Role of diosmin in preventing doxorubicin-induced cardiac oxidative stress, inflammation, and hypertrophy: A mechanistic approach.

Chemotherapeutic drugs, such as doxorubicin (Dox), are commonly used to treat a variety of malignancies. However, Dox-induced cardiotoxicity limits the drug's clinical applications. Hence, this study intended to investigate whether diosmin could prevent or limit Dox-induced cardiotoxicity in an animal setting. Thirty-two rats were separated into four distinct groups of controls, those treated with Dox (20 mg/kg, intraperitoneal, i.p.), those treated with diosmin 100 mg plus Dox, and those treated with diosmin 200 mg plus Dox. At the end of the experiment, rats were anesthetized and sacrificed and their blood and hearts were collected. Cardiac toxicity markers were analyzed in the blood, and the heart tissue was analyzed by the biochemical assays MDA, GSH, and CAT, western blot analysis (NF-kB, IL-6, TLR-4, TNF-α, iNOS, and COX-2), and gene expression analysis (ß-MHC, BNP). Formalin-fixed tissue was used for histopathological studies. We demonstrated that a Dox insult resulted in increased oxidative stress, inflammation, and hypertrophy as shown by increased MDA levels and reduced GSH content and CAT activity. Furthermore, Dox treatment induced cardiac hypertrophy and damage, as evidenced by the biochemical analysis, ELISA, western blot analysis, and gene expression analysis. However, co-administration of diosmin at both doses, 100 mg and 200 mg, mitigated these alterations. Data derived from the current research revealed that the cardioprotective effect of diosmin was likely due to its ability to mitigate oxidative stress and inflammation. However, further study is required to investigate the protective effects of diosmin against Dox-induced cardiotoxicity.

Comprehensive Transcriptome Analysis Reveals the Distinct Gene Expression Patterns of Tumor Microenvironment in HPV-Associated and HPV-Non Associated Tonsillar Squamous Cell Carcinoma.

Head and neck squamous cell carcinomas (HNSCCs) are a common type of cancer, ranking as the sixth most prevalent cancer worldwide and having a high morbidity and mortality rate. Among oropharyngeal squamous cell carcinoma (OPSCC) cancers, tonsillar squamous cell carcinoma (TSCC) is the most prevalent and has a particularly aggressive clinical course with poor disease outcomes. The tumor microenvironment (TME) of HNSCC is complex and heterogeneous, playing a crucial role in effective cancer therapy. Understanding the interaction between cancer inflammation, immunity, oncogenes, and tumor suppressor genes is essential for developing effective cancer treatments. This study aimed to gain a comprehensive understanding of the transcriptomes of the TME in TSCC, both associated with human papillomavirus (HPV) and not associated with HPV. The gene expression profiles of 168 genes linked to various cellular mediators and factors involved in inflammation, immunity crosstalk, transcription, signal transduction, oncogenesis, tumor suppression, angiogenesis, and apoptosis were analyzed. We identified 40 differentially expressed genes related to the communication between tumor cells and the cellular mediators of inflammation and immunity crosstalk. In HPV-positive TSCC patients, 33 genes were over-expressed with a fold change greater than 1.5, and 26 of these genes were unique to this group. In contrast, HPV-negative TSCC patients had 11 up-regulated genes. The results further showed that 48 gene transcripts related to oncogenesis, tumor suppression, angiogenesis, and apoptosis were up-regulated in both HPV-positive and HPV-negative TSCC patients. Among the HPV-positive TSCC patients, 37 genes were over-expressed, while the HPV-negative TSCC patients had 11 up-regulated genes. The tumor microenvironment (TME) of HPV-associated and HPV-non-associated TSCC exhibited distinct characteristics, including the dysregulation of various genes involved in cellular mediators, inflammation, immunity crosstalk, transcription factors, immune signaling pathways, signal transduction, oncogenesis, tumor suppression, angiogenesis, and apoptosis. Additionally, we detected six Hr-HPV genotypes in 81% of the TSCC patients, with HPV-16 and HPV-35 being the most common types, followed by HPV-45 and HPV-18. HPV-39 and 31 were also identified. The presence of Hr-HPV genotypes in TSCC patients varied from single to multiple infections. In conclusion, we observed distinct heterogeneity in the transcriptome of the microenvironment in HPV-associated and non-associated TSCC. Further in vitro and in vivo studies are needed to investigate the functional implications of the identified over-expressed genes. Also, deeper molecular pathways and immunological studies on the TME are required to determine the potential of targeting genes for cancer therapy.

Primary Adrenal Angiosarcoma and its Management: A Case Report.

Primary adrenal angiosarcoma is a very rare malignancy. This is a case report of a 54-year-old female, who presented with right-sided abdominal pain. Magnetic resonance imaging of the abdomen and pelvis showed a right adrenal mass with a maximum dimension of 5.7 cm. The patient went for a laparoscopic right adrenalectomy. The postoperative period was uneventful, and she was discharged on postoperative day 2. The patient was free from complaints at outpatient follow-up visits. Pathology confirmed the diagnosis of adrenal angiosarcoma and the metastasis workup was negative. A multidisciplinary approach through the expertise of medical oncology, surgical oncology, and histopathology is essential for the diagnosis and management of such rare diseases.

Liver Metabolomics and Inflammatory Profiles in Mouse Model of Fentanyl Overdose Treated with Beta-Lactams.

Fentanyl is a highly potent opioid analgesic that is approved medically to treat acute and chronic pain. There is a high potential for overdose-induced organ toxicities, including liver toxicity, and this might be due to the increase of recreational use of opioids. Several preclinical studies have demonstrated the efficacy of beta-lactams in modulating the expression of glutamate transporter-1 (GLT-1) in different body organs, including the liver. The upregulation of GLT-1 by beta-lactams is associated with the attenuation of hyperglutamatergic state, which is a characteristic feature of opioid use disorders. A novel experimental beta-lactam compound with no antimicrobial properties, MC-100093, has been developed to attenuate dysregulation of glutamate transport, in part by normalizing GLT-1 expression. A previous study showed that MC-100093 modulated hepatic GLT-1 expression with subsequent attenuation of alcohol-increased fat droplet content in the liver. In this study, we investigated the effects of fentanyl overdose on liver metabolites, and determined the effects of MC-100093 and ceftriaxone in the liver of a fentanyl overdose mouse model. Liver samples from control, fentanyl overdose, and fentanyl overdose ceftriaxone- or MC-100093-treated mice were analyzed for metabolomics using gas chromatography-mass spectrometry. Heatmap analysis revealed that both MC-100093 and ceftriaxone attenuated the effects of fentanyl overdose on several metabolites, and MC-100093 showed superior effects. Statistical analysis showed that MC-100093 reversed the effects of fentanyl overdose in some metabolites. Moreover, enrichment analysis revealed that the altered metabolites were strongly linked to the glucose-alanine cycle, the Warburg effect, gluconeogenesis, glutamate metabolism, lactose degradation, and ketone body metabolism. The changes in liver metabolites induced by fentanyl overdose were associated with liver inflammation, an effect attenuated with ceftriaxone pre-treatments. Ceftriaxone normalized fentanyl-overdose-induced changes in liver interleukin-6 and cytochrome CYP3A11 (mouse homolog of human CYP3A4) expression. Our data indicate that fentanyl overdose impaired liver metabolites, and MC-100093 restored certain metabolites.

Dapagliflozin Mitigates Hypotension in Lipopolysaccharide-Induced Acute Inflammation Independent of Glycemia Level.

Sodium-glucose cotransporter-2 (SGLT2) inhibitors have been suggested to have anti-inflammatory properties in diabetes. The goal of this study was to evaluate the role of the SGLT2 inhibitor dapagliflozin (DAPA) in the attenuation of lipopolysaccharide (LPS)-induced hypotension. Male Wistar albino rats were divided into normal and diabetic groups and received DAPA (1 mg/kg/day) for two weeks followed by a single dose of 10 mg/kg LPS. Blood pressure was recorded throughout the study and the circulatory levels of cytokines were assessed using a multiplex array, while the aortas were harvested for analysis. DAPA attenuated the vasodilation and hypotension caused by LPS. Mean arterial pressure (MAP) was preserved in the normal and diabetic DAPA-treated septic groups (MAP = 83.17 ± 5.27, 98.43 ± 5.57 mmHg) compared to the vehicle-treated septic groups (MAP = 65.60 ± 3.31, 68.21 ± 5.88 mmHg). Most of the cytokines induced by LPS were decreased in the DAPA-treated septic groups. In the aorta, the inducible nitric oxide synthase-derived nitric oxide had lower expression in the DAPA-treated rats. In contrast, the expression of α-smooth muscle actin, a marker of the vessel's contractile state, was higher in the DAPA-treated rats in comparison with non-treated septic rats. These findings revealed that the protective role of DAPA against LPS-induced hypotension is likely to be glucose-lowering independent, as was observed in the non-diabetic septic group. Taken together, the results show that DAPA has a potential effect in the prevention of the hemodynamic disturbances of sepsis regardless of glycemia levels.

Evidence of Association between CTLA-4 Gene Polymorphisms and Colorectal Cancers in Saudi Patients.

Cytotoxic T lymphocyte antigen-4 (CTLA-4) has been identified as an immunosuppressive molecule involved in the negative regulation of T cells. It is highly expressed in several types of autoimmune diseases and cancers including colorectal cancer (CRC). (1) Objective: To explore the association between CTLA-4 single nucleotide polymorphisms (SNP) and risk to (CRC) in the Saudi population. (2) Methods: In this case-control study, 100 patients with CRC and 100 matched healthy controls were genotyped for three CTLA-4 SNPs: rs11571317 (-658C > T), rs231775 (+49A > G) and rs3087243 (CT60 G > A), using TaqMan assay method. Associations were evaluated using odds ratios (ORs) and 95% confidence intervals (95% CIs) for five inheritance models (co-dominant, dominant, recessive, over-dominant and log-additive). Furthermore, CTLA-4 expression levels were evaluated using quantitative real-time PCR (Q-RT-PCR) in colon cancer and adjacent colon tissues. (3) Results: Our result showed a significant association of the G allele (OR = 2.337, p < 0.0001) and GG genotype of the missense SNP +49A > G with increased risk of developing CRC in codominant (OR = 8.93, p < 0.0001) and recessive (OR = 16.32, p < 0.0001) models. Inversely, the AG genotype was significantly associated with decreased risk to CRC in the codominant model (OR = 0.23, p < 0.0001). In addition, the CT60 G > A polymorphism exhibited a strong association with a high risk of developing CRC for the AA genotype in codominant (OR = 3.323, p = 0.0053) and in allele models (OR = 1.816, p = 0.005). No significant association was found between -658C > T and CRC. The haplotype analysis showed that the G-A-G haplotype of the rs11571317, rs231775 and rs3087243 was associated with high risk for CRC (OR = 57.66; p < 0.001). The CTLA-4 mRNA gene expression was found significantly higher in tumors compared to normal adjacent colon samples (p < 0.001). (4) Conclusions: Our findings support an association between the CTLA-4 rs231775 (+49A > G) and rs3087243 (CT60 G > A) polymorphisms and CRC risk in the Saudi population. Further validation in a larger cohort size is needed prior to utilizing these SNPs as a potential screening marker in the Saudi population.

Diagnostic performances of celiac disease serological tests among Saudi patients.

Background: : The prevalence of celiac disease (CD) is relatively high in Saudi Arabia, and little is known about the accuracy of serological markers in the local population. This study aimed to assess the diagnostic performance of various serological markers for detecting CD in Saudi children and adults. Methods: We conducted a retrospective study of 148 CD patients and 512 controls to assess the diagnostic performances of IgA anti-tissue transglutaminase antibodies (TTG), IgG anti-TTG, IgA anti-deamidated gliadin peptide antibodies (anti-DGP), IgG anti-DGP, and endomysium antibodies (EMA). Results: : Immunoglobulin A (IgA) anti-TTG was the most sensitive test [98.9% (95% confidence interval (CI) 94.1-99.8%)], while EMA was the most specific [100%, 95%CI 98.6-100%]. By applying the criteria of IgA anti-TTG titers ≥10 × upper limit of normal (ULN) and positive EMA, 57.3% of patients could have avoided intestinal biopsy. IgG anti-DGP test had a sensitivity of 85.9% (95% CI = 77.3-91.5%) and a specificity of 93.5% (95% CI = (90.0-95.9%). Titers of IgA anti-TTG, IgA anti-DGP, and IgG anti-DGP were higher in CD patients with the Marsh 3c class than in those with the Marsh 3b and Marsh 3a classes. IgG anti-TTG and IgA anti-DGP had no additional diagnostic value. Conclusions: : IgA anti-TTG and EMA are excellent CD markers in children and adults. The use of IgA anti-TTG titers ≥10 × ULN and positive EMA as criteria for CD diagnosis in children and adults might be a good alternative to intestinal biopsy.

Valsartan prevents gefitinib-induced lung inflammation, oxidative stress, and alteration of plasma metabolites in rats.

Gefitinib (GEF) is an inhibitor of the epidermal growth factor receptor, linked to higher risk of severe/fatal interstitial lung disease (ILD). This study was performed to determine the protective roles of an angiotensin-II type-1 receptor (AT1R) "valsartan (VAL)" in prevention of lung inflammation, oxidative stress and metabolites alteration induced by GEF. Four groups of male Wistar albino rats were received vehicle, VAL (30 mg/kg), GEF (30 mg/kg), or both for four weeks. Blood samples and lungs were harvested for plasma metabolites and histological analysis, respectively, and evaluation of inflammation and oxidative stress. GEF monotherapy showed a dense inflammation in lungs, and significantly increased tumor necrosis factor-α (P = 0.0349), interleukin-6 (P < 0.0001), chemokine ligand-3 (P = 0.0420), and interleukin-1ß (P = 0.0377). GEF increased oxidative stress markers including glutathione, malondialdehyde, and catalase levels. Also, several plasma metabolites including butanoic acid, N-methylphenylethanolamine, oxalic acid, l-alanine, phosphoric acid, l-theorinine, pyroglutamic acid, and 2-bromosebacic acid were changed by GEF. The combination of VAL plus GEF reduced the inflammation and oxidative stress mediated by GEF monotherapy. In addition, the combination treatment returned plasma metabolites to the normal levels compared to GEF monotherapy. These findings revealed that VAL has a possible pulmonary protective role against pulmonary toxicity of GEF, which may lead to novel approaches for management of GEF-induced ILD.

Angiotensin II type 1 receptor blockade attenuates gefitinib-induced cardiac hypertrophy via adjusting angiotensin II-mediated oxidative stress and JNK/P38 MAPK pathway in a rat model.

Gefitinib is a tyrosine kinase inhibitor (TKI) of the epidermal growth factor receptor (EGFR), used for the treatment of advanced or metastatic non-small cell lung cancer. Recently, studies proved that Gefitinib-induced cardiotoxicity through induction of oxidative stress leads to cardiac hypertrophy. The current study was conducted to understand the mechanisms underlying gefitinib-induced cardiac hypertrophy through studying the roles of angiotensin II (AngII), oxidative stress, and mitogen-activated protein kinase (MAPK) pathway. Male Wistar albino rats were treated with valsartan, gefitinib, or both for four weeks. Blood samples were collected for AngII and cardiac markers measurement, and hearts were harvested for histological study and biochemical analysis. Gefitinib caused histological changes in the cardiac tissues and increased levels of cardiac hypertrophy markers, AngII and its receptors. Blocking of AngII type 1 receptor (AT1R) via valsartan protected hearts and normalized cardiac markers, AngII levels, and the expression of its receptors during gefitinib treatment. valsartan attenuated gefitinib-induced NADPH oxidase and oxidative stress leading to down-regulation of JNK/p38-MAPK pathway. Collectively, AT1R blockade adjusted AngII-induced NADPH oxidase and JNK/p38-MAPK leading to attenuation of gefitinib-induced cardiac hypertrophy. This study found a pivotal role of AngII/AT1R signaling in gefitinib-induced cardiac hypertrophy, which may provide novel approaches in the management of EGFRIs-induced cardiotoxicity.

A Constitutional Mismatch Repair Deficiency Syndrome Presented With an Advanced Rectal Cancer in a Juvenile Female: A Case Report and Literature Review.

The constitutional mismatch repair deficiency (CMMRD) syndrome is a rare and challenging condition with a poor prognosis. It results from biallelic mismatch repair gene mutations and leads to multiorgan cancers. Therefore, we report the first case of advanced juvenile rectal cancer related to CMMRD syndrome in the Gulf region. She is a 13-year-old female, born to non-consanguineous parents with a positive family history of malignancy, presented with an eight-month history of a retractable bulging anal mass associated with diarrhea mixed with blood and constitutional symptoms. She was cachectic with café au lait spots all over her body. Upon investigation, she was found to have invasive rectal adenocarcinoma. The case was started on neoadjuvant chemoradiotherapy in addition to genetic testing which showed a homozygous pathogenic variant in PMS2, indicating CMMRD syndrome. The patient underwent pre-operative post-neoadjuvant reassessment followed by laparoscopic total proctocolectomy with ileal J-pouch creation and ileoanal anastomosis with temporary diverting loop ileostomy which later on was reversed with no complications or recurrence. The family declined to continue the adjuvant therapy but accepted the surveillance programs and genetic testing. Unusual or late presentation secondary to a very rare syndrome like CMMRD is a major challenge to clinicians, hence a high index of suspicion and proper utilization of genetics programs might be the best available solutions.

Venetoclax Induces Cardiotoxicity through Modulation of Oxidative-Stress-Mediated Cardiac Inflammation and Apoptosis via NF-κB and BCL-2 Pathway.

Cardiovascular damage induced by anticancer therapy has become the main health problem after tumor elimination. Venetoclax (VTX) is a promising novel agent that has been proven to have a high efficacy in multiple hematological diseases, especially acute myeloid leukemia (AML) and chronic lymphocytic leukemia (CLL). Considering its mechanism of action, the possibility that VTX may cause cardiotoxicity cannot be ruled out. Therefore, this study was designed to investigate the toxic effect of VTX on the heart. Male Sprague-Dawley rats were randomly divided into three groups: control, low-dose VTX (50 mg/kg via oral gavage), and high-dose VTX (100 mg/kg via oral gavage). After 21 days, blood and tissue samples were collected for histopathological, biochemical, gene, and protein analyses. We demonstrated that VTX treatment resulted in cardiac damages as evidenced by major changes in histopathology and markedly elevated cardiac enzymes and hypertrophic genes markers. Moreover, we observed a drastic increase in oxidative stress, as well as inflammatory and apoptotic markers, with a remarkable decline in the levels of Bcl-2. To the best of our knowledge, this study is the first to report the cardiotoxic effect of VTX. Further experiments and future studies are strongly needed to comprehensively understand the cardiotoxic effect of VTX.

Geraniol Ameliorates Doxorubicin-Mediated Kidney Injury through Alteration of Antioxidant Status, Inflammation, and Apoptosis: Potential Roles of NF-κB and Nrf2/Ho-1.

Doxorubicin-mediated kidney impairment is a serious problem in cancer treatment. Accordingly, this work investigated the ability of geraniol to modulate doxorubicin-induced kidney damage using a rat model. Rats were randomly assigned to four groups: control, doxorubicin (20 mg/kg, intraperitoneal, i.p.), doxorubicin plus 100 mg/kg of geraniol, and doxorubicin plus 200 mg/kg of geraniol. A single doxorubicin injection triggered kidney impairment, as evidenced by the altered serum creatinine, blood urea nitrogen, and albumin values; it also caused histological changes in the kidney architecture. Additionally, doxorubicin enhanced lipid peroxidation while lowering reduced glutathione, catalase activity, and the expression of glutathione peroxidase and superoxide dismutase. Interestingly, pre-treatment with geraniol rescued doxorubicin-induced alterations in kidney antioxidant parameters, enzymatic activity, and the expression of inflammatory and apoptosis-mediating gene and proteins. Moreover, prophylactic treatment with geraniol preserved most kidney histological characteristics in a dose-dependent manner. These findings support that geraniol could protect against doxorubicin-mediated kidney dysfunction. However, further research is needed to clarify the mechanisms of geraniol's protective effects against doxorubicin-mediated kidney dysfunction.

Isolated Perianal Endometrioma: A Case Report and Literature Review.

BACKGROUND Endometriosis, a common condition among women of reproductive age and infertile women, occurs when the endometrium extends outside the uterus. When this endometrial tissue grows and sheds, symptoms will develop. The presentation varies depending on the site involved; however, cyclical pain is among its most common symptoms, along with bleeding and cramping. It is frequently observed in the ovaries and fallopian tubes; in contrast, the anal canal is rarely involved. Here, we report a very unusual presentation of the disease. CASE REPORT A 33-year-old woman with a history of episiotomy presented to the Emergency Department reporting perianal swelling in the previous year. The swelling was associated with intermittent pain and difficulty passing stool. She reported no fever. On examination, there was a 3×4 cm palpable tender perianal mass extending to the anal sphincter at the 11 o'clock position. Bedside ultrasound revealed a mass. Magnetic resonance imaging showed a hemorrhagic 3×4 cm mass in the right perianal region pressing on and indenting the right aspect of the distal external sphincter. The mass was excised completely with local perianal incision over the mass at 11'o clock. Surgical pathology revealed an isolated endometrioma in the perianal area. CONCLUSIONS Isolated perianal endometrioma is a rare disease, with only 21 published cases. Its diagnosis is difficult to establish, and a wide range of tests is often needed. Laparoscopic or surgical intervention may be required in cases of rectal endometriosis for an accurate diagnosis. Careful history taking and examination along with a high index of suspicion are necessary to diagnose perianal endometrioma.

Diosmin Alleviates Doxorubicin-Induced Liver Injury via Modulation of Oxidative Stress-Mediated Hepatic Inflammation and Apoptosis via NfkB and MAPK Pathway: A Preclinical Study.

Hepatotoxicity caused by chemotherapeutic drugs (e.g., doxorubicin) is of critical concern in cancer therapy. This study focused on investigating the modulatory effects of diosmin against doxorubicin-induced hepatotoxicity in Male Wistar rats. Male Wistar rats were randomly divided into four groups: Group I was served as control, Group II was treated with doxorubicin (20 mg/kg, intraperitoneal, i.p.), Group III was treated with a combination of doxorubicin and low-dose diosmin (100 mg/kg orally), and Group IV was treated with a combination of doxorubicin and high-dose diosmin (200 mg/kg orally) supplementation. A single dose of doxorubicin (i.p.) caused hepatic impairment, as shown by increases in the concentrations of serum alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase. Doxorubicin produced histological abnormalities in the liver. In addition, a single injection of doxorubicin increased lipid peroxidation and reduced glutathione, catalase, and superoxide dismutase (SOD) levels. Importantly, pre-treatment with diosmin restored hepatic antioxidant factors and serum enzymatic activities and reduced the inflammatory and apoptotic-mediated proteins and genes. These findings demonstrate that diosmin has a protective effect against doxorubicin-induced hepatotoxicity.

Protective effect of diosmin against doxorubicin-induced nephrotoxicity.

Doxorubicin (Dox) is an anthracycline antibiotic that is primarily used for treating various solid tumors including that of pulmonary, ovary, breast, uterine, cervix, and several blood cancers. However, nephrotoxicity associated with Dox treatment limits its clinical use. Administration of Dox in combination with compounds exhibiting antioxidant properties are being used to minimize the side effects of Dox. Diosmin is a flavonoid glycoside with numerous beneficial properties that is found in the pericarp of many citrus fruits. Diosmin has demonstrated antioxidant, anti-inflammatory, and anti-apoptotic effects in response to various insults, although the exact mechanism remains unknown. Therefore, this study was designed to evaluate the effect of diosmin in preventing kidney damage in response to Dox treatment. Male Wistar rats were randomly divided into four groups: control group, Dox group (20 mg/kg, i.p.), Dox plus low-dose diosmin group (100 mg/kg orally), and Dox plus high-dose diosmin group (200 mg/kg orally). A single intraperitoneal injection of Dox resulted in kidney damage as evidenced by significant alterations in kidney markers, histological abnormalities, and the attenuation of antioxidant defense mechanisms (GSH, SOD, and CAT). Moreover, Dox treatment significantly altered the expression of oxidative stress, inflammatory, and anti-apoptotic protein markers. Diosmin pretreatment alleviated Dox-induced nephrotoxicity by ameliorating the antioxidant mechanism, decreasing inflammation and apoptosis, and restoring kidney architecture. In conclusion, our results indicate that diosmin is a promising therapeutic agent for the prevention of nephrotoxicity associated with DOX.

Protective effect of valsartan against doxorubicin-induced cardiotoxicity: Histopathology and metabolomics in vivo study.

Doxorubicin (DOX) treatment has been associated with cardiotoxicity. Therefore, it is crucial to search for a therapeutic that can effectively mitigate DOX-induced cardiotoxicity. This study was conducted to investigate the protective effects of valsartan (VAL) against DOX-induced cardiotoxicity. Sprague-Dawley rats were divided into four treatment groups: Group I: Control, Group II: VAL (30 mg/kg, ip), Group III: DOX (15 mg/kg, ip), and Group IV: VAL + DOX (30 + 15 mg/kg, ip). All groups were treated every other day for 14 days. Blood was isolated for biochemical and metabolomics studies, and sections of the heart were also analyzed for histopathological and immunohistochemical alterations to detect changes in P53, BAX, BCL-2, and P62 expression. The combination of VAL + DOX resulted in a marked decrease in cardiac biomarker enzymes (aminotransferase and creatine phosphokinase) compared to DOX monotherapy. In addition, the histopathological examination of the VAL + DOX combination revealed a low percentage of fibrosis and inflammation. Immunohistochemical expression of p53 and BAX was significantly reduced, whereas BCL-2 expression was significantly increased in the VAL + DOX treatment group compared to DOX monotherapy. Also, the combination of VAL + DOX reverses the negative effect of DOX on nuclear p62 expression. Analysis of serum metabolites showed that DOX monotherapy reduced the number of several amino acids, whereas the combination of VAL + DOX restored these metabolic pathways. This study revealed the potential cardioprotective effect of VAL, which may provide novel and promising approaches for managing cardiotoxicity induced by DOX.

Cystic Ovarian Leiomyoma in a Patient with Progressive Abdominal Pain.

BACKGROUND Ovarian leiomyomas are rare, benign, smooth muscle, solid tumors that occur in women aged 20 to 65 years. Because their histology is benign, the prognosis for patients is good. We report the case of a patient with a huge ovarian leiomyoma who presented to the General Surgery Clinic with chronic abdominal pain and progressive abdominal distention. CASE REPORT A 45-year-old woman with a history of multiple myomectomies and a total abdominal hysterectomy with right oophorectomy presented to the General Surgery Clinic with abdominal pain and a 4-year history of progressive distention. After being examined, the patient underwent an exploratory laparotomy, during which a pelvic cyst was found that measured 3930.2 cm, was filled with serous fluid (10.5 L), and occupied most of the abdominal space. The surgery went smoothly and there were no complications during or after the procedure. The patient was discharged home 7 days later in stable condition. Postoperative pathology using hematoxylin and eosin staining and immunohistochemistry with desmin and alpha-smooth muscle actin resulted in a diagnosis of leiomyoma with cystic degeneration. When the patient was seen in the outpatient clinic 2 weeks and 3 and 6 months after surgery, her tumor markers were within normal limits. Abdominal and pelvic computed tomography scans performed at the 6-month visit showed resolution of the loculated intraperitoneal fluid and no gross local recurrence of the tumor. CONCLUSIONS Ovarian leiomyomas are difficult to diagnose preoperatively. Suspicion for one should be high, however, in patients who present with a large cystic mass in adnexal tissues, especially if they have a history of hysterectomy and oophorectomy.

Chronic Granulomatous Invasive Fungal Sinusitis: A Case Series and Literature Review.

Chronic granulomatous invasive fungal sinusitis (CGIFS) is a peculiar disease of the paranasal sinuses due to its rarity, patient subset, and disease course. We describe 7 cases of histopathologically confirmed CGIFS with different treatment plans and varying outcomes. Of particular note was that one of these patients developed allergic fungal rhinosinusitis after complete resolution of his primary invasive disease, a finding that has never been reported in the literature. Another patient had an atypical fungal species (Aspergillus nidulans) on fungal stain and culture, while one immunodeficient patient had a large intracerebral disease component and died after 2 months of treatment. We also present a review of the pertinent literature investigating this rare disease.

Elucidation of the Molecular Mechanisms Underlying Sorafenib-Induced Hepatotoxicity.

Sorafenib is a small, orally-active multikinase inhibitor that is most frequently used for the management of renal cell carcinoma, hepatocellular carcinoma, and radioactive iodine-resistant thyroid carcinoma. However, recent reports have associated sorafenib with hepatotoxicity that can limit its clinical application, although the mechanism of hepatotoxicity is still to be elucidated. Thus, our study was designed to explore the molecular mechanisms underlying sorafenib-induced hepatotoxicity in an in vivo model. Twenty male adult Wistar rats were randomly placed into two groups; the first group received an oral dose of normal saline (vehicle), and the second received sorafenib (30 mg/kg) once daily for twenty-one consecutive days. After twenty-one days, liver tissues and blood samples were used for gene expression, protein expression, and biochemical analysis. Sorafenib treatment resulted in markedly increased levels of alanine aminotransferase and alkaline phosphatase, which indicate the presence of liver damage. Additionally, sorafenib administration induced the inflammatory and oxidative stress marker NF-κB-p65, while antioxidant enzymes were attenuated. Moreover, sorafenib caused upregulation of both gene and protein for the apoptotic markers cleaved Caspase-3, Bax, and Bid, and downregulation of the antiapoptotic protein Bcl-2. In conclusion, our findings suggest that sorafenib administration is associated with hepatotoxicity, which might be due to the activation of oxidative stress and apoptotic pathways.

Angioleiomyoma of the proper ulnar digital artery: Case report.

INTRODUCTION: With the rarity and benign nature, angioleiomyoma is a tumor of disputed etiology that originates from the tunica media of the blood vessels. Lacking any characteristic clinical or radiological features, often leading to preoperative misdiagnosis, it is only diagnosed confidently on the basis of histopathology; for this reason combined with the rarity, angioleiomyoma would not be usually found at the top of the differential diagnosis list. Local excision is usually curative with excellent prognosis. CASE: This report discusses a case of a 60-year-old healthy lady who complained of a chronic painless mass in the right 2nd digit. Originating from the proper ulnar digital artery, it was excised with no complications. Histopathology results confirmed the diagnosis of angioleiomyoma. No recurrence was observed 6 months following the procedure. DISCUSSION: Out of the handful published papers concerned with angioleiomyoma in hands, few report the origin to be the digital artery. CONCLUSION: Further awareness about this tumor is required and it should be included in the differential diagnoses list of the treating surgeon.