Amelioration of Rheumatoid Arthritis by Fragaria nubicola (Wild Strawberry) via Attenuation of Inflammatory Mediators in Sprague Dawley Rats.

Background and Objectives: Fragaria nubicola has never been evaluated scientifically for its anti-arthritic potential despite its use in folkloric systems of medicine. The research was conducted to assess the potential of F. nubicola against rheumatoid arthritis. Materials and Methods: The current study provided scientific evidence by evaluating the effects of plants using an in vivo CFA-induced model of arthritic rats and subsequent microscopic histopathological evaluation of ankle joints along with the determination of paw edema using a digital water displacement plethysmometer. The study also gave insight by determining levels of pro-inflammatory cytokines, matrix metalloproteinase enzymes (MMPs), prostaglandin E2 (PGE2), nuclear factor kappa B (NF-κB), vascular endothelial growth factor (VEGF), and biochemical and hematological parameters. GCMS analysis was also conducted for the identification of possible anti-inflammatory plant constituents. Results: The data showed that F. nubicola-treated groups attenuated the progression of arthritis and paw edema. Microscopic histopathological evaluation validated the anti-arthritic potential by showing amelioration of bone erosion, infiltration of inflammatory cells, and pannus formation. RT-PCR analysis displayed that treatment with F. nubicola down-regulated IL1ß, IL6, TNFα, NF-κB, VEGF, MMP2, MMP3, and MMP9 levels. Moreover, ELISA exhibited a reduction in levels of PGE2 levels in treatment groups. The levels of RBCs, platelets, WBCs, and Hb content were found to be nearly similar to negative control in the treated group. Statistically, a non-significant difference was found when all groups were compared for urea, creatinine, ALT, and AST analysis, indicating the safety of plant extract and fractions at test doses. GCMS analysis of extract and fractions showed the existence of many anti-inflammatory and antioxidant phytochemicals. Conclusion: In conclusion, F. nubicola possessed anti-arthritic properties that might be attributed to the amelioration of MMPs and pro-inflammatory cytokines.

Effects of Rosmarinus officinalis L. Extract on Neurobehavioral and Neurobiological Changes in Male Rats with Pentylenetetrazol-Induced Epilepsy.

This study investigated the effect of Rosmarinus officinalis L. (RO) extract on neurobehavioral and neurobiological changes in male rats with pentylenetetrazol (PTZ)-induced epilepsy. Rats were assigned into five groups: (1) control rats, (2) RO-treated rats, (3) PTZ-treated rats, (4) PTZ + RO-treated rats, and (5) PTZ + valproic acid (VA)-treated rats. The PTZ-treated rats required a significantly longer time and distance to find the platform in the Morris water maze test than the control and RO-treated rats. Additionally, PTZ-treated rats showed a decrease in tendency to cross over the platform compared to PTZ group. PTZ + RO-treated rats showed decreased swimming time and distance to find the platform compared to PTZ group. PTZ + RO-treated rats showed a significant decrease in seizure score, a reduced number of myoclonic jerks, and an increased onset of the first myoclonic jerk compared to PTZ group. PTZ reduced the time required to enter the dark room in the passive avoidance learning test, which was reversed by RO treatment. Biochemical results revealed that PTZ-treated rats had higher levels of oxidative stress markers. RO significantly increased the antioxidant markers levels and maintained normal rat brain histology. This study revealed that RO can shield the brain and neural tissues from PTZ.

Diosgenin and Monohydroxy Spirostanol from Prunus amygdalus var amara Seeds as Potential Suppressors of EGFR and HER2 Tyrosine Kinases: A Computational Approach.

Cancer continues to be leading cause of death globally, with nearly 7 million deaths per year. Despite significant progress in cancer research and treatment, there remain several challenges to overcome, including drug resistance, the presence of cancer stem cells, and high interstitial fluid pressure in tumors. To tackle these challenges, targeted therapy, specifically targeting HER2 (Human Epidermal Growth Factor Receptor 2) as well as EGFR (Epidermal Growth Factor Receptor), is considered a promising approach in cancer treatment. In recent years, phytocompounds have gained recognition as a potential source of chemopreventive and chemotherapeutic agents in tumor cancer treatment. Phytocompounds are compounds derived from medicinal plants that have the potential to treat and prevent cancer. This study aimed to investigate phytocompounds from Prunus amygdalus var amara seeds as inhibitors against EGFR and HER2 enzymes using in silico methods. In this study, fourteen phytocompounds were isolated from Prunus amygdalus var amara seeds and subjected to molecular docking studies to determine their ability to bind to EGFR and HER2 enzymes. The results showed that diosgenin and monohydroxy spirostanol exhibited binding energies comparable to those of the reference drugs, tak-285, and lapatinib. Furthermore, the drug-likeness and ADMET predictions, performed using the admetSAR 2.0 web-server tool, suggested that diosgenin and monohydroxy spirostanol have similar safety and ADMET properties as the reference drugs. To get deeper insight into the structural steadiness and flexibility of the complexes formed between these compounds and theEGFR and HER2 proteins, molecular dynamics simulations were performed for 100 ns. The results showed that the hit phytocompounds did not significantly affect the stability of the EGFR and HER2 proteins and were able to form stable interactions with the catalytic binding sites of the proteins. Additionally, the MM-PBSA analysis revealed that the binding free energy estimates for diosgenin and monohydroxy spirostanol is comparable to the reference drug, lapatinib. This study provides evidence that diosgenin and monohydroxy spirostanol may have the potential to act as dual suppressors of EGFR and HER2. Additional in vivo and in vitro research are needed to certify these results and assess their efficacy and safety as cancer therapy agents. The experimental data reported and these results are in agreement.

Nanomedicine-driven therapeutic interventions of autophagy and stem cells in the management of Alzheimer's disease.

Drug-loaded, brain-targeted nanocarriers could be a promising tool in overcoming the challenges associated with Alzheimer's disease therapy. These nanocargoes are enormously flexible to functionalize and facilitate the delivery of drugs to brain cells by bridging the blood-brain barrier and into brain cells. To date, modifications have included nanoparticles (NPs) coating with tunable surfactants/phospholipids, covalently attaching polyethylene glycol chains (PEGylation), and tethering different targeting ligands to cell-penetrating peptides in a manner that facilitates their entry across the BBB and downregulates various pathological hallmarks as well as intra- and extracellular signaling pathways. This review provides a brief update on drug-loaded, multifunctional nanocarriers and the therapeutic intervention of autophagy and stem cells in the management of Alzheimer's disease.

Cardioprotective Effect of Taxifolin against Isoproterenol-Induced Cardiac Injury through Decreasing Oxidative Stress, Inflammation, and Cell Death, and Activating Nrf2/HO-1 in Mice.

Oxidative stress and inflammation are key components in cardiovascular diseases and heart dysfunction. Herein, we evaluated the protective effects of (+)-taxifolin (TAX), a potent flavonoid with significant antioxidant and anti-inflammatory actions, on myocardial oxidative tissue injury, inflammation, and cell death, using a mouse model of isoproterenol (ISO)-induced acute myocardial injury. Mice were given TAX (25 and 50 mg/kg, orally) for 14 days before receiving two subsequent injections of ISO (100 mg/kg, s.c.) at an interval of 24 h on the 15th and 16th days. The ISO-induced cardiac tissue injury was evidenced by increased serum creatine kinase-MB (CK-MB), cardiac troponin I (cTnI), and lactate dehydrogenase (LDH), along with several histopathological changes. The ISO also induced increased malondialdehyde (MDA) with concomitant declined myocardial glutathione level and antioxidant enzymes activities. Moreover, ISO-induced heart injury was accompained with elevated cardiac NF-κB p65, TNF-α, IL-1ß, Bax, and caspase-3, as well as decreased Bcl-2, Nrf2, and HO-1. Remarkably, TAX reduced the severity of cardiac injury, oxidative stress, inflammation, and cell death, while enhancing antioxidants, Bcl-2, and Nrf2/HO-1 signaling in ISO-injected mice. In conclusion, TAX protects against ISO-induced acute myocardial injury via activating the Nrf2/HO-1 signaling pathway and attenuating the oxidative tissue injury and key regulators of inflammatory response and apoptosis. Thus, our findings imply that TAX may constitute a new cardioprotective therapy against acute MI, which undoubtedly deserves further exploration in upcoming human trials.

Taxifolin Prevents Cisplatin Nephrotoxicity by Modulating Nrf2/HO-1 Pathway and Mitigating Oxidative Stress and Inflammation in Mice.

Cisplatin (CIS) is an effective chemotherapeutic agent used in the treatment of several malignancies. The clinical use of CIS is associated with adverse effects, including acute kidney injury (AKI). Oxidative stress and inflammation are key events in the development of CIS-induced AKI. This study investigated the protective effect of taxifolin (TAX), a bioactive flavonoid with promising health-promoting properties, on CIS-induced nephrotoxicity in mice. TAX was orally given to mice for 10 days and a single dose of CIS was injected at day 7. Serum blood urea nitrogen (BUN) and creatinine were elevated, and multiple histopathological alterations were observed in the kidney of CIS-administered mice. CIS increased renal malondialdehyde (MDA), nitric oxide (NO), nuclear factor-kappaB (NF-κB) p65, tumor necrosis factor (TNF)-α, and interleukin (IL)-1ß, and decreased cellular antioxidants in mice. TAX remarkably prevented kidney injury, ameliorated serum BUN and creatinine, and renal MDA, NO, NF-κB p65, and pro-inflammatory cytokines, and boosted antioxidant defenses in CIS-administered mice. TAX downregulated Bax and caspase-3, and upregulated Bcl-2. These effects were associated with upregulation of nuclear factor erythroid 2-related factor 2 (Nrf2) expression and heme oxygenase (HO)-1 activity in CIS-administered mice. In conclusion, TAX prevented CIS-induced AKI by mitigating tissue injury, oxidative stress, inflammation, and cell death. The protective efficacy of TAX was associated with the upregulation of Nrf2/HO-1 signaling.

Moringa oleifera leaf extract induces osteogenic-like differentiation of human osteosarcoma SaOS2 cells.

Introduction: Moringa oleifera is known as a 'natural nutrition of the tropics' because it provides vital nutritional supplements and a variety of pharmacological benefits. The focus of this study was to elucidate the dose dependent effects of Moringa oleifera leaf (MOL) extract on the growth of the human osteoblast-like osteosarcoma SaOS-2 cell line and primary osteoblast cells. Methods: Trypan blue & tetrazolium assay, intracellular ROS generation, chromatin condensation, cell cycle analysis, alkaline phosphatase (ALP), mineralization, and osteogenic gene expression were tested on both treated and untreated osteosarcoma SaOS-2 cells. Results: As revealed by cell viability assay, growth activity was observed at concentrations 25 and 50 µg/mL of MOL extract, whereas 100 and 200 µg/mL doses decreased the proliferation activity, resulting in ROS production and chromatin condensation. Cell cycle study revealed that MOL extract at 50 and 100 µg/mL concentrations arrested the cells in the G2/M phase. Low doses increased the ALP levels, mineralization, and expression of the bone morphogenetic protein 2 (BMP2) and runt-related transcription factor 2 (Runx2) genes in osteoblast-like SaOS-2 cells, however, high doses inhibited the proliferation properties of MOL extract. Through AutoDock Vina and iGEMDOCK 2.1, the interaction of active components of MOL, such as ß-sitosterol, quercetin and kaempferol, with BMP2 and Runx2 proteins revealed a reasonable binding affinity. Moreover, these components did not show any Lipinski's rule of five violation and showed predictable pharmacokinetic properties. Conclusion: The results of the biphasic dose-response of MOL extract on the growth activity of osteoblast-like SaOS-2 cells and in silico binding interface, may provide a therapeutic and/or preventive implication in prospective drug development.

Punicalagin Protects against the Development of Methotrexate-Induced Hepatotoxicity in Mice via Activating Nrf2 Signaling and Decreasing Oxidative Stress, Inflammation, and Cell Death.

Despite its effectiveness in treating inflammatory diseases and various malignancies, methotrexate (MTX) is well known to cause hepatotoxicity, which involves increased oxidative stress and inflammation, limiting its clinical use. Herein, we looked into the effect of punicalagin (PU), a polyphenolic molecule having a variety of health-promoting attributes, on MTX-induced hepatotoxicity in mice. PU (25 and 50 mg/kg/day) was given orally to the mice for 10 days, while a single dose of MTX (20 mg/kg) was injected intraperitoneally (i.p.) at day 7. The MTX-induced liver damage was demonstrated by remarkably higher transaminases (ALT and AST), ALP, and LDH, as well as significant histological alterations in hepatic tissues. MTX-injected mice also demonstrated increases in hepatic oxidative stress markers, including malondialdehyde (MDA) and nitric oxide (NO), with a concordant drop in glutathione (GSH) content and superoxide dismutase (SOD) and catalase (CAT) activities. PU significantly attenuated the MTX-induced serum transaminases, ALP and LDH elevations, and hepatic oxidative stress measures and boosted antioxidant defenses in the liver. Moreover, the liver of MTX-treated mice showed increases in NF-κB p65 expression, pro-inflammatory cytokine (IL-6 and TNF-α) levels, and pro-apoptotic protein (caspase-3 and Bax) expression, whereas Bcl-2 and Nrf2 expressions were reduced, which were all attenuated by PU treatment. Collectively, PU inhibits oxidative damage, inflammation, and apoptosis and upregulates Nrf2 in the liver of MTX-induced mice. Thus, these findings suggest that PU may have great therapeutic potential for the prevention of MTX-induced hepatotoxicity, pending further exploration in upcoming studies.

Assessment of antioxidant, antimicrobial, and anticancer activities of Sisymbrium officinale plant extract.

The most efficient and safe source of medications is the natural and traditional medications which are produced from plants and herbs. In this study, Sisymbrium officinale (S. officinale) was tested to explore its total phenolic and flavonoids contents. Antioxidant, antimicrobial, and anticancer activities were assessed as well. S. officinale was bought from a local Palestinian market, air-dried, and extracted with 99% ethanol with the aid of ultrasonication. The extract was tested on three types of bacteria using well diffusion method. The anti-microbial testing included three different types of bacteria, two gram-positive bacteria, Streptococcus and Staphylococcus and E. coli as a gram-negative bacterium. Antioxidant activity of the plant extract was conducted using DPPH method, while total phenolic and flavonoids contents were performed using a well-known assay chemical method. Anticancer activity of the extract was conducted against two cancer cell lines (breast (MCF7) and colon (HCT116) cancer cell lines). Results showed that the extract is rich polyphenolic and flavonoids and has strong antioxidant activity reflected by inhibition of free radicals (DPPH) (193.7 ± 3.4). The plant extract showed also strong antimicrobial activity against both E. coli and Streptococcus bacteria with of inhibition of 10 and 14 mm respectively. The extract of this plant also showed anticancer activity (about 6%) against MCF7 (breast cancer cell line).

Upregulation of Nrf2/HO-1 Signaling and Attenuation of Oxidative Stress, Inflammation, and Cell Death Mediate the Protective Effect of Apigenin against Cyclophosphamide Hepatotoxicity.

Liver injury is among the adverse effects of the chemotherapeutic agent cyclophosphamide (CP). This study investigated the protective role of the flavone apigenin (API) against CP-induced liver damage, pointing to the involvement of Nrf2/HO-1 signaling. Rats were treated with API (20 and 40 mg/kg) for 15 days and received CP (150 mg/kg) on day 16. CP caused liver damage manifested by an elevation of transaminases, alkaline phosphatase (ALP), and lactate dehydrogenase (LDH), and histological alterations, including granular vacuolation, mononuclear cell infiltration, and hydropic changes. Hepatic reactive oxygen species (ROS), malondialdehyde (MDA), and nitric oxide (NO) were increased and glutathione (GSH) and antioxidant enzymes were decreased in CP-administered rats. CP upregulated the inflammatory markers NF-κB p65, TNF-α, IL-6, and iNOS, along with the pro-apoptotic Bax and caspase-3. Pre-treatment with API ameliorated circulating transaminases, ALP, and LDH, and prevented histopathological changes in CP-intoxicated rats. API suppressed ROS, MDA, NO, NF-κB p65, iNOS, inflammatory cytokines, oxidative DNA damage, Bax, and caspase-3 in CP-intoxicated rats. In addition, API enhanced hepatic antioxidants and Bcl-2 and boosted the Nrf2 and HO-1 mRNA abundance and protein. In conclusion, API is effective in preventing CP hepatotoxicity by attenuating oxidative stress, the inflammatory response, and apoptosis. The hepatoprotective efficacy of API was associated with the upregulation of Nrf2/HO-1 signaling.

Chitosan-modified nanocarriers as carriers for anticancer drug delivery: Promises and hurdles.

With the advent of drug delivery, various polymeric materials are being explored to fabricate numerous nanocarriers. Each polymer is associated with a few characteristics attributes which further facilitate its usage in drug delivery. One such polymer is chitosan (CS), which is extensively employed to deliver a variety of drugs to various targets, especially to cancer cells. The desired properties like biological origin, bio-adhesive, biocompatibility, the scope of chemical modification, biodegradability and controlled drug release make it a highly rough after polymer in pharmaceutical nanotechnology. The present review attempts to compile various chemical modifications on CS and showcase the outcomes of the derived nanocarriers, especially in cancer chemotherapy and drug delivery.

Development and Application of a Modified Method to Determine the Encapsulation Efficiency of Proteins in Polymer Matrices.

A modified method to determine protein encapsulation efficiency in polymer matrices has been developed and applied to two proteins and two polymers to demonstrate its wide range of applicability. This study was pursued due to the wide variation in reported protein encapsulation efficiency of polymer-based microcapsules, even when the protein, the polymer, and the microcapsule manufacturing method were consistent. Hemoglobin (Hb) and bovine serum albumin (BSA) were chosen as model proteins and ethylcellulose and poly(lactic-co-glycolic acid) (PLGA) as model polymers. The polymer of the microcapsule was dissolved in dichloromethane/ethanol or dichloromethane/ethyl acetate for ethylcellulose or PLGA microcapsules, respectively. Liberated proteins were simultaneously precipitated, pelleted by centrifugation, isolated by decanting the polymer solution, redissolved in 10% w/v sodium dodecyl sulfate in 0.8 N sodium hydroxide, and quantified using a modified Lowry assay. Blank microcapsules and exogenously added proteins demonstrated ≥ 93.8% recovery of proteins. The mean encapsulation efficiency of ethylcellulose or PLGA microcapsules was 52.4 or 76.9% for Hb and 86.4 or 74.7% for BSA, respectively. This demonstrates the effective use of centrifugation and the importance of an appropriate cosolvent system in the measure of encapsulation efficiency where one solvent dissolves the polymer while the other solvent quantitatively precipitates the liberated protein. It is evident that an alkaline solution of sodium dodecyl sulfate is efficient at quantitatively dissolving precipitated proteins. Remediation of problems observed with current methods and high reproducibility suggest that this modified method is generally applicable to the measure of protein encapsulation efficiency of polymer microcapsules.