Functionalized siRNA-chitosan nanoformulations promote triple-negative breast cancer cell death via blocking the miRNA-21/AKT/ERK signaling axis: in-silico and in vitro studies.

Oncogenic microRNA (miRNA), especially miRNA-21 upregulation in triple-negative breast cancer (TNBC), suggests a new class of therapeutic targets. In this study, we aimed to create GE11 peptide-conjugated small interfering RNA-loaded chitosan nanoparticles (GE11-siRNA-CSNPs) for the targeting of EGFR overexpressed TNBC and selectively inhibit miRNA-21 expression. A variety of in-silico and in vitro cellular and molecular studies were conducted to investigate the binding affinities of specific targets used as well as the anticancer efficacies and mechanisms of GE11-siRNA-CSNPs in TNBC cells. An in-silico assessment reveals a distinct binding affinity of miRNA-21 with siRNA as well as between the extracellular domain of EGFR and synthesized peptides. Notably, the in vitro results showed that GE11-siRNA-CSNPs were revealed to have better cytotoxicity against TNBC cells. It significantly inhibits miRNA-21 expression, cell migration, and colony formation. The results also indicated that GE11-siRNA-CSNPs impeded cell cycle progression. It induces cell death by reducing the expression of the antiapoptotic gene Bcl-2 and increasing the expression of the proapoptotic genes Bax, Caspase 3, and Caspase 9. Additionally, the docking analysis and immunoblot investigations verified that GE1-siRNA-CSNPs, which specifically target TNBC cells and suppress miRNA-21, can prevent the effects of miRNA-21 on the proliferation of TNBC cells via controlling EGFR and subsequently inhibiting the PI3K/AKT and ERK1/2 signaling axis. The GE11-siRNA-CSNPs design, which specifically targets TNBC cells, offers a novel approach for the treatment of breast cancer with improved effectiveness. This study suggests that GE11-siRNA-CSNPs could be a promising candidate for further assessment as an additional strategy in the treatment of TNBC.

Association of ACE*(Insertion/Deletion) Variant with the Elevated Risk of Preeclampsia Among Gestational Women.

The renin-angiotensin-aldosterone system has an indispensable function in the uteroplacental circulation, placental growth, and blood pressure optimization. The angiotensin I converting enzyme (ACE) gene is a critical integrator for electrolyte balance, and water retention, along with inhibiting preeclampsia. The main goal of this pertaining study is to assess the contribution of ACE*(Ins/Del) variant with the susceptibility for preeclampsia with focus on the severity of the disease among gestational hypertensive women. This retrospective study included 225 participants [125 PE gestational women, and 100 normotensive healthy controls] matching with age, and geographical region. PE women classified into 82 early-onset PE women, accompanied with 43 late-onset PE women. Additionally, PE women categorized into 59 mild PE women, together with 66 severe PE women. The genotyping and characterization of ACE*(Ins/Del) variant were applied using the PCR technique. Our findings indicated higher frequency of the ACE*(Del/Del) genotype and ACE*(D allele) with elevated risk of preeclampsia compared to normotensive controls under recessive (OR = 2.09, and p-value = 0.007), and allelic (OR = 1.75, and p-value = 0.012) models. In addition, testing logistic regression revealed that the levels of endothelin-1 and malondialdehyde exposed significant difference for the ACE*(Del/Del) genotype among early-onset and late-onset PE women (p-value = 0.024, and 0.23, respectively). Furthermore, carriers of the ACE*(Del/Del) genotype observed statistically significant with lower sodium concentrations among severe PE women (p-value = 0.034). The ACE*(Del/Del) genotype and ACE*(D allele) were associated with increased risk preeclampsia among gestational women. Furthermore, early-onset PE and late-onset PE were correlated with endothelin-1 and malondialdehyde concentrations among Egyptian women.

Medicinal Herbs: Promising Immunomodulators for the Treatment of Infectious Diseases.

Humans are constantly at high risk of emerging pandemics caused by viral and bacterial infections. The emergence of new pandemics is mainly caused by evolved viruses and bacteria that are highly resistant to existing medications. The rapid evolution of infectious agents demands the urgent investigation of new therapeutic strategies to prevent and treat these infections at an early stage. One of these therapeutic strategies includes the use of medicinal herbs for their antibacterial and antiviral properties. The use of herbal medicines as remedies is very ancient and has been employed for centuries. Many studies have confirmed the antimicrobial activities of herbs against various pathogens in vitro and in vivo. The therapeutic effect of medicinal herbs is mainly attributed to the natural bioactive molecules present in these plants such as alkaloids, flavonoids, and terpenoids. Different mechanisms have been proposed for how medicinal herbs enhance the immune system and combat pathogens. Such mechanisms include the disruption of bacterial cell membranes, suppression of protein synthesis, and limitation of pathogen replication through the inhibition of nucleic acid synthesis. Medicinal herbs have been shown to treat a number of infectious diseases by modulating the immune system's components. For instance, many medicinal herbs alleviate inflammation by reducing pro-inflammatory cytokines (e.g., tumor necrosis factor-alpha (TNF-α), interleukin-1, IL-6) while promoting the production of anti-inflammatory cytokines (e.g., IL-10). Medicinal herbs also play a role in defense against viral and intracellular infections by enhancing the proliferation and functions of natural killer cells, T-helper-1 cells, and macrophages. In this review, we will explore the use of the most common herbs in preventing and treating infectious and non-infectious diseases. Using current and recently published studies, we focus on the immunomodulatory and therapeutic effects induced by medicinal herbs to enhance immune responses during diseases.

Actinidia deliciosa Extract as a Promising Supplemental Agent for Hepatic and Renal Complication-Associated Type 2 Diabetes (In Vivo and In Silico-Based Studies).

Type 2 diabetes (T2D) is a chronic metabolic condition associated with obesity, oxidative stress-mediated inflammation, apoptosis, and impaired insulin signaling. The utilization of phytochemical therapy generated from plants has emerged as a promising approach for the treatment of diabetes and its complications. Kiwifruit is recognized for its substantial content of antioxidative phenolics. Therefore, this work aimed to examine the effect of Actinidia deliciosa (kiwi fruit) on hepatorenal damage in a high-fat diet (HFD) and streptozotocin (STZ)-induced T2D in rats using in vivo and in silico analyses. An increase in hepatic and renal lipid peroxidation was observed in diabetic rats accompanied by a decrease in antioxidant status. Furthermore, it is important to highlight that there were observable inflammatory and apoptotic responses in the hepatic and renal organs of rats with diabetes, along with a dysregulation of the phosphorylation levels of mammalian target of rapamycin (mTOR), protein kinase B (Akt), and phosphoinositide 3-kinase (PI3K) signaling proteins. However, the administration of kiwi extract to diabetic rats alleviated hepatorenal dysfunction, inflammatory processes, oxidative injury, and apoptotic events with activation of the insulin signaling pathway. Furthermore, molecular docking and dynamic simulation studies revealed quercetin, chlorogenic acid, and melezitose as components of kiwi extract that docked well with potential as effective natural products for activating the silent information regulator 1(SIRT-1) pathway. Furthermore, phenolic acids in kiwi extract, especially syringic acid, P-coumaric acid, caffeic acid, and ferulic acid, have the ability to inhibit the phosphatase and tensin homolog (PTEN) active site. In conclusion, it can be argued that kiwi extract may present a potentially beneficial adjunctive therapy approach for the treatment of diabetic hepatorenal complications.

Discovery of new 5-substituted-indole-2-carboxamides as dual epidermal growth factor receptor (EGFR)/cyclin dependent kinase-2 (CDK2) inhibitors with potent antiproliferative action.

A new series of 5-substituted-3-ethylindole-2-carboxamides 5a-k and 6a-c was designed and synthesised in an attempt to develop a dual targeted antiproliferative agent. Various spectroscopic methods of analysis were used to confirm the structures of the new compounds. The antiproliferative effect of compounds 5a-k and 6a-c against four cancer cell lines was investigated. Compounds 5a-k and 6a-c had significant antiproliferative activity against the four cancer cell lines tested, with mean GI50 values ranging from 37 nM to 193 nM. The most powerful derivatives were compounds 5g, 5i, and 5j, with GI50 values of 55 nM, 49 nM, and 37 nM, respectively, in comparison to the reference erlotinib, which had a GI50 of 33 nM. The four most potent compounds, 5c, 5g, 5i, and 5j, were then investigated for their efficacy as EGFR inhibitors, and the findings showed that the tested compounds inhibited EGFR with IC50 values ranging from 85 nM to 124 nM when compared to the reference erlotinib (IC50 = 80 nM). Moreover, compounds 5c and 5g inhibited CDK2 with IC50 values of 46 ± 05 nM and 33 ± 04 nM, respectively. The EGFR and CDK2 assays revealed that compounds 5i and 5j displayed potent antiproliferative activity and can be considered as potential dual EGFR and CDK2 inhibitors.

Amelioration of Age-Related Multiple Neuronal Impairments and Inflammation in High-Fat Diet-Fed Rats: The Prospective Multitargets of Geraniol.

Neuroinflammation is documented to alter brain function as a consequence of metabolic changes linked with a high-fat diet (HFD). The primary target of this study is to see how geraniol is effective in manipulating age- and diet-associated multiple toxicity and neuroinflammation in HFD-fed rats. Sixty-four adult male Wistar rats were partitioned into two groups: Group 1 (untreated normal young and aged rats) and Group 2 (HFD-fed young and aged rats) that received HFD for 16 weeks before being orally treated with geraniol or chromax for eight weeks. The results revealed a dropping in proinflammatory cytokines (TNF-α and IL-6) and leptin while boosting adiponectin in geraniol-supplemented rats. The liver, kidney, and lipid profiles were improved in geraniol-HFD-treated groups. HFD-induced brain insulin resistance decreased insulin clearance and insulin-degrading enzyme (IDE) levels significantly after geraniol supplementation. Geraniol suppressed acetylcholinesterase (AChE) activity and alleviated oxidative stress by boosting neuronal reduced glutathione (GSH), catalase (CAT), glutathione-S-transferase (GST), and superoxide dismutase (SOD) activities. It lowered malondialdehyde concentration (TBARS), nitric oxide (NO), and xanthine oxidase (XO) and restored the structural damage to the brain tissue caused by HFD. Compared with model rats, geraniol boosted learning and memory function and ameliorated the inflammation status in the brain by lowering the protein levels of IL-1ß, iNOS, NF-κBp65, and COX-2. In addition, the expression levels of inflammation-related genes (MCP-1, TNF-α, IL-6, IL-1ß, and IDO-1) were lessened significantly. Remarkably, the supplementation of geraniol reversed the oxidative and inflammation changes associated with aging. It affected the redox status of young rats. In conclusion, our results exhibit the effectiveness of dietary geraniol supplementation in modifying age-related neuroinflammation and oxidative stress in rats and triggering off the use of geraniol as a noninvasive natural compound for controlling age- and diet-associated neuronal impairments and toxicity.

New insights into geraniol's antihemolytic, anti-inflammatory, antioxidant, and anticoagulant potentials using a combined biological and in silico screening strategy.

The study aims to assess the antihemolytic and antioxidant activities of geraniol versus 2, 2'-azobis, 2-amidinopropane dihydro-chloride- (AAPH-) induced oxidative damage and hemolysis to erythrocytes and its anti-inflammatory potential against lipopolysaccharide- (LPS-) induced inflammation in white blood cells (WBCs) with a focus on its integrated computational strategies against different targeted receptors participating in inflammation and coagulation. The rats' erythrocyte suspension was incubated with different geraniol concentrations. Molecular docking and simulation were used to explore the possible interaction patterns of geraniol against the potential targeted proteins for therapeutic screening. The results displayed that geraniol had a prolonged noteworthy effect on activated partial thromboplastin time and thromboplastin time. Geraniol displayed strong antioxidant effects via reduced malondialdehyde (MDA) formation and increased GSH level and SOD activity. We observed dose-dependent prevention of K+ ion leakage along with a remarkable decline of hemolysis in erythrocytes pretreated with geraniol. Geraniol 100 µg/mL and diclofenac 100 µM were nontoxic to WBCs. Geraniol significantly reduces the expression and release of cellular pro-inflammatory factors TNF-α, IL-1ß, IL-8, and nitric oxide, accompanied by a significant upregulation of gene expression of anti-inflammatory cytokine IL-10 in LPS-induced WBCs compared to nontreated cells. It demonstrates a much stronger inhibition potential than diclofenac in terms of inflammation inhibition. When comparing molecular docking and simulation data, current work showed that geraniol has a good affinity toward apoptosis signal-regulating kinase 1 (ASK1) and human P2Y12 receptors and could be developed as an antioxidant, anti-inflammatory, and anticoagulant medication in the future. Consequently, geraniol is recommended to have a defensive influence against oxidative stress, and hemolysis also could be developed as a promising anti-inflammatory, antioxidant, and anticoagulant medication.

Geraniol ameliorates the progression of high fat-diet/streptozotocin-induced type 2 diabetes mellitus in rats via regulation of caspase-3, Bcl-2, and Bax expression.

The study was designed to evaluate the geraniol's effect on the kidney and liver damage triggered by a high-fat diet (HFD)/streptozotocin (STZ)-induced type 2 diabetes mellitus in rats. Firstly, in vitro inhibitory geraniol's effect against α-amylase and α-glucosidase activities was confirmed by in-silico molecular docking, which revealed higher binding affinity toward α-amylase than for α-glucosidase. The protective effect of geraniol with two separate doses (100 and 200 mg/kg b.wt) against diabetes' kidney and liver dysfunctions in Wistar rats was then evaluated. Results indicate that geraniol treatment for 6 weeks instigated a remarkable retrieval of the lipid profile, liver, and kidney function. Geraniol noticeably reinforced the antioxidant enzymes, parameters of oxidative stress of the kidney and liver in this type of diabetes. Also, geraniol treatment prompted a significant reduction in the expression levels of caspase-3 (Casp3) and Bax mRNA. In conclusion, geraniol ameliorates the progress of HFD/STZ-induced type 2 diabetes mellitus in rats via dependently upregulating the expression of Bcl-2 and downregulating Casp3 and Bax expression. PRACTICAL APPLICATIONS: Geraniol is a naturally occurring substantial acyclic monoterpenoid compound that has numerous pharmacological activities. The positive effect of geraniol in inhibiting in vitro diabetic markers by a silico molecular docking study was evidenced by illustrating the binding sites of geraniol with both α-amylase and α-glucosidase. This study also focused on the therapeutic impact of geraniol against the damage caused by high fat-diet/streptozotocin-induced type 2 diabetic complications in Wistar rats. Geraniol limits the oxidative stress of liver and kidney tissue, and it might be used as an antiapoptotic agent in type 2 diabetes.