Mechanistic insights into carvedilol's potential protection against doxorubicin-induced cardiotoxicity.

Doxorubicin (DOX) is an anthracycline chemotherapy drug widely employed in the treatment of various cancers, known for its potent antineoplastic properties but often associated with dose-dependent cardiotoxicity, limiting its clinical use. This review explores the complex molecular details that determine the heart-protective effectiveness of carvedilol in relation to cardiotoxicity caused by DOX. The harmful effects of DOX on heart cells could include oxidative stress, DNA damage, iron imbalance, disruption of autophagy, calcium imbalance, apoptosis, dysregulation of topoisomerase 2-beta, arrhythmogenicity, and inflammatory responses. This review carefully reveals how carvedilol serves as a strong protective mechanism, strategically reducing each aspect of cardiac damage caused by DOX. Carvedilol's antioxidant capabilities involve neutralizing free radicals and adjusting crucial antioxidant enzymes. It skillfully manages iron balance, controls autophagy, and restores the calcium balance essential for cellular stability. Moreover, the anti-apoptotic effects of carvedilol are outlined through the adjustment of Bcl-2 family proteins and activation of the Akt signaling pathway. The medication also controls topoisomerase 2-beta and reduces the renin-angiotensin-aldosterone system, together offering a thorough defense against cardiotoxicity induced by DOX. These findings not only provide detailed understanding into the molecular mechanisms that coordinate heart protection by carvedilol but also offer considerable potential for the creation of targeted treatment strategies intended to relieve cardiotoxicity caused by chemotherapy.

The multifaceted role of beta-blockers in overcoming cancer progression and drug resistance: Extending beyond cardiovascular disorders.

Beta-blockers are commonly used medications that antagonize ß-adrenoceptors, reducing sympathetic nervous system activity. Emerging evidence suggests that beta-blockers may also have anticancer effects and help overcome drug resistance in cancer treatment. This review summarizes the contribution of different isoforms of beta-adrenoceptors in cancer progression, the current preclinical and clinical data on associations between beta-blockers use and cancer outcomes, as well as their ability to enhance responses to chemotherapy and other standard therapies. We discuss proposed mechanisms, including effects on angiogenesis, metastasis, cancer stem cells, and apoptotic pathways. Overall, results from epidemiological studies and small clinical trials largely indicate the beneficial effects of beta-blockers on cancer progression and drug resistance. However, larger randomized controlled trials are needed to firmly establish their clinical efficacy and optimal utilization as adjuvant agents in cancer therapy.

Hedgehog signaling mastery: R51211's promise in augmenting the therapeutic efficacy of sorafenib.

Sorafenib is a multikinase inhibitor employed for managing hepatocellular carcinoma (HCC). The emergence of sorafenib resistance presents an obstacle to its therapeutic efficacy. One notable approach to overcoming sorafenib resistance is the exploration of combination therapies. The role of hedgehog signaling in sorafenib resistance has been also examined in HCC. R51211, known as itraconazole, has been safely employed in clinical practice. Through in vitro and in vivo investigations, we assessed the potential of R51211 to enhance the therapeutic efficacy of sorafenib by inhibiting the hedgehog signaling. The zero-interaction potency synergy model demonstrated a synergistic interaction between R51211 and sorafenib, a phenomenon reversed by the action of a smoothened receptor agonist. This dual therapy exhibited an increased capacity to induce apoptosis, as evidenced by alterations in the Bax/BCL-2 ratio and caspase-3, along with a propensity to promote autophagy, as indicated by changes in BECN1, p62, and the LC3I/LC3II ratio. Furthermore, the combination therapy resulted in significant reductions in biomarkers associated with liver preneoplastic alterations, improved liver microstructure, and mitigated changes in liver function enzymes. The substantial decrease in hedgehog components (Shh, SMO, GLI1, and GLI2) following R51211 treatment appears to be a key factor contributing to the increased efficacy of sorafenib. In conclusion, our study highlights the potential of R51211 as an adjunct to sorafenib, introducing a new dimension to this combination therapy through the modulation of the hedgehog signaling pathway. Further investigations are essential to validate the therapeutic efficacy of this combined approach in inhibiting the development of liver cancer.

Cell cycle machinery in oncology: A comprehensive review of therapeutic targets.

The cell cycle is tightly regulated to ensure controlled cell proliferation. Dysregulation of the cell cycle machinery is a hallmark of cancer that leads to unchecked growth. This review comprehensively analyzes key molecular regulators of the cell cycle and how they contribute to carcinogenesis when mutated or overexpressed. It focuses on cyclins, cyclin-dependent kinases (CDKs), CDK inhibitors, checkpoint kinases, and mitotic regulators as therapeutic targets. Promising strategies include CDK4/6 inhibitors like palbociclib, ribociclib, and abemaciclib for breast cancer treatment. Other possible targets include the anaphase-promoting complex/cyclosome (APC/C), Skp2, p21, and aurora kinase inhibitors. However, challenges with resistance have limited clinical successes so far. Future efforts should focus on combinatorial therapies, next-generation inhibitors, and biomarkers for patient selection. Targeting the cell cycle holds promise but further optimization is necessary to fully exploit it as an anti-cancer strategy across diverse malignancies.

A novel combination therapy targets sonic hedgehog signaling by the dual inhibition of HMG-CoA reductase and HSP90 in rats with non-alcoholic steatohepatitis.

Non-alcoholic steatohepatitis (NASH) is characterized by liver inflammation, fat accumulation, and collagen deposition. Due to the limited availability of effective treatments, there is a pressing need to develop innovative strategies. Given the complex nature of the disease, employing combination approaches is essential. Hedgehog signaling has been recognized as potentially promoting NASH, and cholesterol can influence this signaling by modifying the conformation of PTCH1 and SMO activity. HSP90 plays a role in the stability of SMO and GLI proteins. We revealed significant positive correlations between Hedgehog signaling proteins (Shh, SMO, GLI1, and GLI2) and both cholesterol and HSP90 levels. Herein, we investigated the novel combination of the cholesterol-lowering agent lovastatin and the HSP90 inhibitor PU-H71 in vitro and in vivo. The combination demonstrated a synergy score of 15.09 and an MSA score of 22.85, as estimated by the ZIP synergy model based on growth inhibition rates in HepG2 cells. In a NASH rat model induced by thioacetamide and a high-fat diet, this combination therapy extended survival, improved liver function and histology, and enhanced antioxidant defense. Additionally, the combination exhibited anti-inflammatory and anti-fibrotic potential by influencing the levels of TNF-α, TGF-ß, TIMP-1, and PDGF-BB. This effect was evident in the suppression of the Col1a1 gene expression and the levels of hydroxyproline and α-SMA. These favorable outcomes may be attributed to the combination's potential to inhibit key Hedgehog signaling molecules. In conclusion, exploring the applicability of this combination contributes to a more comprehensive understanding and improved management of NASH and other fibrotic disorders.

Linagliptin, a DPP-4 inhibitor, activates AMPK/FOXO3a and suppresses NFκB to mitigate the debilitating effects of diethylnitrosamine exposure in rat liver: Novel mechanistic insights.

Accumulating evidence suggests that dysregulation of FOXO3a plays a significant role in the progression of various malignancies, including hepatocellular carcinoma (HCC). FOXO3a inactivation, driven by oncogenic stimuli, can lead to abnormal cell growth, suppression of apoptosis, and resistance to anticancer drugs. Therefore, FOXO3a emerges as a potential molecular target for the development of innovative treatments in the era of oncology. Linagliptin (LNGTN), a DPP-4 inhibitor known for its safe profile, has exhibited noteworthy anti-inflammatory and anti-oxidative properties in previous in vivo studies. Several potential molecular mechanisms have been proposed to explain these effects. However, the capacity of LNGTN to activate FOXO3a through AMPK activation has not been investigated. In our investigation, we examined the potential repurposing of LNGTN as a hepatoprotective agent against diethylnitrosamine (DENA) intoxication. Additionally, we assessed LNGTN's impact on apoptosis and autophagy. Following a 10-week administration of DENA, the liver underwent damage marked by inflammation and early neoplastic alterations. Our study presents the first experimental evidence demonstrating that LNGTN can reinstate the aberrantly regulated FOXO3a activity by elevating the nuclear fraction of FOXO3a in comparison to the cytosolic fraction, subsequent to AMPK activation. Moreover, noteworthy inactivation of NFκB induced by LNGTN was observed. These effects culminated in the initiation of apoptosis, the activation of autophagy, and the manifestation of anti-inflammatory, antiproliferative, and antiangiogenic outcomes. These effects were concomitant with improved liver function and microstructure. In conclusion, our findings open new avenues for the development of novel therapeutic strategies targeting the AMPK/FOXO3a signaling pathway in the management of chronic liver damage.

Garden Cress Seed Oil Abrogates Testicular Oxidative Injury and NF-kB-Mediated Inflammation in Diabetic Mice.

Diabetes mellitus is a metabolic disorder associated with various complications encompassing male reproductive dysfunction. The present study aimed to investigate the therapeutic potential of biologically active Lepidium sativum seed oil (LSO) against the testicular dysfunction associated with streptozotocin (STZ)-induced diabetes. Male adults (n = 24) were divided into four groups: control, LSO-administered, diabetic (D), and LSO-treated diabetic (D+LSO) groups. LSO was extracted from L. sativum seeds, and its chemical composition was determined using GC-MS. Serum testosterone levels, testicular enzymatic antioxidants (catalase (CAT) and superoxide dismutase (SOD)), an oxidative stress (OS) biomarker, malondialdehyde (MDA), pro-inflammatory markers (NF-kB, IL-1, IL-6, and TNF-α), and the expression level of NF-kB were assessed. In addition, histopathological changes were evaluated in testicular tissues. The results obtained showed that the chemical composition of LSO indicated its enrichment mainly with γ-tocopherol (62.1%), followed by 2-methylhexacosane (8.12%), butylated hydroxytoluene (8.04%), 10-Methylnonadecane (4.81%), and δ-tocopherol (3.91%). Moreover, LSO administration in the D+LSO mice significantly increased testosterone levels and ameliorated the observed testicular oxidative damage, inflammatory response, and reduced NF-kB expression compared to the diabetic mice. Biochemical and molecular analyses confirmed the histological results. In conclusion, LSO may prevent the progression of diabetes-induced impairment in the testes through inhibition of the OS- and NF-kB-mediated inflammatory response.

Rutin, a Flavonoid Compound Derived from Garlic, as a Potential Immunomodulatory and Anti-Inflammatory Agent against Murine Schistosomiasis mansoni.

Schistosomiasis is a tropical disease caused by trematode worms. The inflammatory response of the host to schistosome eggs leads to formation of granuloma in the liver and intestine. Praziquantel (PZQ) is still an effective treatment for schistosomiasis, however resistance development may reduce its efficacy. The current study investigated the possible immunomodulatory and anti-inflammatory action of rutin, a natural flavonoid compound isolated from garlic, on liver fibrotic markers in mice infected with S. mansoni in comparison to PZQ. Male albino CD1 mice were infected with 100 ± 2 S. mansoni cercariae/mouse and treated with garlic, rutin, or PZQ. At the end of the experiment, the liver and intestines were harvested for parasitological and histological assessment and to analyze the proinflammatory cytokine. Rutin significantly affects the pathological alterations caused by Schistosoma in the liver. This may be partially explained by a decrease in the number of eggs trapped in the tissues of the liver and a modification in the serum levels of certain cytokines, which are implicated in the formation of Schistosoma granuloma. In conclusion, rutin has strong anti-schistosome properties in vivo, raising the possibility that rutin might be further investigated as a therapy for S. mansoni.

Phenolic-Compound-Rich Opuntia littoralis Ethyl Acetate Extract Relaxes Arthritic Symptoms in Collagen-Induced Mice Model via Bone Morphogenic Markers.

Rheumatoid arthritis (RA) is an autoimmune disease that causes inflammation and progressive joint dysfunction. Opuntia littoralis (OL) has a high nutritional content and is thought to offer a number of health advantages. We aimed to evaluate the anti-arthritic potential of OL extracts against collagen-induced arthritis (CIA). We designed three OL cladode fractions from the concentrated aqueous extract: hexane, ethyl acetate (EAE), and hydro alcohol (HAE). We investigated the nitric oxide and MDA levels of EAE against lipopolysaccharide-induced RAW264.7 cells; then, we administered EAE to the mice with CIA to confirm the anti-inflammatory effects against RA. HPLC analysis of the OL extracts showed a high concentration of phenolic compounds in EAE. Treatment with EAE (10 and 20 mg/100 g body weight of mice) after 10 days of immunization with collagen showed a significant inhibition of joint inflammation, paw swelling, and edemas. MDA and cytokine levels (IL-1ß, IL-6R, IL-6, IL-17, and IL-23) were significantly reduced. EAE effectively ameliorated COX-2, NF-kB, STAT-3, PTEN, and RANKL expression. OL-EAE therapy significantly upregulated the expression of miR-28 and miR-199a. In conclusion, the anti-inflammatory actions of OL-EAE altered the cellular localization of the inflammatory mediators, therefore preventing joint inflammation via partial epigenetic and metabolic regulations in experimental mice.

The Protective Role of Toll-Like Receptor Agonist Monophosphoryl Lipid A Against Vaccinated Murine Schistosomiasis.

PURPOSE: Schistosomiasis is a disease that afflicts over 220 million people worldwide. To date, there is no vaccine against schistosomiasis and chemotherapy relies basically on a single drug, praziquantel. The current study was undertaken to investigate the therapeutic effects of monophosphoryl lipid A (MPLA) as an adjuvant in soluble egg antigen (SEA)-vaccinated and Schistosoma mansoni-infected mice. METHODS: Mice were divided into two groups of uninfected and Schistosoma mansoni infected. The two groups were treated differently with MPLA, SEA and praziquantel. Study parameters included parasitological, immunological and biochemical parameters. RESULTS: Parasitological parameters revealed that intraperitoneal injection of MPLA into SEA-vaccinated and S. mansoni-infected mice was effective in reducing the worm and egg burden, granuloma count and diameter as well as the total area of infection in their livers versus SEA-untreated but infected ones. In addition, MPLA showed ameliorative action on the elevated liver oxidative stress marker, including malondialdehyde (MDA) and a decrease in the level of the antioxidant enzymes, reduced glutathione (GSH) and catalase (CAT) which may have a role in the liver damage and fibrosis due to S. mansoni infection. CONCLUSION: Treatment with MPLA has multi-functions in attenuating the deleterious impacts of S. mansoni infection in mice livers. Its effects are mediated through a reduction of ova count, worm burden, granuloma diameter and amelioration of antioxidant defense systems, and liver function biomarkers.

Evaluation of awareness and understanding of cancer immunotherapy among healthcare professionals in eastern Saudi Arabia.

INTRODUCTION: Cancer immunotherapy is a complicated field that develops rapidly; in the past decades, immunotherapy has become the standard treatment for several cancer types. The aim of the current study was to estimate the awareness and understanding of cancer immunotherapy and associated immunological concepts among healthcare professionals (HCPs) in eastern Saudi Arabia in order to assess educational needs. METHODS: A cross-sectional questionnaire was conducted among multidisciplinary HCPs in healthcare institutions in eastern Saudi Arabia from April 2019 to June 2019. The survey was designed to assess the awareness and understanding of HCPs' basic scientific knowledge of cancer immunotherapy. The data were analyzed using the Statistical Package for the Social Sciences (SPSS). Reliability was tested through Cronbach's alpha, and a χ2 or Fisher's exact test was used to determine the distribution of categorical variables between groups. RESULTS: The study included 360 HCPs: 43.6% physicians, 21.9% nurses, 20.8% medical laboratory scientists, and 13.6% pharmacists. Only 20.6% of the HCPs considered immunotherapy the best-known cancer therapy. The overall level of awareness of cancer immunotherapy was low (55.8%), and only 6.4% of the participants had a high knowledge rate. The majority of the respondents indicated the importance of studying the science of immunotherapy. Cronbach's alphas for the HCPs' perceptions, self-evaluation rate, and reflection scales were 0.74, 0.90, and 0.66, respectively. Simple linear regression showed a significant relationship between reflection and self-evaluation. CONCLUSIONS: A reliable and consistent study revealed a low level of awareness and understanding of immunotherapy among multidisciplinary HCPs.

DNA vaccination using recombinant Schistosoma mansoni fatty acid binding protein (smFABP) gene.

Schistosomiasis is a fatal disease that has a negative impact on health and economics. Praziquantel (PZQ) is the drug of choice for schistosomiasis treatment, but it has no prophylactic effect; therefore, vaccination is an essential requirement in schistosomiasis control. This work was carried out to investigate the possible effect of DNA vaccination against Schistosoma mansoni infection using recombinant S. mansoni fatty acid binding protein (rsmFABP). The smFABP gene was cloned into the eukaryotic expression vector pcDNAI/Amp in order to obtain an smFABP-pcDNAI recombinant plasmid (DNA vaccine) and was used for the intramuscular DNA vaccination of out-bread Swiss albino mice prior to infection with S. mansoni cercariae. Infected groups, either DNA vaccinated or unvaccinated, were treated with PZQ at week 6 post-infection. After 8 weeks post-infection, all mouse groups were sacrificed and parasitological, immunological and histopathological parameters were studied. DNA vaccinated mice showed a high titer of anti-smFABP-IgG antibodies and acquired significant protection (74.2%, p < 0.01) against S. mansoni infection, with a reduction in ova and granuloma counts. DNA vaccinated and PZQ treated animals had higher titers of anti-smFABP-IgG antibodies and decreased (87%, P < 0.001) parenchymal granulomas compared to the DNA vaccinated PZQ untreated group. Infected mice, either non DNA vaccinated or vaccinated, had very high collagen content and fibrous granulomas (74%) compared to the PZQ treated group (10.3% fibrous granuloma) and PZQ treated + DNA vaccinated group (0% fibrous granuloma). In conclusion, DNA vaccination had protective and anti-pathological effects in naive mice and greatly improved the pathological status in PZQ-treated animals, suggesting an immunological and pathological modulating effect of PZQ treatment.

Efficacy of soluble glycoprotein fraction from Allium sativum purified by size exclusion chromatography on murine Schistosomiasis mansoni.

In this work, the efficiency of crude MeOH extracts and soluble glycoprotein fraction of Allium sativum purified by size-exclusion chromatography (SEC) on parasitological, histopathological and some biochemical parameters in Schistosoma mansoni infected mice were investigated. Animals were infected by tail immersion with 100 cercariae/each mouse and divided into five groups in addition to the normal control. The results revealed a significant decrease in mean worm burden in all treated mice especially in the group treated with soluble glycoprotein fraction of A. sativum as compared to infected non-treated control with the disappearance of female worms. Administration of the studied extracts revealed remarkable amelioration in the levels of all the measured parameters in S. mansoni infected mice. In addition, treatment of mice with crude A. sativum MeOH extract and soluble glycoprotein fraction of A. sativum decreased significantly the activities of studied enzymes as compared to the infected untreated group. The highest degrees of enhancement in pathological changes was observed in the treated one with soluble glycoprotein fraction of A. sativum compared to the infected group represented by small sized, late fibro-cellular granuloma, the decrease in cellular constituents and degenerative changes in eggs. In conclusion, A. sativum treatment had effective schistosomicidal activities, through reduction of worm burden and tissue eggs, especially when it was given in purified glycoprotein fraction. Moreover, the soluble glycoprotein fraction of A. sativum largely modulates both the size and the number of granulomas.