The interplay between mitochondrial dysfunction and NLRP3 inflammasome in multiple sclerosis: Therapeutic implications and animal model studies.

Multiple sclerosis (MS) is a complex autoimmune disorder that impacts the central nervous system (CNS), resulting in inflammation, demyelination, and neurodegeneration. The NOD-like receptor (NLR) family pyrin domain-containing 3 (NLRP3) inflammasome, a multiprotein complex of the innate immune system, serves an essential role in the pathogenesis of MS by regulating the production of pro-inflammatory cytokines (IL-1ß & IL-18) and the induction of pyroptotic cell death. Mitochondrial dysfunction is one of the main potential factors that can trigger NLRP3 inflammasome activation and lead to inflammation and axonal damage in MS. This highlights the importance of understanding how mitochondrial dynamics modulate NLRP3 inflammasome activity and contribute to the inflammatory and neurodegenerative features of MS. The lack of a comprehensive understanding of the pathogenesis of MS and the urge for the introduction of new therapeutic strategies led us to review the therapeutic potential of targeting the interplay between mitochondrial dysfunction and the NLRP3 inflammasome in MS. This paper also evaluates the natural and synthetic compounds that can improve mitochondrial function and/or inhibit the NLRP3 inflammasome, thereby providing neuroprotection. Moreover, it summarizes the evidence from animal models of MS that demonstrate the beneficial effects of these compounds on reducing inflammation, demyelination, and neurodegeneration. Finally, this review advocates for a deeper investigation into the molecular crosstalk between mitochondrial dynamics and the NLRP3 inflammasome as a means to refine therapeutic targets for MS.

Nanophytosomes for enhancement of rutin efficacy in oral administration for diabetes treatment in streptozotocin-induced diabetic rats.

Rutin is a natural antioxidant compound with several therapeutic benefits. However, the application of this bioactive compound is limited due to its low stability and bioavailability. To overcome these limitations, this study aimed to encapsulate rutin into nanophytosomes (NPs) and evaluate the therapeutic potency of this nanocarrier in streptozotocin (STZ)-induced diabetic rats. The particle size, zeta potential, and encapsulation efficiency of the prepared NPs were 72.72 nm, -22 mV, and 93.7%, respectively. The in vivo study showed that the oral administration of rutin-loaded NPs (containing 25 mg rutin/kg per day) for 4 weeks was more effective than free rutin in the control of hyperglycemia and hyperlipidemia in the STZ-induced diabetic rats. Additionally, the administration of rutin-loaded NPs regulated the activities of liver marker enzymes and the levels of total hemoglobin and glycated hemoglobin in the diabetic rats. The antioxidant defenses in the diabetic rats were increased by the administration of rutin-loaded NPs more than free rutin. Moreover, the histopathological study showed that the administration of rutin-loaded NPs restored the diabetes-induced damages in kidney, liver, and pancreas. In conclusion, encapsulation of rutin with phytosomes is an effective technique to benefit from its therapeutic potential, especially to attenuate diabetic complications.

Restoration of miR-330 expression suppresses lung cancer cell viability, proliferation, and migration.

Lung cancer is one of the most common cancers and its incidence is rising around the world. Various studies suggest that miR-330 acts as a tumor-suppressor microRNA (miRNA) in different types of cancers, but precisely how has remained unclear. In this study, we investigate miR-330 expression in lung cancer patient samples, as well as in vitro, by studying how normalization of miR-330 expression affects lung cancer cellular phenotypes such as viability, apoptosis, proliferation, and migration. We establish that low miR-330 expression predicts poor lung cancer prognosis. Stable restoration of reduced miR-330 expression in lung cancer cells reduces cell viability, increases the fraction of apoptotic cells, causes G2/M cell cycle arrest, and inhibits cell migration. These findings are substantiated by increased mRNA and protein expression of markers for apoptosis via the intrinsic pathway, such as caspase 9, and decreased mRNA and protein expression of markers for cell migration, such as vimentin, C-X-C chemokine receptor type 4, and matrix metalloproteinase 9. We showed that reduced miR-330 expression predicts poor lung cancer survival and that stable restoration of miR-330 expression in lung cancer cells has a broad range of tumor-suppressive effects. This indicates that miR-330 is a promising candidate for miRNA replacement therapy for lung cancer patients.

False-Positive Mycobacterium tuberculosis Detection: Ways to Prevent Cross-Contamination.

The gold standard method for diagnosis of tuberculosis is the isolation of Mycobacterium tuberculosis through culture, but there is a probability of cross-contamination in simultaneous cultures of samples causing false-positives. This can result in delayed treatment of the underlying disease and drug side effects. In this paper, we reviewed studies on falsepositive cultures of M. tuberculosis. Rate of occurrence, effective factors, and extent of false-positives were analyzed. Ways to identify and reduce the false-positives and management of them are critical for all laboratories. In most cases, falsepositive is occurring in cases with only one positive culture but negative direct smear. The three most crucial factors in this regard are inappropriate technician function, contamination of reagents, and aerosol production. Thus, to reduce false-positives, good laboratory practice, as well as use of whole-genome sequencing or genotyping of all positive culture samples with a robust, extra pure method and rapid response, are essential for minimizing the rate of false-positives. Indeed, molecular approaches and epidemiological surveillance can provide a valuable tool besides culture to identify possible false positives.

Left Atrial Malignant Fibrous Histiocytoma with Right Atrium Invasion.

BACKGROUND: Primary cardiac tumors are rare (0.001 to 0.03%). Malignant tumors account for 25%, of which 75% are cardiac sarcomas. CASE PERSENTATION: Here, we report a case of a 57-year-old male with palpitation and history of left atrial (LA) myxoma resection presented to cardiology clinic for postsurgical follow up and transthoracic echocardiography revealed a large non-homogenous mass in LA with right atrium invasion, which was confirmed by trans-esophageal echocardiography. The patient underwent surgical resection of tumor and the pathological diagnosis was malignant fibrous histiocytoma (MFH). CONCLUSION: MFH could be asymptomatic and the diagnosis be established as a surgical or complementary examination. In patients with history of myxoma resection and cardiac masses, further evaluation is recommended.

Cystic Degeneration of Cerebellar Tonsil 1 Year After Chiari I Malformation Surgery: A Case Report and Review of the Literature.

BACKGROUND: Chiari malformation results from a bony structural anomaly of the skull base. The structural defect causes downward displacement of the cerebellar tonsils through the foramen magnum. The herniated tonsils block the normal flow of cerebrospinal fluid, which causes a wide spectrum of clinical symptoms. CASE REPORT: In May 2015, a 16-year-old girl was referred to our center because of a 1-year history of occipital headache, most often triggered by exercise and physical activity at school. She had experienced new-onset numbness in both hands, more severe on the right side, associated with some degrees of weakness. Eventually, an evaluation of her condition included magnetic resonance imaging in T1 and T2 sequences, which revealed a 20-mm downward migration of the cerebellar tonsils, associated with a cervical cord syrinx at the level of the fourth and fifth cervical vertebrae. The patient underwent posterior fossa decompression and C1 and partial C2 laminectomies. Postoperatively there were no complications, and the patient was discharged on day 3. Postoperatively, she experienced some improvement in her symptoms. After 2 months of routine outpatient follow-up, she was better, the headaches had subsided, she could resume some activities, and there was no paresis in her limbs. CONCLUSIONS: In cases of progressive symptoms of Chiari malformation, surgical decompression is important and should be considered after shunt insertion to the hindbrain.

Serum overexpression of miR-301a and miR-23a in patients with colorectal cancer.

BACKGROUND: Extracellular vesicles (EVs) are a heterogeneous group of membrane-bound vesicles with complex cargoes including proteins, lipids, and nucleic acids. EVs have received significant attention due to their specific features including stability under harsh conditions and involvement in cell-to-cell communication. Circulating EVs and the molecules associated with them are important in the diagnosis and prognosis of cancers. MicroRNAs (miRNAs) are a group of small noncoding RNAs that have a role in regulating gene expression. Current literature shows that circulating miRNAs can be used as noninvasive biomarkers for early detection of cancers. The present study was set to investigate the potential role of serum exosomal miRNA expression levels in colorectal cancer (CRC) patients and evaluate their correlation with clinicopathologic features. METHODS: Exosome-enriched fractions were isolated from the serum of 25 CRC patients and 13 age- and sex-matched healthy controls using a polymer-based precipitation method. During the pilot phase, real-time polymerase chain reaction (RT-PCR) was carried out on 12 CRC patients and eight healthy participants to evaluate the expression difference of 11 candidate miRNAs between CRC patients and tumor free subjects. Finally, the results were validated in a separate group, which was similar in size to the pilot group. The clinicopathologic data were also collected and the relationship between aberrant miRNA expression and clinicopathological parameters were investigated. RESULTS: There were high expressions of exosomal miR-23a and miR-301a in serum samples of CRC patients compared to normal controls in training and validation phases; these differences were not significantly correlated with clinicopathologic features. Receiver operating characteristic curve analysis showed that miR-301a and miR-23a were able to discriminate CRC patients from normal subjects. CONCLUSION: The findings provide evidence on the roles of miR-301a and miR-23a in CRC development and their potential roles as noninvasive biomarkers for early detection of CRC.

Comparative of in-vitro Evaluation between Erlotinib Loaded Nanostructured Lipid Carriers and Liposomes against A549 Lung Cancer Cell Line.

Erlotinib (ELT) as a small molecule with poor solubility, poor bioavailability, and instability in gastrointestinal environment, has been considered as a therapeutic agent for Non-Small-Cell Lung Cancer (NSCLC) therapy through oral administration. In the present study, ELT-liposome and ELT-NLCs were successfully prepared and characterized by assessment of the particle size, zeta potential (ZP), polydispersity index (PDI), encapsulation efficiency (EE), and drug loading (DL). DAPI staining and Flow cytometry techniques were employed to probe anticancer activities of the optimal formulations. The obtained results indicated that the average size of optimized ELT-NLCs was 109 ± 2 nm, while the optimal formulation of ELT-liposome was 130 ± 4 nm. In addition, the values of EE, DL, and cellular uptake were higher in ELT-NLCs than ELT-liposome. Moreover, the stability of ELT-NLCs and ELT-liposome were not significantly changed (P > 0.05) within storage time. The results of anti-cancer assessment indicated that ELT-NLCs caused more cell viability reduction than ELT-liposome and free ELT. According to the Flow cytometry and DAPI staining results, the exposed A549 cells with ELT-NLCs had more rates of apoptosis than ELT-liposome. The obtained data from this study clearly showed that ELT-NLCs had better anti-cancer activity than ELT-liposome, which may be related to the effective nano particle size, PDI, EE, and DL of ELT-NLCs.

In vivo Evaluation of Anti-Hyperglycemic, Anti-hyperlipidemic and Anti-Oxidant Status of Liver and Kidney of Thymol in STZ-Induced Diabetic Rats.

AIM: The evaluation of the positive and protective effects thymol as a natural compound on the STZ -induced diabetic rats. MATERIALS AND METHODS: In this study, seven groups of the streptozotocin induced diabetic and normal rats (overall 42 males) were tested through various biochemical and histopathological factors such as: serum glucose, insulin, creatinine, lipids, lipoproteins, liver function-related enzymes, and antioxidant status in liver and kidney. RESULTS: The obtained results in this work indicated that thymol had a significant anti-hypoglycemic, anti-hypolipidemic activities on the STZ-induced diabetic rats. Further, the assessment different biochemical parameters revealed that the levels of creatinine, low-density lipoprotein cholesterol, very low density lipoprotein cholesterol, and liver function-related enzymes such as aspartate aminotransferase and alanine aminotransferase were decreased in the treated diabetes rats under 20 and 40 mg/kg thymol compared to the control diabetes group. Considerably, the anti-oxidant enzymes status that were achieved from the liver and kidney organs were modulated after treatment with thymol in the diabetic rats. CONCLUSION: The results of this research has brough a new aspect concerning the proteevtive and positive effects of thymol on the diabetic complications in the animal model.

Overexpression of SSH1 in gastric adenocarcinoma and its correlation with clinicopathological features.

BACKGROUND: Gastric adenocarcinoma is known to be the fourth most common cancer type and the second cause of cancer-related deaths. Movement and invasion of cancer cells is one of the major characteristics of the cancer phenotype that various types of network regulate this. Expression levels of slingshot diphosphatase 1 (SSH1) gene has been modulated in this pathway. SSH1 acts as a dephosphorylation and activator of cofilin that this regulating and activating by SSH1 can play a major role in the mobility and migration of the cell. The aim of this study was to compare the expression level of SSH1 genes between tumor and corresponding adjacent non tumor gastric tissues and healthy tissue of gastric adenocarcinoma. METHODS: In this study, mRNA of 40 gastric adenocarcinoma and corresponding adjacent non tumor gastric tissues and 15 healthy biopsy samples was extracted, then after cDNA synthesis, real-time polymerase chain reaction was performed to measure gene expression. RESULTS: According to REST analysis, the relative expression of SSH1 was significantly increased in gastric cancer tissues compared to the corresponding adjacent non tumor gastric tissue samples and normal tissue. Nevertheless, the result revealed no substantial correlation between the expression levels of SSH1 with clinical features. The biomarker index for SSH1 was obtained as 0.89. CONCLUSIONS: The results obtained from investigating SSH1 expression are indicative of significant changes in the expression of this gene in gastric adenocarcinoma. This gene can also be used as a biomarker for gastric cancer.

Procalcitonin: The marker of pediatric bacterial infection.

Timely recognition of systemic bacterial infections in pediatric care setting is the basis for effective treatment and control. This review provides an overview of procalcitonin (PCT) as an early marker for the detection of severe, invasive bacterial infection in children. Almost all articles on biochemical property and clinical studies in PubMed and Scopus databases regarding their use in pediatric infections and the use of PCT as a marker of bacterial infections were examined. Various methods and analyzers are currently available for the evaluation of PCT. Employment of PCT in the identification of neonatal bacterial infection is a complex process in some conditions. Age specific cut-off, underlying syndrome, and maternal antibiotics usage should be considered when PCT is to be applied in neonates. PCT might be false-negative in these conditions. However, if used appropriately, it can lead to a higher specificity than other immunologic markers. Due to its correlation with the severity of infection, PCT can consequently be used as a prognostic indicator especially for sepsis and urinary tract infection. It is, therefore, a practical supplementary means for the identification of bacterial infections in pediatric health settings.

Oral pathogenesis of Aggregatibacter actinomycetemcomitans.

Aggregatibacter actinomycetemcomitans (A. actinomycetemcomitans) is a Gram-negative, facultative anaerobic bacillus that causes periodontal diseases such as localized aggressive periodontitis (LAP) and. consequently. bone resorption. The potential virulence factors of this organism are powerful leukotoxin, lipopolysaccharide (LPS), cell surface-associated materials, enzymes, and less well-defined virulence factors that will modulate the activity of the host defenses. This organism can induce bone resorption by various virulence factors in periodontal disease. In this review article, we reviewed the pathogenic roles of A. actinomycetemcomitans in periodontal disease and the mechanism which can induce bone resorption. Findings from several studies indicate that the interaction between virulence factors and the host immune system's response often progress bone resorption in periodontal disease. In this organism, GroEL, DnaK, HtpG, LTX, CDT, LPS, and cell surface-associated materials produce cytokines when exposed to the immune system. The produced cytokines are the main cause of tissue destruction and bone resorption in A. actinomycetemcomitans inflammation in periodontal disease.

Diagnostic and prognostic performances of serum procalcitonin in patients with bloodstream infections: A parallel, case-control study comprising adults and elderly.

OBJECTIVE:: To examine the diagnostic and prognostic performances of serum procalcitonin (PCT) in adult and elderly patients with bloodstream infections (BSIs). METHOD:: A total of 176 patients with culture-proven BSIs and 200 healthy counterparts were studied prospectively. Participants were studied in two adult (age≤65 years, n=92) and elderly (age>65 years, n=84) groups. Admission serum PCT level was measured using a standard enzyme-linked immunosorbent assay (ELISA) technique. RESULTS:: The mean serum PCT level (in ng/mL) was significantly higher in cases than in controls (0.18 vs. 0.07, p=0.01 in adults; 0.20 vs. 0.07, p=0.002 in elderly). At cut-off values of 0.09 ng/mL in adults and 0.08 ng/mL in the elderly, the corresponding sensitivity and specificity were 82.6 and 82.0% in adults, and 69.1 and 70.0% in elderly, respectively. At a cut-off value of 0.2 ng/mL, the sensitivity and specificity of serum PCT in predicting 28-day mortality were 81 and 81.7% in adults, and 75 and 80.4% in elderly, respectively. CONCLUSION:: Although admission serum PCT is a sensitive and specific biomarker for the diagnosis of BSIs in patients younger than 65 years old, its short-term prognostic value is comparable between adults and the elderly.

Diagnostic and prognostic performances of serum procalcitonin in patients with bloodstream infections: A parallel, case-control study comprising adults and elderly

Summary Objective: To examine the diagnostic and prognostic performances of serum procalcitonin (PCT) in adult and elderly patients with bloodstream infections (BSIs). Method: A total of 176 patients with culture-proven BSIs and 200 healthy counterparts were studied prospectively. Participants were studied in two adult (age≤65 years, n=92) and elderly (age>65 years, n=84) groups. Admission serum PCT level was measured using a standard enzyme-linked immunosorbent assay (ELISA) technique. Results: The mean serum PCT level (in ng/mL) was significantly higher in cases than in controls (0.18 vs. 0.07, p=0.01 in adults; 0.20 vs. 0.07, p=0.002 in elderly). At cut-off values of 0.09 ng/mL in adults and 0.08 ng/mL in the elderly, the corresponding sensitivity and specificity were 82.6 and 82.0% in adults, and 69.1 and 70.0% in elderly, respectively. At a cut-off value of 0.2 ng/mL, the sensitivity and specificity of serum PCT in predicting 28-day mortality were 81 and 81.7% in adults, and 75 and 80.4% in elderly, respectively. Conclusion: Although admission serum PCT is a sensitive and specific biomarker for the diagnosis of BSIs in patients younger than 65 years old, its short-term prognostic value is comparable between adults and the elderly.

In vitro inhibition of platelets aggregation with generic form of clopidogrel versus branded in patients with stable angina pectoris.

Introduction: Clopidogrel is a potent platelet activation and aggregation inhibitor that prevents thrombosis in coronary artery diseases (CADs). In comparison to locally produced generic one (Osvix®), original brand of clopidogrel (Plavix®) is expensive. This study was designed to evaluate the effectiveness and uniformity of Osvix® versus Plavix® in patients with percutaneous coronary intervention (PCI) by means of platelet aggregation indexes. Methods: This randomized, double blind clinical study was conducted at Shahid Madani heart hospital, Tabriz, Iran, and 129 patients with previous PCI were enrolled in two independent treatment groups. All patients participated in this study were on dual antiplatelet therapy at least for 30 days. ASA 80 mg/d and clopidogrel 75 mg/d and a stat dose of 300 mg of clopidogrel before PCI were administered for all patients. To evaluate the anti-platelet activity, blood samples were taken from the patients and platelet aggregation test was performed. Results: The total study population represents a group of 129 patients (99 men and 30 women) with mean age of 57.7 ± 9.7 years with stable angina pectoris. The baseline characteristics and laboratory findings of two groups (except mean platelet volume [MPV]) were not different statistically. The mean platelets aggregation at 30th day was 13.7±7.0 in Plavix® group and 14.8±5.8 in Osvix® group (P value = 0.35). Conclusion: This study showed that Osvix® as a generic form of clopidogrel was not significantly different from the original brand (Plavix) in terms of in vitro platelet inhibition.

Multi-vesicular pulmonary hydatid cyst, the potent underestimated factor in the formation of daughter cysts of pulmonary hydatid disease.

Pulmonary multi-vesicular hydatid disease (HD) with Echinococcus granulosus is rare. A 28-year-old woman presented to our center with cough and respiratory distress. Chest x-ray and computerized tomography scan revealed bilateral giant cysts with water-lily sign (ruptured hydatid cysts). The left cyst was in vicinity of heart. With thoracotomy cysts of both lungs were removed. Thousands of translucent, homogenized small daughter cysts were discovered from the left side cyst. Pathologic examinations revealed the ruptured hydatid cysts of both lungs with daughter cysts on the left lung cyst. To best of our knowledge probably this is the first report of multi-vesicular HD in lung. We suppose that the heart pulsation was effective in the formation of daughter cysts.

Giant Pulmonary Hydatid Cyst and Trauma in a 9 Year-Old Child: A Case Report.

Herein, we report a case of giant lung hydatid cyst in a nine-year-old boy. For four years, he experienced mild chest pain and chronic nonproductive cough. He had a trauma resulted from a fall two days before admission. Chest X-ray showed misdiagnosed massive pleural effusion, and was aspirated in the other hospital. However, after admission, the computed tomography revealed a giant lung hydatid cyst filling the right hemithorax completely. Being considered by the diagnosis of ruptured lung hydatid cyst, he was treated surgically by right-thoracotomy. The existing hydatid cyst, (e.g., with a dimension of 30*22*20cm) filled all cavity of hemithorax extended from the right diaphragm to the apex of the lung situated in the right lower lobe. After evacuation of the hydatid fluid and laminated membrane, right lower lobectomy was carried out due to remaining no salvageable parenchyma without any complications. Also, the pathologic examination have confirmed hydatid cyst. In conclusion, giant hydatid cysts are probably misdiagnosed with massive pleural effusion in the endemic area. And, because of the risk of allergic reactions, anaphylactic shock and dissemination, it should not be aspirated.

Effects of a triplex mixture of Peganum harmala, Rhus coriaria, and Urtica dioica aqueous extracts on metabolic and histological parameters in diabetic rats.

CONTEXT: Several therapeutic effects such as antioxidant and blood glucose-lowering activities have been reported for Peganum harmala L (Zygophyllaceae) (PH) seeds, Rhus coriaria L (Anacardiaceae) (RC) fruits, and Urtica dioica L (Urticaceae) (UD) leaves. OBJECTIVE: This study investigates the effects of a triplex mixture (1:1:1) of these medicinal plants on metabolic and histological parameters in diabetic rats. MATERIALS AND METHODS: Aqueous extracts of PH, RC and UD were administered as either monotherapy or in combination at a final dose of 200 mg/kg to alloxan-induced diabetic rats by daily gavage. Biochemical parameters including blood glucose, liver function-related enzymes, lipid profile, and creatinine were estimated by spectrophotometric methods. Tissues from the liver and kidney stained with hematoxylin/eosin were histologically examined. The results obtained from the exposure groups were compared to either healthy or diabetic control groups. RESULTS: Compared with the diabetic control rats, all aqueous extracts (ED50 = 11.5 ± 2.57 mg/ml) led to significant decreases in the levels of ALP (1.39-2.23-fold, p < 0.05), low-density lipoprotein cholesterol (LDL-C) (1.79-3.26-fold, p < 0.05), and blood glucose (1.27-4.16-fold, p < 0.05). The serum concentrations of TG was decreased only by treatment with UD and triplex mixture (1.25- and 1.20-fold, respectively, p < 0.05). Among the studied parameters, alanine aminotransferase (ALT), LDL-C, TG, and creatinine recovered to healthy control levels after 4 weeks of treatment with the extract mixture. CONCLUSION: This study showed that PH, RC, and UD extracts, especially their combination, had significant antidiabetic, hypolipidemic, and liver and renal damage recovering effects.

Serum and tissue endothelin-1 are independent from intima-media thickness of peripheral arteries in patients with chronic kidney disease.

AIM: We aimed to study the relationship of peripheral arteries' atherosclerosis with serum and tissue endothelin-1 in chronic kidney disease patients. METHODS: Ninety patients were enrolled, including 35 patients with chronic kidney disease (case group), 31 patients with coronary artery diseases who were candidates for coronary artery bypass grafting (positive control group), and 24 living kidney donors (negative control group). Intima-media thickness of the common carotid and femoral arteries was determined by ultrasonography. Serum and tissue endothelin-1 were measured by ELISA method. RESULTS: The mean serum and tissue endothelin-1 levels in the donor group were significantly lower than other groups (p < 0.001 for both). The coronary artery bypass grafting group had higher carotid and femoral intima-media thickness than other groups (p < 0.001), and the chronic kidney disease group had higher carotid and femoral intima-media thickness than the donor group (p < 0.001). Regression analysis in all groups did not reveal any correlation between the carotid intima-media thickness/femoral intima-media thickness and the serum/tissue endothelin-1. There was a direct linear correlation between the carotid and femoral intima-media thickness (p < 0.001) in all groups. CONCLUSIONS: Endothelin-1 level and intima-media thickness were higher in the chronic kidney disease patients and coronary artery bypass grafting candidates, without any correlation between endothelin-1 and peripheral arteries' intima-media thickness of both groups. Perhaps endothelin-1 rises and remains high upon endothelial damage and initiation of atherosclerosis.