Suppressing NLRP3 activation and PI3K/AKT/mTOR signaling ameliorates amiodarone-induced pulmonary fibrosis in rats: a possible protective role of nobiletin.

Amiodarone (AMD), a medicine used to treat life-threatening arrhythmias, is frequently linked to pulmonary fibrosis (PF). Despite the involvement of NLRP3 inflammasome and PI3K/Akt/mTOR axis in fibrosis modulation and development, their significance in the etiology of AMD-induced PF remains uncertain. Nobiletin (NOB), a citrus flavonoid, has recently gained attention for its ability to reduce fibrotic processes in a variety of organs through inhibiting NLRP3-associated inflammation and suppressing PI3K/AKT/mTOR fibrotic pathway. Therefore, this research aimed to investigate the possible beneficial impact of NOB against AMD-induced PF, taking into account the roles of NLRP3 and PI3K/AKT/mTOR axis in its pathogenesis. Twenty-four rats were randomly specified into Vehicle; NOB 20 mg/kg; AMD 30 mg/kg, and NOB + AMD. All treatments were administered orally once a day for 4 weeks. The lung oxidant/antioxidant status, as well as the expression of inflammatory and fibrotic markers were all assessed. The results revealed that NOB, by improving Nrf2/HO-1 pathway, could reduce ROS production and NLRP3 activation, which in turn hindered IL-1ß release, prohibited TGF-ß1-related PI3K/AKT/mTOR cascade, suppressed α-SMA expression, and impeded collagen deposition. These findings point to a novel strategy by which NOB may alleviate the AMD-prompted NLRP3 inflammatory responses and associated PF through blocking PI3K/AKT/mTOR signaling.

Ellagic acid regulates hyperglycemic state through modulation of pancreatic IL-6 and TNF- α immunoexpression.

Background: Type 2 diabetes (T2DM) is a chronic metabolic disorder. Although therapeutic pharmaceutical agents continue to advance, herbal medicines are potential complementary treatments for the promotion of glucose homeostasis, with minimal adverse effects. Conventionally, ellagic acid (EA) has been utilized for the therapy of a range of pathologies owing to its anti-inflammatory and anti-diabetic actions. Objective: The aim of this study is to determine the activity of EA on serum α-amylase and lipase titers, and on pancreatic tumor necrosis factor-α (TNF-α), proliferating cell nuclear antigen (PCNA) and interleukin-6 (IL-6) concentrations using the streptozocin-induced T2DM rodent model. Methods: EA extract synthesized from fresh strawberry fruit was employed for therapy. 50 adults male Wistar rats were randomized into either control, EA, diabetic, co-treated or post- treated cohorts. Results: EA diminished fasting blood glucose levels, altered lipase, amylase, IL-6, PCNA and TNF- α expression and enhanced islet cell renewal, insulin, and immunoreactivities. Conclusion: Inflammatory indicators are elevated in the presence of T2DM. Extract of EA has overall tissue reparative and safeguarding properties, as indicated by the augmented ß- cell population and enhanced glucose homeostasis. Thus, EA may be an innovative treatment approach for the maintenance of normoglycemia in individuals with T2DM.

Factors Affecting the Incidence, Progression, and Severity of COVID-19 in Type 1 Diabetes Mellitus.

OBJECTIVES: This study screened for factors affecting coronavirus disease 2019 (COVID-19) incidence in type 1 diabetes mellitus (T1DM) patients, appraised vitamin D's efficacy in preventing COVID-19, and assessed the effects of clinical characteristics, glycemic status, vitamin D, and hydroxychloroquine administration on COVID-19's progression and severity in T1DM patients. METHODS: This retrospective research on 150 adults was conducted at Security Forces Hospital, Riyadh, KSA. Participants were allocated to three groups (50/group): control, T1DM, and T1DM with COVID-19. Participants' fasting blood glucose (FBG), glycated hemoglobin (HbA1c), complete blood count, vitamin D, C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), ferritin, lactate dehydrogenase (LDH), prothrombin time, activated partial thromboplastin time, D-dimer, liver and kidney function, and hydroxychloroquine treatment were retrieved and analyzed. RESULTS: The percentages of comorbidities and not taking hydroxychloroquine were significantly higher among T1DM patients with COVID-19 than patients with T1DM only. Mean vitamin D level was significantly lower in T1DM with COVID-19 patients than in the other two groups. Vitamin D showed a significant negative correlation with LDH, CRP, ESR, ferritin, and D-dimer, which was the most reliable predictor of COVID-19 severity in T1DM patients. CONCLUSION: Comorbidities and vitamin D deficiency are risk factors for COVID-19 in patients with T1DM. Patients who do not take hydroxychloroquine and have higher FBG and HbA1c levels are vulnerable to COVID-19. Vitamin D may be useful for preventing COVID-19 in T1DM patients. Comorbidities, higher FBG and HbA1c levels, not taking hydroxychloroquine, and vitamin D inadequacy elevate COVID-19 progression and severity in patients with T1DM.

Therapeutic Impact of Costus (Saussurea lappa) Against Ehrlich Solid Tumor-Induced Cardiac Toxicity and DNA Damage in Female Mice.

Breast cancer remains the most common cause of cancer deaths among women globally. Ehrlich solid tumor (EST) is a transplantable tumor model for simulating breast cancer. This study aims to describe the protective role of costus (Saussurea lappa) root against EST-induced cardiac toxicity. Forty female mice were randomly and equally divided into four groups (G1, control group; G2, costus group; G3, EST group; G4, EST + costus). The results showed that compared to the control, EST induced a significant increase in lactate dehydrogenase, creatine kinase, creatine kinase myoglobin, aspartate aminotransferase, and alkaline phosphatase activities; in potassium, chloride ion, cholesterol, triglyceride, and low density lipoprotein levels; in DNA damage and cardiac injury; and in p53 and vascular endothelial growth factor expression. Conversely, EST induced a significant decrease in sodium ion and high density lipoprotein levels and Ki67 expression compared to the control. Treatment of EST with costus improved cardiac toxicity, lipid profiles, electrolytes, and apoptosis, and protected against EST. This indicates the potential benefits of costus as an adjuvant in the prevention and treatment of cardiac toxicity.

Alpha-2 beta-adrenergic receptor (301-303 I/D) gene polymorphism in hypertension and type 2 diabetes mellitus diseases among Saudi cases in the Qassim region.

The hypertension (HTN) and type 2 diabetes mellitus (T2DM) are a common multifactorial disease due to genetics and environmental factors. The alpha 2B adrenergic receptor (α2B-AR) has relationship with secretion of insulin and mediates the vasoconstriction that elevate blood pressure. This study aimed to determine the association between α2B-AR gene polymorphism with HTN and T2DM in Saudi cases. 200 cases and 100 healthy controls from Saudi population were recruited from the Internal Medicine clinic, Qassim University. The patients were grouped into: 72 HTN without T2DM; 62 HTN with T2DM and 66 T2DM only. Full medical history, examination and biochemical assays were performed for all participants. Genomic DNA was isolated from blood lymphocytes of all subjects for detection of α2B-AR gene polymorphism by using polymerase chain reaction (PCR). The results found a significant association between D carriers genotype and HTN with T2DM cases (p < 0.05) as well as with T2DM-only cases, (p < 0.05) compared to control. Regardless of HTN status, only cases with HTN and T2DM as well as those with T2DM were significantly associated with the recessive model DD versus II+ID (p < 0.05). So, D carriers genotype was significantly associated with total cases of HTN and T2DM (p < 0.05) compared to controls. Our results suggested that there is a relationship between the α2B-AR I/D gene polymorphism and the risk for T2DM with or without HTN, but no such comparable relationship is evident with HTN-only cases among Saudi population in Qassim region.

Clinical Significance of Helicobacter pylori Infection on Psoriasis Severity.

The aim of the study was to appraise the link between psoriasis and Helicobacter pylori, investigate the influence of H. pylori treatment on psoriasis severity, determine the cutoff value of haptoglobin as a psoriatic biomarker, and determine the most reliable predictor for psoriasis in patients with H. pylori. This study was carried out on 100 adult Saudi participants from the Security Forces Hospital (Riyadh, Kingdom of Saudi Arabia). All participants were allocated into 5 groups (20/group): controls (G1), psoriatic patients (G2), patients with H. pylori (G3), psoriatic patients with untreated H. pylori (G4), and psoriatic patients with treated H. pylori (G5). The study was approved by the ethics committee of Security Forces Hospital, Riyadh, Saudi Arabia. The psoriasis area and severity index (PASI) score, 13C-urea breath test (13C-UBT), C-reactive protein (CRP), haptoglobin, platelet P-selectin, cluster of differentiation 4/cluster of differentiation 8 (CD4/CD8) ratio, and lymphocyte percentages were recorded. The haptoglobin level was significantly elevated in psoriatic patients compared with G1. In G5, there was significant attenuation in the PASI score, P-selectin, CRP, CD4/CD8 ratio, and lymphocyte percentage compared with G4. There was a significant positive correlation between psoriasis severity and 13C-UBT. In addition, 13C-UBT and PASI scores were significantly positively correlated with CRP, platelet P-selectin, and percentage of lymphocytes. H. pylori plays a potential role in psoriasis pathogenesis. H. pylori treatment attenuates psoriasis severity. Haptoglobin could be utilized as a psoriatic biomarker with 1.95 g/L as the cutoff value. The most reliable predictor for psoriasis in infected patients with H. pylori is 13C-UBT.

The impact of chicory (Cichoriumintybus L.) on hemodynamic functions and oxidative stress in cardiac toxicity induced by lead oxide nanoparticles in male rats.

BACKGROUND: A common environmental pollutant, lead can induce toxicity in several organ systems. A range of industrial and/or household materials and products contain lead, and food/liquid ingestion and inhalation are the mechanisms through which lead is introduced into the human body. OBJECTIVE: Since knowledge about the cardiac toxicity of acute lead nanoparticles is limited, this work sought to shed more light on the issue by investigating the therapeutic effects of chicory extract based on rat models to elevate cardiac functions and oxidative stress. METHODS: Four research groups were used, each consisting of ten albino rats of male sex and adult age. The groups were: control group, chicory group, lead oxide nanoparticle group, and lead oxide nanoparticle + chicory group. RESULTS: Compared to the control and chicory groups, the lead oxide nanoparticle group displayed a notable increase in heart functions and oxidative stress markers as well as alterations in cardiac histological structure. On the other hand, cardiac function modifications were counteracted through four-week administration of lead oxide nanoparticles alongside chicory. CONCLUSION: Heart damage caused by lead oxide nanoparticles may be attenuated by chicory through scavenging of free radicals.

Impact of smoking on heavy metal contamination and DNA fragmentation.

Tobacco is smoked by different techniques through cigarette and shisha smoking. The prevalence of tobacco is considered one of the major threats to public health. This study aims to assess the effect of cigarette, shisha, and mixed (cigarette/shisha) smoking on heavy metal contamination in hair samples, hair loss, and DNA fragmentation, to correlate age, incidence of hair loss, and smoking duration with the amount of accumulated metals and the DNA fragmentation, and to correlate the level of heavy metal contamination with DNA fragmentation. This study was implemented in Saudi Arabia among sixty males divided into four groups (15/group): control and cigarette, shisha, and mixed smokers. Heavy metal contamination in hair samples and urinary DNA levels were assayed. All metal and urinary DNA levels were significantly elevated in cigarette, shisha, and mixed smokers compared to non-smokers. Hair loss was also higher among smokers especially among participants with high DNA concentrations. There were positive significant correlations of age and incidence of hair loss with urinary DNA concentration. There were positive significant correlations between urinary DNA concentration and all heavy metal levels. Cigarette, shisha, and mixed smoking trigger metal contamination, DNA fragmentation, and hair loss. Moreover, hair loss was observed to be associated with Sb, Cd, and Ni as well as urinary DNA level, while age was associated only with lead and urinary DNA levels. The duration of smoking had a major impact on Pb and Sb levels. Finally, contamination with all six metals was significantly associated with DNA fragmentation.

Evaluation of the testicular protection conferred by damiana (Turnera diffusa Willd.) against amitriptyline-induced testicular toxicity, DNA damage and apoptosis in rats.

Psychiatric drugs, such as antidepressants, are used to treat depression based on their ability to modify chemical imbalances of the key neurotransmitters in the brain, including dopamine, serotonin, and norepinephrine. Amitriptyline, a first-reference tricyclic antidepressant derived from dibenzocycloheptadine, is frequently used, especially in neuropsychiatry, to address general depression, major depressive disorders, and fibromyalgia. Therefore, this study attempted to examine the sexual dysfunction attendant on the use of Amitriptyline by investigating the protective role that can be played by damiana. To this end, this study used damiana (Turnera diffusa Willd.) as adjuvant therapy in male albino rats receiving Amitriptyline. Sixty male albino rats were randomly allocated to six groups, with 10 rats being assigned to each group; the first group was a control, the second was treated with damiana only, the third group was given Amitriptyline, the fourth group received Amitriptyline and damiana simultaneously, the fifth group was given Amitriptyline and post-treated with damiana, and the sixth group was given Amitriptyline and then allowed time for self-healing. The findings of this study suggest that oxidative stress occurs in testicular tissue in rat groups treated with Amitriptyline, as manifested by inappropriate activity of TBARS, SOD, GSH, GR, GST, and GPx. Amitriptyline also repressed reproductive hormonal activity, as confirmed by histopathological lesions, DNA damage, and p53 protein expression. The addition of damiana, however, showed aprotective role in all testicular activity indices.

Sinapic Acid Attenuates Cardiovascular Disorders in Rats by Modulating Reactive Oxygen Species and Angiotensin Receptor Expression.

The main avoidable risk factor for cardiovascular conditions is high blood pressure (hypertension). At global level, hypertension is believed to be responsible for a 54% stroke-related mortality rate and a 47% mortality rate associated with coronary heart disease. It is postulated that sinapic acid (SA) could help in hypertension management because it displays robust antioxidant, antihyperglycemic, and peroxynitrite scavenging effects. To explore this hypothesis, this work examined the effect of SA on oxidative stress and cardiovascular disease in rats with hypertension by comparison against captopril. For this purpose, 50 male rats were used and equally allocated to five groups, namely, normal control, positive control (L-NAME), L-NAME with concomitant captopril administration, L-NAME with concomitant SA administration, and L-NAME with concomitant administration of both SA and captopril. Results showed that, by contrast to control, L-NAME exhibited marked elevation in serum CK-MB, total cholesterol, triglycerides, VLDL-C, LDL-C, Ang II, AT2R, ET-1, and angiopoietin-2; on the other hand, L-NAME exhibited marked reduction in serum HDL-C, superoxide dismutase (SOD) activity, nitric oxide synthase 3 (NOS3), and glutathione (GSH). Furthermore, joint administration of SA and captopril ameliorated hypertension, enhanced cardiovascular function, hindered hyperlipidemia, and decreased oxidative stress and myocardial hypertrophy displayed by rats with hypertension. Based on such findings, better chemopreventive or therapeutic approaches can be devised to manage hypertension and cardiovascular conditions.

The Toll-Like Receptor 3 Agonist Polyriboinosinic Polyribocytidylic Acid Increases the Numbers of NK Cells with Distinct Phenotype in the Liver of B6 Mice.

One of the activating factors of the cells of the innate immune system is the agonists of toll-like receptors (TLRs). Our earlier publications detailed how poly(I:C), a TLR3 agonist, elevates the NK cell population and the associated antigen-specific CD8+ T cell responses. This study involved a single treatment of the B6 mice with poly(I:C) intraperitoneally. To perform a detailed phenotypic analysis, mononuclear cells were prepared from each of the liver, peripheral blood, and spleen. These cells were then examined for their NK cell population by flow cytometric analysis following cell staining with indicated antibodies. The findings of the study showed that the NK cell population of the liver with an NK1.1highCD11bhighCD11chigh B220+Ly6G- phenotype was elevated following the treatment with poly(I:C). In the absence of CD11b molecule (CR3-/- mice), poly(I:C) can still increase the remained numbers of NK cells with NK1.1+CD11b- and NK1.1+Ly6G- phenotypes in the liver while their numbers in the blood decrease. After the treatment with anti-AGM1 Ab, which induced depletion of NK1.1+CD11b+ cells and partial depletion of CD3+NK1.1+ and NK1.1+CD11b- cell populations, poly(I:C) normalized the partial decreases in the numbers of NK cells concomitant with increased numbers of NK1.1-CD11b+ cell population in both liver and blood. Regarding mice with a TLR3-/- phenotype, their injection with poly(I:C) resulted in the partial elevation in the NK cell population as compared to wild-type B6 mice. To summarise, the TLR3 agonist poly(I:C) results in the elevation of a subset of liver NK cells expressing the two myeloid markers CD11c and CD11b. The effect of poly(I:C) on NK cells is partially dependent on TLR3 and independent of the presence of CD11b.

Antineoplastic Activity and Curative Role of Avenanthramides against the Growth of Ehrlich Solid Tumors in Mice.

Interest is growing in finding natural sources of effective antitumor agents that generate fewer side effects than conventional chemotherapeutic drugs. Avenanthramides (Avns) are such compounds; these phenolic molecules naturally occur in oats and have antioxidant, anti-inflammatory, and antiproliferative effects making them worthy of further research. The aim of this study is to characterise Avns' curative ability and antineoplastic activity on solid-form Ehrlich tumors. For the study, 75 female mice were randomly and equally allocated to five groups (group 1-control, group 2-DMSO, group 3-positive control receiving Avns, group 4-mice with Ehrlich solid tumor, and group 5-Ehrlich solid tumor treated with Avns). Mice with Ehrlich solid tumors exhibit increased tumor volume; elevated expression of AFP, ALT, AST, Bcl2, CEA, cholesterol, creatinine, urea, MDA, PCNA, potassium, triglycerides, TNF-α, and NF-κB; and a concomitant decline in catalase, GSH, P53, and SOD. In the mice with Ehrlich tumors who received Avns, there appeared to be improvement in NF-κB TNF-α, tumor markers (AFP and CEA), electrolytes, liver and kidney function enzymes, and lipid profiles; reduced MDA level; improved antioxidant parameters; normalised liver protein, P53, and PCNA; and reduced Bcl2 expression. Pathological examination of tumor lesions also indicated improvement. These results suggest that Avns exhibit antineoplastic activity and possess antioxidant properties that enhance the antioxidant defence system, thus reducing the oxidative stress caused by Ehrlich solid tumors.

Cyclophosphamide eradicates murine immunogenic tumor coding for a non-self-antigen and induces antitumor immunity.

Although the majority of cancers respond to chemotherapy, most cancer types relapse, at least in part, due to the poor immunogenicity of most tumor. We have reported before that treatment of tumor bearing mice with a combination of the anti-cancer chemotherapy cyclophosphamide (CTX) and immunotherapy can result in complete tumor regression using T-cell receptor (TCR) transgenic CD8+ T cells specific to antigens. This study aimed to determine whether chemotherapy can cure immunogenic tumor which expresses non-self-tumor antigen and result in antitumor immunity. Either EL4 cell line, a poorly immunogenic thymoma, or EG7, a clone of EL4 cells transfected with ovalbumin (OVA), as a non-self-antigen were inoculated subcutaneously into wild type or splenectomized C57BL/6 mice and then treated once with intraperitoneal (i.p.) injection of 4 mg CTX/mouse. In certain experiments, the mice were rechallenged with the same tumor type 1-2 months after the primary challenge. Treatment of EL4 bearing mice with CTX induced transient antitumor effect followed by tumor progression. Interestingly, however, treatment of EG7-bearing mice with CTX resulted in regression of early and advanced tumors. EG7 tumor-free mice rejected the second and the third challenges with EG7 cells, but not with challenge EL4 cells. These antitumor effects did not require spleen, since splenectomized mice showed similar antitumor effects of CTX on EG7 cells. Taken together, these data indicate that expression of non-self-antigen by poorly immunogenic tumor might be a reliable means to increase its immunogenicity and its response to chemotherapy.

Ameliorating effect of anti-Alzheimer's drugs on the bidirectional association between type 2 diabetes mellitus and Alzheimer's disease.

Mild to severe forms of nervous system damage were exhibited by approximately 60-70% of diabetics. It is important to understand the association between type 2 diabetes mellitus and Alzheimer's disease. The aim of the present work is to understand the bidirectional association between type 2 diabetes and Alzheimer's disease pathogenesis, that was monitored by glycaemic status, lipid profile, amyloid beta 40 and 42 (Aß40 and Aß42), C-reactive protein, total creatine kinase, total lactate dehydrogenase, D-dimer and magnesium measurements, to assess the association between theses biochemical markers and each other, to estimate the possibility of utilizing the amyloid beta as biochemical marker of T2D in Alzheimer's patients, and to evaluate the effect of piracetam and memantine drugs on diabetes mellitus. This study involved 120 subjects divided into 20 healthy control (group I), 20 diabetic patients (group II), 20 Alzheimer's patients (group III), 20 diabetic Alzheimer's patients with symptomatic treatment (group IV), 20 diabetic Alzheimer's patients treated with memantine (group V), and 20 diabetic Alzheimer's patients treated with piracetam (group VI). The demographic characteristics, diabetic index, and lipid profile were monitored. Plasma amyloid beta 40 and amyloid beta 42, C-reactive protein, total creatine kinase, total lactate dehydrogenase, D-dimer, and magnesium were assayed. The levels of amyloid beta 40 and amyloid beta 42 were significantly elevated in diabetic Alzheimer's patients with symptomatic treatment (group IV) compared to group II (by 50.5 and 7.5 fold, respectively) and group III (by 25.4 and 2.8 fold, respectively). In groups II, III, IV, V and VI, significant and positive associations were monitored between insulin and amyloid beta 40, amyloid beta 42, C-reactive protein, total creatine kinase, and D-dimer. Diabetic markers were significantly decreased in diabetic Alzheimer's patients treated with anti-Alzheimer's drugs (especially piracetam) compared to group IV. This study reveals the role of amyloid beta 40, amyloid beta 42, insulin, HbA1c, lipid profile disturbance, C-reactive protein, D-dimer, and magnesium in the bidirectional correlation between T2D and pathogenesis of Alzheimer's disease, that is powered by their correlations, and therefore the possibility of utilizing Aß as a biochemical marker of T2D in Alzheimer's patients is recommended. Impact statement Several aspects associated with T2D that contribute to AD and vice versa were investigated in this study. Additionally, this work reveals the role of Aß40, Aß42, insulin, HbA1c, lipid profile disturbance, CRP, D-dimer, and magnesium in the bidirectional association between T2D and the pathogenesis of AD, that is powered by their correlations, and therefore the possibility of utilizing Aß as a biochemical marker of T2D in Alzheimer's patients is recommended. Furthermore, the ameloriating effect of anti-Alzheimer's drugs on diabetes mellitus confirms this association. Hereafter, a new approach for treating insulin resistance and diabetes may be developed by new therapeutic potentials such as neutralization of Aß by anti-Aß antibodies.