Concomitant Effects of Metformin and Vitamin C on Indomethacin-Induced Gastric Ulcer in Rats: Biochemical and Histopathological Approach.

INTRODUCTION: Gastric ulcer is one of the most common and serious conditions in the gastrointestinal tract. One of the main causes of gastric ulcers is using of non-steroidal anti-inflammatory drugs (NSAIDs) which have limited their use in clinical practice. Several studies have revealed that metformin and Vitamin C (Vit C) exhibit protective effects against gastric mucosal damage in different animal models. However, no studies indicate their combination's effect on gastric ulcer models. Therefore, this study aims to investigate the protective effects of metformin and Vit C combination on indomethacin-induced gastric ulcers. MATERIAL AND METHODS: In total, thirty rats were divided into six groups, including the control group, rats received indomethacin (50 mg/kg, i.p.), rats received indomethacin and pretreated with ranitidine (100 mg/kg), metformin (100 mg/kg, i.p.), Vit C (100 mg/kg), or metformin combined with Vit C. Four hours after indomethacin administration, rats were euthanized, and gastric tissues were removed for macroscopic, histopathologic, and biochemical examinations. RESULTS: All therapeutics used in this study were found to alleviate gastric mucosal injury caused by indomethacin, as observed in histopathologic and macroscopic evaluations. Both Vit C and metformin were observed to significantly decrease lipid peroxidation and enhance the activity of anti-oxidative enzymes, SOD, GPx, and catalase. However, a more significant effectiveness was observed in catalase and GPx activities when Vit C was co-administered with metformin. CONCLUSIONS: In conclusion, the present study revealed that metformin and Vit C combination therapy could potentially treat gastric ulcers associated with indomethacin.

STING agonists as promising vaccine adjuvants to boost immunogenicity against SARS-related coronavirus derived infection: possible role of autophagy.

As a major component of innate immunity and a positive regulator of interferons, the Stimulator of interferon gene (STING) has an immunotherapy potential to govern a variety of infectious diseases. Despite the recent advances regarding vaccines against COVID-19, nontoxic novel adjuvants with the potential to enhance vaccine efficacy are urgently desired. In this connection, it has been well-documented that STING agonists are applied to combat COVID-19. This approach is of major significance for boosting immune responses most likely through an autophagy-dependent manner in susceptible individuals against infection induced by severe acute respiratory syndrome Coronavirus (SARS­CoV­2). Given that STING agonists exert substantial immunomodulatory impacts under a wide array of pathologic conditions, these agents could be considered novel adjuvants for enhancing immunogenicity against the SARS-related coronavirus. Here, we intend to discuss the recent advances in STING agonists' recruitment to boost innate immune responses upon vaccination against SARS-related coronavirus infections. In light of the primordial role of autophagy modulation, the potential of being an antiviral vaccine adjuvant was also explored.

Evaluation of the safety and efficacy of direct oral anticoagulants compared with vitamin-k antagonists in the treatment of left ventricular thrombosis. A systematic review and meta-analysis.

BACKGROUND: Since the introduction of direct oral anticoagulants (DOACs) and their comparison with vitamin K antagonists (VKAs), conflicting results have been reported regarding the optimal treatment for left ventricular thrombosis (LVT). OBJECTIVES: In this meta-analysis, we intend to comprehensively evaluate the safety and efficacy of these treatments. METHODS: All clinical trials and cohorts that compared the efficacy or safety of VKAs with DOACs in the treatment of LVTs were systematically searched until April 15, 2023. RESULTS: The results of 32 studies with a pooled sample size of 4213 patients were extracted for meta-analysis. DOACs, especially rivaroxaban and apixaban, cause faster resolution, lower mortality, and fewer complications (SSE and bleeding events) than VKAs in the management of LVTs. CONCLUSION: Compared with VKAs, DOACs result in significantly faster (only rivaroxaban) and safer resolution of left ventricular thrombosis.

The interplay between the PI3K/AKT pathway and circadian clock in physiologic and cancer-related pathologic conditions.

The circadian clock is responsible for the regulation of different cellular processes, and its disturbance has been linked to the development of different diseases, such as cancer. The main molecular mechanism for this issue has been linked to the crosstalk between core clock regulators and intracellular pathways responsible for cell survival. The PI3K/AKT signalling pathway is one of the most known intracellular pathways in the case of cancer initiation and progression. This pathway regulates different aspects of cell survival including proliferation, apoptosis, metabolism, and response to environmental stimuli. Accumulating evidence indicates that there is a link between the PI3K/AKT pathway activity and circadian rhythm in physiologic and cancer-related pathogenesis. Different classes of PI3Ks and AKT isoforms are involved in regulating circadian clock components in a transcriptional and functional manner. Reversely, core clock components induce a rhythmic fashion in PI3K and AKT activity in physiologic and pathogenic conditions. The aim of this review is to re-examine the interplay between this pathway and circadian clock components in normal condition and cancer pathogenesis, which provides a better understanding of how circadian rhythms may be involved in cancer progression.

Protective effects of topiramate on acetic acid-induced colitis in rats through the inhibition of oxidative stress.

Ulcerative colitis is an intestinal inflammatory condition characterized by a rise in inflammatory mediator production and oxidative stress. Topiramate is an anticonvulsant agent with effectiveness on a wide range of seizures, which is anti-oxidative. This study aims to examine the protective effects of topiramate on acetic acid-induced ulcerative colitis in rats. Rats were randomly divided into four groups as follows: control, acetic acid, acetic acid + topiramate, and acetic acid + dexamethasone groups. Topiramate (100 mg/kg/day) or dexamethasone (2 mg/kg/day) was administered for six consecutive days, and ulcerative colitis was induced on the first day of the study by transrectal administration of 4% acetic acid. Four hours after the last dose of treatments, animals of each group were sacrificed, and colon tissues were removed for further macroscopic, histopathologic, and biochemical analyses. Treatment with topiramate markedly decreased colonic lesions and macroscopic scores as well as the improvement of histopathologic changes. Topiramate also effectively decreased the levels of malondialdehyde and upregulated the activity of anti-oxidative enzymes, including catalase, superoxide dismutase, and glutathione peroxidase. Our results reveal that the administration of topiramate ameliorates acetic acid-induced colitis in rats via anti-oxidative properties, and further studies may introduce it as an effective therapeutic candidate to decrease ulcerative colitis severity.

The pharmacological effects of Berberine and its therapeutic potential in different diseases: Role of the phosphatidylinositol 3-kinase/AKT signaling pathway.

The phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway plays a central role in cell growth and survival and is disturbed in various pathologies. The PI3K is a kinase that generates phosphatidylinositol-3,4,5-trisphosphate (PI (3-5) P3), as a second messenger responsible for the translocation of AKT to the plasma membrane and its activation. However, due to the crucial role of the PI3K/AKT pathway in regulation of cell survival processes, it has been introduced as a main therapeutic target for natural compounds during the progression of different pathologies. Berberine, a plant-derived isoquinone alkaloid, is known because of its anti-inflammatory, antioxidant, antidiabetic, and antitumor properties. The effect of this natural compound on cell survival processes has been shown to be mediated by modulation of the intracellular pathways. However, the effects of this natural compound on the PI3K/AKT pathway in various pathologies have not been reviewed so far. Therefore, this paper aims to review the PI3K/AKT-mediated effects of Berberine in different types of cancer, diabetes, cardiovascular, and central nervous system diseases.

Role of Bmal1 and Gut Microbiota in Alzheimer's Disease and Parkinson's Disease Pathophysiology: The Probable Effect of Melatonin on Their Association.

In recent years, the role of new factors in the pathophysiology of neurodegenerative diseases has been investigated. Alzheimer's disease (AD) and Parkinson's disease (PD) are the most common neurodegenerative diseases worldwide. Although pathological changes such as the accumulation of aggregated proteins in the brain and inflammatory responses are known as the main factors involved in the development of these diseases, new studies show the role of gut microbiota and circadian rhythm in the occurrence of these changes. However, the association between circadian rhythm and gut microbiota in AD and PD has not yet been investigated. Recent results propose that alterations in circadian rhythm regulators, mainly Bmal1, may regulate the abundance of gut microbiota. This correlation has been linked to the regulation of the expression of immune-related genes and Bmal-1 mediated oscillation of IgA and hydrogen peroxide production. These data seem to provide new insight into the molecular mechanism of melatonin inhibiting the progression of AD and PD. Therefore, this manuscript aims to review the role of the gut microbiota and circadian rhythm in health and AD and PD and also presents a hypothesis on the effect of melatonin on their communication.

Concomitant effects of paclitaxel and celecoxib on genes involved in apoptosis of triple-negative metastatic breast cancer cells.

Although triple-negative breast cancer accounts for less than one-fifth of breast cancers, it has a higher rate of metastasis and mortality. This study investigated the effects of combination treatment with paclitaxel and celecoxib on the expression of genes involved in the apoptosis of triple-negative metastatic breast cancer cells. MDA-MB-231 cells were cultured and then treated with certain concentrations of celecoxib (CLX), paclitaxel (PTX), and combination of them for 24 and 48 h. Cell viability was assessed by the MTT method. The real-time PCR method was utilized to assess the expression level of the genes involved in apoptosis. Western blotting was used for evaluating protein expression. IC50 values for CLX and PTX were 73.95 µM and 3.15 µM, respectively. The results demonstrated that PTX, CLX, and PTX + CLX significantly (p < 0.05) reduced cell viability. The comparison of combination treatment with PTX showed a significant increase in caspase 3 gene expression at both time points, in Bax gene expression after 48 h, and a remarkable decrease in Bcl-2 gene expression at both times. Western blotting results were in line with genes' expression. These findings indicate that a combination of PTX and CLX results in a significantly more reduction in cell viability of breast cancer cells. In addition, it seems CLX may be an effective agent in regulating the expression level of caspase 3, Bax, and Bcl-2 when combined with PTX.

Risk and protective factors for resilience among adolescents and young adults with beta-thalassemia major.

BACKGROUND: Resilience is the ability to overcome adversity in response to a potentially traumatic event. It can relieve people's discomfort and build personal capacity when facing a stressful situation such as beta thalassemia major. Resilience is a complex and multidimensional concept and is influenced by protective and risk factors. Therefore, the aims of the present study were to (1) investigate the relationship between protective (social support and hope) and risk (uncertainty and defensive coping) factors with resilience and (2) examine the mediating role of courageous coping between these protective and risk factors in resilience. METHODS: This descriptive-analytical study was performed on 312 adolescents and young adults with beta-thalassemia major aged 12-24 years; they were selected using purposeful sampling from two different outpatient thalassemia clinics in the south of Iran. Data were collected in a face-to-face survey using Zimmet Multidimensional Scale of Perceived Social Support, Herth Hope, Stewart Uncertainty in Illness scale, Jalowiec Coping, and Connor-Davidson resilience Scale from April 2022 to November 2022. The collected data were analyzed using descriptive tests, Pearson correlation, and a structural equation model. RESULTS: According to the main findings of mediation analysis, courageous coping partially mediated the relationship between social support and resilience [(ß = 0.042; 95% BC CI (0.003, 0.131)] and fully mediated the relationship between hope and resilience [(ß = 0.166; 95% BC CI (0.031, 0.348)]. In other cases, uncertainty and defensive coping had a direct and indirect effect on resilience, respectively. CONCLUSION: Based on these results, health professionals and healthcare policymakers should consider this mediator in developing programs to improve resilience. Also, the use of courageous coping could modulate the effect of defensive coping on resilience. Therefore, teaching the use of courageous coping can play an important role in improving resilience.

Abnormal Pap smear among pregnant women - Feasibility of opportunistic cervical screening.

Objective: The uptake of cervical cancer screening is poor, especially in developing countries. Thus, pregnancy represents a good opportunity to have the test done. The aim of this study is to determine the prevalence of abnormal Pap smear among pregnant women during their antenatal check-ups. Study design: A prospective study involving five hundred and ninety-six women was recruited over a 1-year duration from 15th January 2018 until 14th January 2019 in a tertiary referral center, in Malaysia. Pap smears were performed on all consented pregnant women using liquid-based cytology and the results were obtained to evaluate the prevalence of abnormal Pap smear during pregnancy. Maternal risk factors associated with abnormal Pap smear were identified and the outcomes of abnormal Pap smear were followed up. Results: A total of 670 participants were approached and 596 participants agreed to participate, giving a response rate of 89.0 %. Therefore, 587 participants were available for analysis. There were nine unsatisfactory smears (1.5 %). The prevalence of premalignant lesions reported on p % ap smear was 0.8 %. Three respondents had atypical squamous cells of undetermined significance (ASCUS) (0.5 %) and two respondents had low-grade squamous intraepithelial lesions (LSIL) (0.3 %). Almost one-third (30.3 %) of respondents had an infection and 24 (4.1 %) smears were reported as reactive changes associated with inflammation. Respondents between the age of 20-30 years old had a significant association with an abnormal pre-cancerous smear (p = 0.000) as well as nulliparity (p = 0.0.40). There was no significant association between height, weight, BMI, sexual partner, age of first intercourse, smoking habit, history of sexually transmitted disease and history of abnormal Pap smear. Conclusion: The prevalence of abnormal pre-cancerous smears during pregnancy is low. However, it is desirable to perform cervical screening as it provides an opportunity to no screening at all.

Protective effects of empagliflozin on testicular injury induced by torsion/detorsion in adult male rats.

INTRODUCTION: Testicular torsion is a known urologic emergency condition and one of the common causes of infertility in males. Hence, prompt diagnosis and treatment play a crucial role in prevention of testicular injury. It has been observed that empagliflozin, a drug for management of hyperglycemia, has anti-oxidative properties against different pathologies, the most important of which are ischemia reperfusion related injuries. OBJECTIVE: This study aims to evaluate the protective effects of empagliflozin on a testicular torsion injury in adolescent rats followed by ischemia/reperfusion (I/R) phenomena. STUDY DESIGN: Thirty-six rats were randomly assigned into three groups including sham-operated group received all surgical procedures except testicular torsion-detorsion, torsion/detorsion + dimethyl sulfoxide (DMSO) as vehicle, and torsion/detorsion + empagliflozin (10 mg/kg). Testicular torsion was performed for 2 h through rotating right testis 720° in the clockwise direction. Thirty minutes before detorsion, a single intraperitoneal dose of empagliflozin was injected to treatment group. Four hours later, orchiectomy was conducted for histopathological and biochemical examinations of testicular tissue specimens. RESULTS: The malondialdehyde (MDA) content in the torsion/detorsion animals was markedly greater than in the animals under sham operated procedure. Moreover, the testicular MDA levels in the torsion/detorsion + empagliflozin group were significantly lower than in the torsion/detorsion group. Also, significant decreases observed in catalase, superoxide dismutase, and glutathione peroxidase activities in the torsion/detorsion group in comparison with sham operated group. These values were significantly improved in the empagliflozin group. Furthermore, histopathological examinations also revealed severe testicular injury which were improved by empagliflozin administration. DISCUSSION: Empagliflozin prevented increases in oxidative stress markers and subsequently reduced the tissue injury induced by torsion/detorsion in the current study. CONCLUSION: It can be concluded that administration of empagliflozin before prevents I/R related cellular damage in testicular torsion, possibly via oxidative stress inhibition.

The effect of Crocus sativus L. (saffron) herbal tea on happiness in postmenopausal women: a randomized controlled trial.

BACKGROUND: Evidence suggests that menopause can be associated with a variety of negative psychological changes such as depression and anxiety, and improving the mental health status of women during menopause is one of the important priorities and challenges of the health system. The aim of this study was to determine the effect of saffron (Crocus sativus L., Iridaceae) herbal tea on happiness in postmenopausal women. METHODS: In this randomized clinical trial which was conducted in 2021, 72 postmenopausal women were enrolled and divided into intervention and control groups. The randomization blocks method was used for random allocation, and the Oxford Happiness Questionnaire was utilized to measure the scores. The intervention included the use of 30 mg of dried stigmas of the saffron plant, which was boiled once (in the morning, in 300 ml of boiling water for 10-15 min) and consumed with white rock candy as one cup of saffron tea daily. To compare the trend of changes and after removing the effect of other variables, generalized estimating equation (GEE) was used. RESULTS: There was no significant difference between the intervention and control groups in any of the quantitative and qualitative characteristics (p > 0.05). The results of paired samples t-test showed that the happiness mean score in the intervention group increased significantly (p < 0.001) from 42.93 ± 8.54 to 61.58 ± 8.24, while in the control group, there was no significant difference between the happiness mean score at the beginning and end of the study (p = 0.861). Also, after applying the treatment program in the intervention group, there was a significant difference between the two groups in terms of the happiness mean scores (p < 0.001). CONCLUSION: Saffron herbal tea had a positive effect on reducing depression and increasing the happiness score; thus, it is recommended that it should be used as a complementary treatment in consultation with the treating physician. TRIAL REGISTRATION: The present study was registered with the code of IRCT20210403050818N1 (Registration date: 09/04/2021) in the Iranian Registry of Clinical Trials. It was also approved by the Ethics Committee of Larestan University of Medical Sciences (Approval ID: IR.LARUMS.REC.1399.017).

Gut microbiota and circadian rhythm in Alzheimer's disease pathophysiology: a review and hypothesis on their association.

Alzheimer's disease (AD) is the most common neurodegenerative disease and the leading cause of dementia worldwide. Different pathologic changes have been introduced to be involved in its progression. Although amyloid-ß (Aß) deposition and tau hyperphosphorylation and aggregation are mainly considered the main characterizations of AD, several other processes are involved. In recent years, several other changes, including alterations in gut microbiota proportion and circadian rhythms, have been noticed due to their role in AD progression. However, the exact mechanism indicating the association between circadian rhythms and gut microbiota abundance has not been investigated yet. This paper aims to review the role of gut microbiota and circadian rhythm in AD pathophysiology and introduces a hypothesis to explain their association.

Antileishmanial effects and drugability characteristics of a heterocyclic copper complex: An in silico, in vitro and molecular study.

Leishmaniasis caused by the protozoan Leishmania presents a severe illness, principally in tropical and subtropical areas. Antileishmanial metal complexes, like Glucantime®ï¸ with proven activity, are routinely studied to probe their potency. We investigated the effects of a Cu (II) homoleptic complex coordinated by two dimethyl-bipyridine ligands against Leishmania major stages in silico and in vitro. The affinity of this heterocyclic Cu (II) complex (CuDMBP) towards a parasitic metacaspase was studied by molecular docking. Key pharmacokinetic and pharmacodynamic properties of the complex were predicted using three web-based tools. CuDMBP was tested for in vitro antileishmanial activities using MTT assay, model murine macrophages, flow cytometry, and quantitative real-time polymerase chain reaction (qPCR). Molecular docking confirmed the tendency between the target macromolecule and the complex. ADMET evaluations highlighted CuDMBP's key pharmacological features, including P-glycoprotein-associated GI absorption and lack of trans-BBB permeability. MTT showed significant inhibitory effects against promastigotes. CuDMBP significantly increased the level of cellular IL-12 expression (p < 0.05), while the upregulation observed in the expression of iNOS was considered not significant (p > 0.05). It decreased the expression of IL-10 significantly (p < 0.05). Findings demonstrated that CuDMBP deserves to be introduced as a leishmanicidal candidate provided further studies are carried out.

Bmal1 and Gut-lung axis in SARS-CoV-2 infection: New insight into the effects of melatonin on COVID-19 patients?

Coronavirus disease 2019 (COVID-19), is known as one of the most known challenge worldwide. Numerous studies have tried to introduce different mechanisms involved in the pathophysiology of COVID-19 and efforts in this field are also ongoing. The presence of SARS-CoV-2 RNA in feces of COVID-19 patients along with a variety of gastrointestinal symptoms may show a significant association between gut microbiota and SARS-CoV-2 infection. However, the exact mechanism indicating how SARS-CoV-2 and gut flora influence each other remains unknown. This paper aims to introduce a possible molecular mechanism based on recent findings on the association between circadian rhythm and gut flora in COVID-19 patients to express a new insight into the probable mechanism of melatonin in protection against SARS-CoV-2 infection.

Sociodemographic Predictors of Initiating Antenatal Care Visits by Pregnant Women During First Trimester of Pregnancy: Findings from the Afghanistan Health Survey 2018.

Purpose: Initiating antenatal care (ANC) visits by pregnant women during first trimester, known as timely initiation of ANC visits, is crucial for wellbeing of mothers and their unborn babies. We examined whether sociodemographic characteristics of pregnant women predict timely initiation of ANC visits. Patients and Methods: Data collected for the Afghanistan Health Survey 2018 (AHS 2018) were analyzed. A binary outcome variable was created as women with ANC visits in 0-3 months (first trimester) vs women with ANC visits in ≥4 months of pregnancy. A multivariable generalized linear model was employed. Results: A total of 6862 ever-married women, aged 14-49 years, with a history of pregnancy, including current pregnancy, were included. The prevalence of timely initiation of ANC visits was 55.8%. The likelihood (OR = odds ratio) of timely initiation of ANC visits was higher in women aged 30-39 years [OR 1.12 (95% CI: 1.00-1.25)], in women who could read and write [OR 1.12 (95% CI: 0.99-1.21)], in women who used public primary care facilities [OR 1.14 (95% CI: 1.01-1.28)], in women who received consultation on ANC from a doctor or midwife [OR 1.22 (95% CI: 0.72-2.08), OR 1.13 (95% CI: 0.67-1.92)] respectively, in women at fourth and highest quintiles of wealth status [OR 1.24 (95% CI: 1.04-1.48), OR 1.14 (95% CI: 0.92-1.40)] respectively, in women who intended to become pregnant [OR 1.56 (95% CI: 1.35-1.81)], in women who used the internet [OR 1.53 (95% CI: 1.13-2.06)], and in women who listened to radio [OR 1.16 (95% CI: 1.03-1.30)]. However, the likelihood was lower in women who had given birth at least twice [OR 0.67 (95% CI: 0.50-0.89)], and in women who lived in rural areas [OR 0.87 (95% CI: 0.75-1.00)]. Conclusion: To promote timely initiation of ANC visits, healthcare interventions to increase availability of midwives and doctors, and improve accessibility to primary care clinics, especially in rural areas, need to be implemented.

Protective effects of sitagliptin on methotrexate-induced nephrotoxicity in rats.

Methotrexate (MTX), a cytotoxic chemotherapeutic and immunosuppressant agent, is widely used in the treatment of autoimmune diseases and different types of cancers. However, its use has been limited by its life-threatening side effects, including nephrotoxicity and hepatotoxicity. The purpose of this study was to investigate the protective effect of sitagliptin on methotrexate (MTX)-induced nephrotoxicity in rats. Twenty-four rats were divided into four groups: control group, which received the vehicle for 6 days; MTX group, which received a single dose of MTX, followed by five daily doses of vehicle dosing; MTX + sitagliptin group, which received a single dose of MTX 1 h after the first sitagliptin treatment and six daily doses of sitagliptin; and sitagliptin group, which received sitagliptin for 6 days. Both MTX and sitagliptin were given as intraperitoneal injections at a dose of 20 mg/kg body weight. All rats were euthanized on the seventh day of the study. Kidney tissues were harvested and blood samples were collected. Serum levels of blood urea nitrogen (BUN) and creatinine were evaluated. Furthermore, catalase, glutathione peroxidase, superoxide dismutase activities, and malondialdehyde (MDA) levels were determined in kidney tissue. In addition, histopathological analysis was conducted. Histopathological evaluation showed that MTX-induced marked kidney injury. Biochemical analysis revealed a significant increase of BUN and creatinine in the serum of the MTX group. Furthermore, oxidative stress and depressed antioxidant system of the kidney tissues were evident in the MTX group. Sitagliptin did not affect these endpoints when administered alone, but it significantly attenuated the observed MTX-induced effects. These results suggest that sitagliptin exhibits potent anti-oxidant properties against the nephrotoxicity induced by MTX in rats.

Therapeutic potential of ADAM10 modulation in Alzheimer's disease: a review of the current evidence.

Alzheimer's disease (AD), the most common neurodegenerative disease worldwide, is caused by loss of neurons and synapses in central nervous system. Several causes for neuronal death in AD have been introduced, the most important of which are extracellular amyloid ß (Aß) accumulation and aggregated tau proteins. Increasing evidence suggest that targeting the process of Aß production to reduce its deposition can serve as a therapeutic option for AD management. In this regard, therapeutic interventions shown that a disintegrin and metalloproteinase domain-containing protein (ADAM) 10, involved in non-amyloidogenic pathway of amyloid precursor protein processing, is known to be a suitable candidate. Therefore, this review aims to examine the molecular properties of ADAM10, its role in AD, and introduce it as a therapeutic target to reduce the progression of the disease. Video abstract.