Volume 35, Issue 1-2

Liver diseases are complex conditions, significantly influenced by oxidative stress. This comprehensive review assesses the therapeutic role of antioxidants like l -ascorbic acid and α tocopherol, beta-carotene, various minerals, and plant-based ingredients in mitigating oxidative stress-induced liver diseases. The manuscript delves into the critical influence of genetic and epigenetic factors on disease susceptibility, progression, and response to antioxidant therapy. While animal studies suggest antioxidant efficacy in liver disease treatment, human trials remain inconclusive, and caution is advised due to its possible potential pro-oxidant effects. Moreover, the interactions of antioxidants with other drugs necessitate careful consideration in the management of polypharmacy in liver disease patients. The review underscores the need for further research to establish the clinical benefits of antioxidants with understanding of possible antioxidant toxicities to elucidate the intricate interplay of genetic, epigenetic, and environmental factors in liver diseases. The aim is to foster a better understanding of the knowledge on hepatic disease management with judicial antioxidant therapies.

Introduction In view of limited treatment options (those too may fail) for Crohn’s disease, cannabinoids have been tried as a therapeutic. However, their efficacy is not unequivocally established. This systematic review and meta-analysis was planned to pool data from randomised controlled trials (RCTs) evaluating effect of cannabinoids in Crohn’s disease with an intention to take this uncertainty away. Content Following literature search in Medline, EMBASE, Scopus and Google Scholar databases, RCTs assessing the effect of cannabinoids on mild-to-moderate Crohn’s disease in adults were included. Crohns’ disease activity index (CDAI), QoL (Quality of life), number participants achieving full remission and serum CRP at eight weeks of treatment were the outcomes considered for meta-analysis. Quality of studies was assessed using Cochrane’s RoB2 tool. Random effect model was applied for meta-analysis. Heterogeneity was assessed by Cochrane ‘Q’ statistics and I 2 test. Sensitivity analysis was performed to identify the major contributor(s) to heterogeneity and assess robustness of the results. Summary Risk of bias for the four included studies varied from ‘low’ to ‘some concern’. Overall effect estimate (SMD −0.92; 95 % CI −1.80, −0.03) indicated a statistically significant effect of cannabinoids as compared to control (p<0.05) on CDAI score. Effect of cannabinoids on rest of the outcome parameters was comparable to that of placebo. Magnitude of heterogeneity for different outcome parameters ranged from ‘low’ to ‘substantial’. Outlook Cannabinoids were superior to placebo for favourably affecting the disease severity in terms of CDAI score. However, no statistically significant difference was found between the two for improving QoL, causing full disease-remission and reducing inflammatory markers. The results must be interpreted with caution in view of relatively high heterogeneity among the studies.

The humanised monoclonal antibody donanemab is being developed to treat early onset Alzheimer’s disease (AD). This drug targets N-truncated pyroglutamate amyloid-peptide at position 3 (N3pG), a modified form of deposited amyloid-peptide. The symptoms of Alzheimer’s disease include gradual memory loss and other cognitive impairments. This disease is characterized by amyloid plaques, which are formed as a result of an accumulation of amyloid-(A-β) peptides. Despite granting donanemab breakthrough therapy designation in June 2021, the FDA rejected donanemab’s accelerated approval application in January 2023, due to inadequate safety data. According to the baseline amyloid level, the time to achieve plaque clearance (amyloid plaque level <24.1 centiloids) varied. Patients with higher baseline levels were more likely to achieve amyloid clearance. The safety of the drug was demonstrated by amyloid-related imaging abnormalities (ARIA), which ranged from 26.1 to 30.5 % in the studies. Clinical trial results have shown that donanemab delays cognitive and functional deterioration in patients with mild to moderate AD. However, it is not yet known whether donenameb offers therapeutic benefits that can change and improve the clinical condition of AD patients. To achieve significant clinical benefits in AD patients with cognitive impairment, further studies may be needed to investigate the interaction between A-β plaque reduction and toxic tau levels.

Alzheimer’s disease (AD) is spreading its root disproportionately among the worldwide population. Many genes have been identified as the hallmarks of AD. Based upon the knowledge, many clinical trials have been designed and conducted. Attempts have been made to alleviate the pathology associated with AD by targeting the molecular products of these genes. Irrespective of the understanding on the genetic component of AD, many clinical trials have failed and imposed greater challenges on the path of drug discovery. Therefore, this review aims to identify research and review articles to pinpoint the limitations of drug candidates (thiethylperazine, CT1812, crenezumab, CNP520, and lecanemab), which are under or withdrawn from clinical trials. Thorough analysis of the cross-talk pathways led to the identification of many confounding factors, which could interfere with the success of clinical trials with drug candidates such as thiethylperazine, CT1812, crenezumab, and CNP520. Though these drug candidates were enrolled in clinical trials, yet literature review shows many limitations. These limitations raise many questions on the rationale behind the enrollments of these drug candidates in clinical trials. A meticulous prior assessment of the outcome of clinical studies may stop risky clinical trials at their inceptions. This may save time, money, and resources.

Objectives Psoriasis is a persistent autoimmune inflammatory condition that is primarily affecting the skin. Pioglitazone (PGZ), a peroxisome proliferator activated receptor gamma (PPARγ) agonist, has been reported to have anti-inflammatory effects. However, the role of PGZ in psoriatic disease remains unclear. In this study, we aimed to repurpose the use of the PGZ for the treatment of psoriasis. Methods To investigate its efficacy, we employed an imiquimod (IMQ)-induced rat model. Wistar rats are randomly allocated to four different groups. Group, I served as a negative control, Group II IMQ control, Group III was treated with pioglitazone hydrogel and Group IV received standard drug betamethasone cream. PASI score was monitored on every alternative day and on day 7 animals were sacrificed and histopathology of skin was performed. Level of nitric oxide (NO) and myeloperoxidase (MPO) was also performed using established methods. Results The results of the experiment revealed that treatment with PGZ significantly (p<0.05) reduced redness, scaling, and skin thickening, surpassing the effectiveness of standard drugs. Our result also indicates that PGZ significantly (p<0.05) inhibits the release of both MPO and NO from the psoriatic lesions. Conclusions PGZ effectively reduces the severity of psoriasis possibly by inhibiting the accumulation of neutrophil at the psoriatic area which indirectly regulates the release of NO in the affected area. Our study showed we can repurpose the PGZ for the management of psoriasis.

Objectives Empagliflozin, a sodium-dependent glucose co-transporter 2 (SGLT2) inhibitor, and liraglutide, a GLP-1 receptor (GLP-1R) agonist, are commonly recognized for their cardiovascular benefits in individuals with type 2 diabetes (T2D). In prior studies, we have demonstrated that both drugs, alone or in combination, were able to protect cardiomyocytes from injury induced by diabetes. Mechanistic investigations also suggested that the cardioprotective effect may be independent of diabetes In this study, we utilized a hypoxia-reoxygenation (H/R) model to investigate the cardiovascular benefits of SGLT2 inhibitor empagliflozin and GLP-1 receptor (GLP-1R) agonist liraglutide, both alone and in combination, in the absence of T2D. Our hypothesis was that empagliflozin and liraglutide, either individually or in combination, would demonstrate cardioprotective properties against H/R-induced injury, with an additive and/or synergistic effect anticipated from combination therapy. Methods In this study, the cardiac muscle cell line, HL-1 cells, were treated with vehicle, empagliflozin, liraglutide, or a combination of the two drugs. The cells were then subjected to a hypoxia-reoxygenation (H/R) protocol, consisting of 1 h of hypoxia followed by 24 h of reoxygenation. The effects of the treatments on cytotoxicity, oxidative stress, endothelial nitric oxide synthase (eNOS) activity, phospho-protein kinase C (PKC) beta and phospho-eNOS (Thr 495 ) expression were subsequently evaluated at the end of the treatments. Results We found that H/R increased cytotoxicity and reduces eNOS activity, empagliflozin, liraglutide or combination treatment attenuated some or all of these effects with the combination therapy showing the greatest improvement. Conclusions Empagliflozin, liraglutide or combination of these two have cardioprotective effect regardless of diabetes. Cardioprotective effects of SGLT2 inhibitor and GLP-1R agonist is additive and synergistic.

Objectives How gaseous signalling molecules affect ion transport processes contributing to the physiological functions of the gastrointestinal tract under hypoxic conditions still needs to be clarified. The objective of the present study was to characterize the impact of gaseous signalling molecules on parameters of colonic ion transport during a hypoxia/reoxygenation cycle and the remaining secretory capacity of the epithelium after such a cycle. Methods Short-circuit current (I sc ) and tissue conductance (G t ) recordings in Ussing chamber experiments were performed on rat colon samples using CORM-2 (putative CO donor; 35 and 350 µM), sodium nitroprusside (NO donor; 100 µM), NaHS (fast H 2 S donor; 10 – 1,000 µM), GYY 4137 (slow H 2 S donor; 50 µM) and Angeli’s salt (HNO donor; 100 µM) as donors for gasotransmitters. Inhibition of endogenous synthesis of H 2 S was operated by inhibitors of cystathionin-γ-lyase, i.e.  dl -propargylglycine (1 mM) or β-cyano- l -alanine (5 mM), and the inhibitor of cystathionine-β-synthase, amino-oxyacetate (5 mM). Results The fast gasotransmitter donors NaHS, sodium nitroprusside and Angeli’s salt, administered 5 min before the onset of hypoxia, induced an increase in I sc . The response to the subsequently applied hypoxia was characterized by a decrease in I sc , which tended to be reduced only in the presence of the lowest concentration of NaHS (10 µM) tested. Reoxygenation resulted in a slow increase in I sc , which was unaffected by all donors or inhibitors tested. The stable acetylcholine derivative carbachol (50 µM) was administered at the end of each hypoxia/reoxygenation cycle to test the secretory capacity of the epithelium. Pretreatment of the tissue with the putative CO donor CORM-2 suppressed the secretory response induced by carbachol. The same was observed when cystathionin-γ-lyase and cystathionin-γ-synthase were inhibited simultaneously. Under both conditions, G t drastically increased suggesting an impaired tissue integrity. Conclusions The present results demonstrate that none of the exogenous gasotransmitter releasing drugs significantly ameliorated the changes in epithelial ion transport during the hypoxia/reoxygenation cycle ex vivo. In contrast, the putative CO donor CORM-2 exerted a toxic effect on the epithelium. The endogenous production of H 2 S, however, seems to have a protective effect on the mucosal integrity and the epithelial transport functions, which – when inhibited – leads to a loss of the secretory ability of the mucosa. This observation together with the trend for improvement observed with a low concentration of the H 2 S donor NaHS suggests a moderate protective role of low concentrations of H 2 S under hypoxic conditions.

Objectives Lifestyle, overnutrition, socioeconomic status, environmental conditions, and genetics are factors that cause obesity. Lifestyle modification with a nonpharmacological approach based on physical exercise is the starting point in overcoming obesity. However, physical exercise with the appropriate and effective intensity for obese subjects is still debated. Therefore, this study aims to prove the effect of intensity differences with aerobic-resistance combination exercise on increasing irisin and IL-6 levels in obese women. Methods A total of 32 obese women were selected as subjects and administered the interventions of low-intensity combination exercise (Q 2 ), moderate-intensity combination exercise (Q 3 ), and high-intensity combination exercise (Q 4 ). ELISA was used to measure irisin and IL-6 levels in all samples. Statistical analysis used one-way ANOVA and Turkey’s-Honest Significant Difference (HSD) post hoc test. Results The mean Δ IL-6 levels in the control groups (Q 1 ), Q 2 , Q 3 , and Q 4 were 0.27 ± 2.54, 2.07 ± 2.55, 5.99 ± 6.25, and 7.98 ± 2.82 pg/mL with (p=0.015). The mean Δ irisin levels were 0.06 ± 0.81 ng/mL in Q 1 , 0.59 ± 0.67 ng/mL in Q 2 , 1.99 ± 1.65 ng/mL in Q 3 , 4.63 ± 3.57 ng/mL in Q 4 with (p=0.001). Conclusions This study proved that all three types of combined exercise intensity increased myokine levels, such as irisin and IL-6. However, high-intensity combination exercise provided the most optimal improvement in myokine levels in obese women. Future studies are needed to design long-term exercise programs specifically for obese adolescent women using the findings from this study.

Objective The objective of our study was to assess the impact of heat stress on hydration and cognition among outdoor workers in hot environment. Methods Area heat stress assessments were measured using Quest Temp WBGT monitor. Sweat rate for dehydration and reaction time for acute cognitive processing were recorded using standard procedures. Results Heat stress measurements ranged from 23.8 °C – 42 °C. More than 50 % of the workers had high sweat rate (>1.2 L/h) when exposed to high environmental temperatures. Positive correlation was obtained between WBGT, sweat rate and reaction time which indicates that hyperthermia has an impact on neural network processing. Heart rate and reaction time also increased with rise in WBGT and heavy physical activity. Conclusions There was impairment of cognitive functions (reaction time) under heat stress conditions. Hence, reaction time can be used to assess the short-term impact of heat stress on neural modulation and will help to plan effective intervention strategies to reduce morbidity and mortality among workers.

Objectives The principal motive of this study is to explore the influence maternal separation (MS) exhibits on the mRNA expression of major drug metabolizing-cyp450s in parallel with the assessment of pathological changes that can be induced by MS in the livers of experimental mice. Methods Eighteen Balb/c mouse pups, comprising of both males and females, were separated from their mothers after birth. Following a six-week period during when the pups became adults, the mice were sacrificed and their livers were isolated for analysis of weight, pathohistological alterations, and the mRNA expression of drug metabolizing cyp450 genes: cyp1a1 , cyp3a11 , cyp2d9 , and cyp2c29 . Results The study demonstrated that MS markedly downregulated (p<0.05) the mRNA expression of all tested drug-metabolizing cyp450s in livers of female and male mice. Furthermore, the mRNA levels of major drug-metabolizing cyp450s were notably lower (p<0.05) in livers of female MS mice as compared with male MS mice. It was found that values of the total body weight and liver weight of MS mice did not vary significantly (p>0.05) from those of the control groups. Additionally, histological examination revealed that the hepatic tissue of MS mice was normal, similar to that of the control mice. Conclusions In summary, MS downregulates the gene expression of major hepatic drug-metabolizing cyp450s without inducing pathological alterations in the livers of mice. These findings provide an explanation for the heterogeneity in pharmacokinetics and drug response of patients with early life stress.

Objectives Meckel’s diverticulum (MD) is a common asymptomatic congenital intestinal anomaly. Clinical manifestations of MD can occur in about 4 % of cases by the presentation of its complications, generally intestinal occlusion, bleeding, and diverticular inflammation. MD’s complications are challenging preoperative diagnoses, as manifest with clinical symptoms that overlap with those of other acute non-traumatic abdominal diseases. Thus, in the emergency setting, abdominal computed tomography (CT) represents an essential tool for the correct diagnosis of complicated MD. Case presentation We present a case of a preoperative CT diagnosis of perforated Meckel’s diverticulitis in a young patient admitted to our Emergency Department complaining of acute abdominal pain. Conclusions The case highlights the importance of evaluating Meckel’s diverticulum complications among the differential diagnoses of acute non-traumatic abdominal pain and the high sensitivity of CT in assessing their presence in the proper clinical setting.