monkeypox is an emerging global threat. Hundreds of publications were disseminated in the last few months. This study aimed to map, analyze, and evaluate the bibliometric indicators of the global monkeypox research output. Materials and Methods: All documents published in the past 20 years were retrieved using the Scopus database. Papers published in English and peer-reviewed journals were included. VOSviewer was used to create density and network visualization maps. Results: A total of 1725 published documents were retrieved. Of these, 53% were published in 2022. The average number of authors per document was 4.2. Authors from the USA were the most active and published about 42.1% of the total documents. International collaboration was evident between the USA and both UK and Congo. Keywords mapping identified the main research lines in this field that correlate monkeypox with public health, smallpox, vaccination, and antiviral treatment. Conclusion: This study analyzed and mapped the expanding field of monkeypox research across the world. The bibliometric analysis revealed that the United States has contributed greatly in terms of both individual researchers and academic institutions. There was less cooperation on a global scale than was anticipated. Fostering international cooperation is essential for countering this worldwide danger. Additional scientific research should be conducted to investigate the link between smallpox immunization and monkeypox epidemics.

Insights into the Molecular Mechanisms Mediating Extravasation in Brain Metastasis of Breast Cancer, Melanoma, and Lung Cancer.

Brain metastasis is an incurable end-stage of systemic cancer associated with poor prognosis, and its incidence is increasing. Brain metastasis occurs through a multi-step cascade where cancer cells spread from the primary tumor site to the brain. The extravasation of tumor cells through the blood-brain barrier (BBB) is a critical step in brain metastasis. During extravasation, circulating cancer cells roll along the brain endothelium (BE), adhere to it, then induce alterations in the endothelial barrier to transmigrate through the BBB and enter the brain. Rolling and adhesion are generally mediated by selectins and adhesion molecules induced by inflammatory mediators, while alterations in the endothelial barrier are mediated by proteolytic enzymes, including matrix metalloproteinase, and the transmigration step mediated by factors, including chemokines. However, the molecular mechanisms mediating extravasation are not yet fully understood. A better understanding of these mechanisms is essential as it may serve as the basis for the development of therapeutic strategies for the prevention or treatment of brain metastases. In this review, we summarize the molecular events that occur during the extravasation of cancer cells through the blood-brain barrier in three types of cancer most likely to develop brain metastasis: breast cancer, melanoma, and lung cancer. Common molecular mechanisms driving extravasation in these different tumors are discussed.

Leptin and the rs2167270 Polymorphism Are Associated with Glycemic Control in Type Two Diabetes Mellitus Patients on Metformin Therapy.

Background and Objectives: Type two diabetes mellitus (T2DM) is a chronic disease with debilitating complications and high mortality. Evidence indicates that good glycemic control delays disease progression and is hence a target of disease management protocols. Nonetheless, some patients cannot maintain glycemic control. This study aimed to investigate the association between serum leptin levels and several SNPs of the LEP gene with the lack of glycemic control in T2DM patients on metformin therapy. Materials and Methods: In a hospital-based case-control study, 170 patients with poor glycemic control and 170 patients with good glycemic control were recruited. Serum leptin was measured. Patients were genotyped for three SNPs in the LEP gene (rs7799039, rs2167270, and rs791620). Results: Serum leptin was significantly lower in T2DM patients with poor glycemic control (p < 0.05). In multivariate analysis, serum leptin levels significantly lowered the risk of having poor glycemic control (OR = 0.985; CI: 0.976-0.994; p = 0.002); moreover, the GA genotype of rs2167270 was protective against poor glycemic control compared to the GG genotype (OR = 0.417; CI: 0.245-0.712; p = 0.001). Conclusions: Higher serum leptin and the GA genotype of the rs2167270 SNP of the LEP gene were associated with good glycemic control in T2DM patients on metformin therapy. Further studies with a larger sample size from multiple institutions are required to validate the findings.

The Emerging Importance of Cirsimaritin in Type 2 Diabetes Treatment.

Cirsimaritin is a dimethoxy flavon that has different biological activities such as antiproliferative, antimicrobial, and antioxidant activities. This study aims to investigate the anti-diabetic effects of cirsimaritin in a high-fat diet and streptozotocin-(HFD/STZ)-induced rat model of type 2 diabetes mellitus (T2D). Rats were fed HFD, followed by a single low dose of STZ (40 mg/kg). HFD/STZ diabetic rats were treated orally with cirsimaritin (50 mg/kg) or metformin (200 mg/kg) for 10 days before terminating the experiment and collecting plasma, soleus muscle, adipose tissue, and liver for further downstream analysis. Cirsimaritin reduced the elevated levels of serum glucose in diabetic rats compared to the vehicle control group (p < 0.001). Cirsimaritin abrogated the increase in serum insulin in the treated diabetic group compared to the vehicle control rats (p < 0.01). The homeostasis model assessment of insulin resistance (HOMA-IR) was decreased in the diabetic rats treated with cirsimaritin compared to the vehicle controls. The skeletal muscle and adipose tissue protein contents of GLUT4 (p < 0.01 and p < 0.05, respectively) and pAMPK-α1 (p < 0.05) were upregulated following treatment with cirsimaritin. Cirsimaritin was able to upregulate GLUT2 and AMPK protein expression in the liver (p < 0.01, <0.05, respectively). LDL, triglyceride, and cholesterol were reduced in diabetic rats treated with cirsimaritin compared to the vehicle controls (p < 0.001). Cirsimaritin reduced MDA, and IL-6 levels (p < 0.001), increased GSH levels (p < 0.001), and reduced GSSG levels (p < 0.001) in diabetic rats compared to the vehicle control. Cirsimaritin could represent a promising therapeutic agent to treat T2D.

Inhibition of transglutaminase 2 (TG2) ameliorates ventricular fibrosis in isoproterenol-induced heart failure in rats.

AIMS: Transglutaminase (TG) inhibitors represent promising therapeutic interventions in cardiac fibrosis and related dysfunctions. However, it remains unknown how TG inhibition, TG2 in particular, affects the signaling systems that drive pathological fibrosis. This study aimed to examine the effect TG inhibition by cystamine on the progression of isoproterenol (ISO)-induced cardiac fibrosis and dysfunction in rats. MATERIALS AND METHODS: Cardiac fibrosis was established by intraperitoneal injection of ISO to rats (ISO group), followed by 6 weeks of cystamine injection (ISO + Cys group). The control groups were administered normal saline alone or with cystamine. Hemodynamics, lipid profile, liver enzymes, urea, and creatinine were assessed in conjunction with heart failure markers (serum NT-proANP and cTnI). Left ventricular (LV) and atrial (LA) fibrosis, total collagen content, and mRNA expression of profibrotic markers including TG2 were quantified by Masson's trichrome staining, LC-MS/MS and quantitative PCR, respectively. KEY FINDINGS: Cystamine administration to ISO rats significantly decreased diastolic and mean arterial pressures, total cholesterol, triglycerides, LDL, liver enzymes, urea, and creatinine levels, while increasing HDL. NT-proANP and cTnI serum levels remained unchanged. In LV tissues, significant reductions in ISO-induced fibrosis and elevated total collagen content were achieved after cystamine treatment, together with a reduction in TG2 concentration. Reduced mRNA expression of several profibrotic genes (COL1A1, FN1, MMP-2, CTGF, periostin, CX43) was also evidenced in LV tissues of ISO rats upon cystamine administration, whereas TGF-ß1 expression was depressed in LA tissues. Cystamine decreased TG2 mRNA expression in the LV of control rats, while LV expression of TG2 was relatively low in ISO rats irrespective of cystamine treatment. SIGNIFICANCE: TG2 inhibition by cystamine in vivo exerted cardioprotective effects against ISO-induced cardiac fibrosis in rats decreasing the LV abundance of several profibrotic markers and the content of TG2 and collagen, suggesting that TG2 pharmacological inhibition could be beneficial to alleviate cardiac fibrosis.

Expression of substance P, neurokinin 1 receptor, Ki-67 and pyruvate kinase M2 in hormone receptor negative breast cancer and evaluation of impact on overall survival.

BACKGROUND: Chronic inflammation is a hallmark of cancer, and it can be stimulated by many factors. Substance P (SP), through binding to neurokinin 1 receptor (NK1R), and pyruvate kinase M2 (PKM2) play critical roles in cancer development and progression via modulating the tumor microenvironment. This study aimed to investigate the prognostic significance of SP and PKM2 in combination with NK1R and Ki-67 in hormone receptor negative (HR-ve) breast cancer. METHODS: Immunohistochemical expression levels of SP, NK1R, PKM2, and Ki-67 were measured in 144 paraffin-embedded breast cancer tissues (77 h -ve and 67 h + ve). SP, NK1R, and PKM2 were scored semiquantitatively, while Ki-67 was obtained by the percentage of total number of tumor cells with nuclear staining. The optimal cutoff value for SP, NK1R, PKM2, and Ki-67 were assessed by Cutoff Finder. RESULTS: High SP expression in HR -ve breast cancer was associated with TNM stage (p = 0.020), pT stage (p = 0.035), pN stage (p = 0.002), axillary lymph node metastasis (p = 0.003), and NK1R expression level (p = 0.010). In HR + ve breast cancer, SP expression was associated with HER2 status (p = 0.001) and PKM2 expression level (p = 0.012). Regarding PKM2 expression level, it significantly associated with HER2 status (p = 0.001) and history of DCIS (p = 0.046) in HR-ve tumors, and with HER2 status (p < 0.001) and SP expression level (p = 0.012) in HR + ve tumors. Survival analysis revealed that high SP level negatively impacted overall survival in HR-ve tumors that had low NK1R level (p = 0.021). Moreover, high SP negatively impacted overall survival in HR-ve tumors that had low Ki-67 level (p = 0.005). High PKM2 negatively impacted overall survival in HR-ve cases with low SP (p = 0.047). CONCLUSION: Combined expression levels of SP with NK1R or Ki-67, and PKM2 with SP could be used to predict survival in breast cancer patients with HR-ve tumors. Our findings suggest a role of SP/NK1R pathway and PKM2 in HR-ve breast cancer pathogenesis which should be further investigated to unveil the underlying molecular mechanisms.

Involvement and possible role of transglutaminases 1 and 2 in mediating fibrotic signalling, collagen cross-linking and cell proliferation in neonatal rat ventricular fibroblasts.

Transglutaminase (TG) isoforms control diverse normal and pathophysiologic processes through their capacity to cross-link extracellular matrix (ECM) proteins. Their functional and signalling roles in cardiac fibrosis remain poorly understood, despite some evidence of TG2 involvement in abnormal ECM remodelling in heart diseases. In this study, we investigated the role of TG1 and TG2 in mediating fibrotic signalling, collagen cross-linking, and cell proliferation in healthy fibroblasts by siRNA-mediated knockdown. siRNA for TG1, TG2 or negative control was transfected into cultured neonatal rat ventricular fibroblasts and cardiomyocytes. mRNA expression of TGs and profibrotic, proliferation and apoptotic markers was assessed by qPCR. Cell proliferation and soluble and insoluble collagen were determined by ELISA and LC-MS/MS, respectively. TG1 and TG2 were both expressed in neonatal rat cardiomyocytes and fibroblasts before transfection. Other TGs were not detected before and after transfection. TG2 was predominantly expressed and more effectively silenced than TG1. Knocking down TG1 or TG2 significantly modified profibrotic markers mRNA expression in fibroblasts, decreasing connective tissue growth factor (CTGF) and increasing transforming growth factor-ß1 compared to the negative siRNA control. Reduced expression of collagen 3A1 was found upon TG1 knockdown, while TG2 knockdown raised α-smooth muscle actin expression. TG2 knockdown further increased fibroblast proliferation and the expression of proliferation marker cyclin D1. Lower insoluble collagen content and collagen cross-linking were evidenced upon silencing TG1 or TG2. Transcript levels of collagen 1A1, fibronectin 1, matrix metalloproteinase-2, cyclin E2, and BCL-2-associated X protein/B-cell lymphoma 2 ratio were strongly correlated with TG1 mRNA expression, whereas TG2 expression correlated strongly with CTGF mRNA abundance. These findings support a functional and signalling role for TG1 and TG2 from fibroblasts in regulating key processes underlying myocardial ECM homeostasis and dysregulation, suggesting that these isoforms could be potential and promising targets for the development of cardiac fibrosis therapies.

Isorhamnetin Reduces Glucose Level, Inflammation, and Oxidative Stress in High-Fat Diet/Streptozotocin Diabetic Mice Model.

Background: Isorhamnetin is a flavonoid that is found in medical plants. Several studies showed that isorhamnetin has anti-inflammatory and anti-obesity effects. This study aims to investigate the anti-diabetic effects of isorhamnetin in a high-fat diet and Streptozotocin-(HFD/STZ)-induced mice model of type 2 diabetes. Materials and Methods: Mice were fed with HFD followed by two consecutive low doses of STZ (40 mg/kg). HFD/STZ diabetic mice were treated orally with isorhamnetin (10 mg/kg) or (200 mg/kg) metformin for 10 days before sacrificing the mice and collecting plasma and soleus muscle for further analysis. Results: Isorhamnetin reduced the elevated levels of serum glucose compared to the vehicle control group (p < 0.001). Isorhamnetin abrogated the increase in serum insulin in the treated diabetic group compared to the vehicle control mice (p < 0.001). The homeostasis model assessment of insulin resistance (HOMA-IR) was decreased in diabetic mice treated with isorhamnetin compared to the vehicle controls. Fasting glucose level was significantly lower in diabetic mice treated with isorhamnetin during the intraperitoneal glucose tolerance test (IPGTT) (p < 0.001). The skeletal muscle protein contents of GLUT4 and p-AMPK-α were upregulated following treatment with isorhamnetin (p > 0.01). LDL, triglyceride, and cholesterol were reduced in diabetic mice treated with isorhamnetin compared to vehicle control (p < 0.001). Isorhamnetin reduced MDA, and IL-6 levels (p < 0.001), increased GSH levels (p < 0.001), and reduced GSSG levels (p < 0.05) in diabetic mice compared to vehicle control. Conclusions: Isorhamnetin ameliorates insulin resistance, oxidative stress, and inflammation. Isorhamnetin could represent a promising therapeutic agent to treat T2D.