Natural Immunomodulatory Agents as a Complementary Therapy for Poxviruses.

Poxviruses target innate immunity mediators such as tumor necrosis factors, interleukins, interferons, complement, and chemokines. It also targets adaptive immunity such as CD4+ T cells, CD4+ T cells, and B cells. Emerging of the recent epidemic of monkeypox virus (MPXV), a zoonotic disease native to Central and Western Africa, besides the lack of permitted treatments for poxviruses infections, encouraged researchers to identify effective inhibitors to help in preventing and treating poxviruses infections. Natural bioactive components, particularly polyphenolics, are promising for creating powerful antioxidants, anti-inflammatory, immune-stimulating, and antiviral agents. As a result, they are potentially effective therapies for preventing and treating viral diseases, such as infections caused by poxviruses including the recent pandemic MPXV. Polyphenolics: rosmarinic acid, caffeic acid, resveratrol, quercitrin, myricitrin, gingerol, gallotannin, and propolis-benzofuran A, as well as isoquinoline alkaloids: galanthamine and thalimonine represent prospective antiviral agents against MPXV, they can inhibit MPXV and other poxviruses via targeting different viral elements including DNA Topoisomerase I (TOP1), Thymidine Kinase (TK), serine/threonine protein kinase (Ser/Thr kinase), and protein A48R. The bioactive extracts of different traditional plants including Guiera senegalensis, Larrea tridentata, Sarracenia purpurea, Kalanchoe pinnata (Lam.) Pers., Zingiber officinale Roscoe, Quercus infectoria, Rhus chinensis, Prunella vulgaris L., Salvia rosmarinus, and Origanum vulgare also can inhibit the growth of different poxviruses including MPXV, vaccinia virus (VACV), variola virus, buffalopox virus, fowlpox virus, and cowpox virus. There is an urgent need for additional molecular studies to identify and confirm the anti-poxviruses properties of various natural bioactive components, especially those that showed potent antiviral activity against other viruses.

Phoenix dactylifera L.: An Overview of Phytochemical Constituents and Impact on Women's Health.

Phoenix dactylifera L. (date palm) is the most significant member of the palm family (Arecaceae), particularly in the Middle East and Arab World. It is a valuable source of both primary and secondary metabolites including sugars, amino acids, phenolic acids, flavonoids, proanthocyanidins, carotenoids, phytosterols, terpenes and sphingolipids, besides vitamins and minerals. Besides, it possesses a wide array of pharmacologic activities viz. immunomodulatory, antioxidant, anti-inflammatory, hepatoprotective, nephroprotective, anti-mutagenic and anti-cancer activities, in addition to its positive effects on male and female fertility. Further research is still required to deeply understand its clinical implications, especially concerning women's health. Moreover, there are other Phoenix species that still need to be investigated to learn more about their undiscovered phytochemical components and biological activities.

Tannic acid coated nanosuspension for oral delivery of chrysin intended for anti-schizophrenic effect in mice.

Chrysin is a flavonoid drug with numerous therapeutic activities. It suffers from low intestinal absorption owing to its hydrophobicity. Therefore, the aim of this study is to exploit the efficient technique of nanosuspension (NSP) to formulate chrysin-NSP coated with tannic acid (TA) to improve the solubility and anti-schizophrenic activity of chrysin. A 23 full factorial design was constructed where the independent factors were type of polymer, surfactant concentration (0.5 or 1 %) and the aqueous phase volume (5 or 15 mL), while the dependent responses were the particle size (PS) of the obtained formulation as well as the % chrysin dissolved after 2 h (Q2h). The optimum formulation (NSP-4) composed of 1 % PEG 400 and 1 % Cremophor RH40 in 15 mL aqueous phase. It achieved a PS and Q2h values of 108.00 nm and 38.77 %, respectively. NSP-4 was then coated with TA (TA-coated NSP-4) for further enhancement of chrysin solubility. TA-coated NSP-4 revealed PS and zeta potential values of 150 ± 14 nm and -32.54 ± 2.45 mV, respectively. After 6 h, chrysin dissolved % were 53.97 and 80.22 for uncoated NSP-4 and TA-coated NSP-4, respectively, compared with only 9.47 for free chrysin. The developed formulations and free chrysin were assessed regarding their effect on schizophrenia induced in mice by cuprizone (CPZ). Treatment with the developed formulations and free chrysin ameliorated demyelination and behavioral deficit induced by CPZ via elevating MBP and PI3K/PKC activities as well as reducing GFAP expression levels. The developed formulations and free chrysin inhibited Galactin-3 and TGF-ß expressions and stimulated GST antioxidant enzyme. Furthermore, they maintained the balances in glutamatergic and dopaminergic neurotransmission via modulation on neuregulin-1 and alleviated nuclear pyknosis and degeneration in the neurons. The order of activity was: TA-coated NSP-4 > NSP-4 > free chrysin.

Molecular networking-guided investigation of the secondary metabolome of four Morus species and their in vivo neuroprotective potential for the mitigation of Alzheimer's disease.

Alzheimer's Disease (AD) is a fatal age-related neurodegenerative condition with a multifactorial etiology contributing to 70% of dementia globally. The search for a multi-target agent to hit different targets involved in the pathogenesis of AD is crucial. In the present study, the neuroprotective effects of four Morus extracts were assessed in LPS-induced AD in mice. Among the studied species, M. macroura exhibited a profound effect on alleviating the loss of cognitive function, improved the learning ability, restored the acetylcholine esterase (AChE) levels to normal, and significantly reduced the tumor necrosis factor alpha (TNF-α) brain content in LPS-treated mice. To investigate the secondary metabolome of the studied Morus species, ultra-performance liquid chromatography coupled to tandem mass spectrometry (UPLC-HRMS/MS), aided with feature-based molecular networking, was employed. Among the annotated features, aryl benzofurans and prenylated flavonoids were suggested as being responsible for the observed neuroprotective effect. Furthermore, some of the detected metabolites were proposed as new natural products such as moranoline di-O-hexoside (1), isomers of trimethoxy-dihydrochalcone-O-dihexoside (59 & 76), (hydroxy-dimethoxyphenyl)butenone-O-hexoside (82), and O-methylpreglabridin-O-sulphate (105). In conclusion, our findings advocate the potential usage of M. macroura leaves for the management of AD, yet after considering further clinical trials.

Phytochemical Elucidation and Effect of Maesa indica (Roxb.) Sweet on Alleviation of Potassium Dichromate-Induced Pulmonary Damage in Rats.

Maesa indica (Roxb.) Sweet is one of the well-known traditionally-used Indian plants. This plant is rich in secondary metabolites like phenolic acids, flavonoids, alkaloids, glycosides, saponins, and carbohydrates. It contains numerous therapeutically active compounds like palmitic acid, chrysophanol, glyceryl palmitate, stigmasterol, ß-sitosterol, dodecane, maesaquinone, quercetin 3-rhaminoside, rutin, chlorogenic acid, catechin, quercetin, nitrendipine, 2,3-dihydroxypropyl octadeca-9,12-dienoate, kiritiquinon, and ß-thujone. The Maesa indica plant has been reported to have many biological properties including antidiabetic, anticancer, anti-angiogenic, anti-leishmanial, antioxidant, radical scavenging, antibacterial, antiviral, and anti-coronavirus effects. One purpose of the current study was to investigate the leaves' metabolome via Triple-Time-of-Flight-Liquid-Chromatography-Mass Spectrometry (T-TOF LC/MS/MS) to identify the chemical constituents of the Maesa indica ethanolic extract (ME). Another purpose of this study was to explore the protective effect of ME against potassium dichromate (PD)-induced pulmonary damage in rats. Rats were assigned randomly into four experimental groups. Two different doses of the plant extract, (25 and 50 mg/kg), were administered orally for seven consecutive days before PD instillation injection. Results of our study revealed that ME enhanced cellular redox status as it decreased lipid peroxidation marker, MDA and elevated reduced glutathione (GSH). In addition, ME upregulated the cytoprotective signaling pathway PI3K/AKT. Moreover, ME administration ameliorated histopathological anomalies induced by PD. Several identified metabolites, such as chlorogenic acid, quercetin, apigenin, kaempferol, luteolin, and rutin, had previously indicated lung-protective effects, possibly through an antioxidant effect and inhibition of oxidative stress and inflammatory mediators. In conclusion, our results indicated that ME possesses lung-protective effects, which may be the result of its antioxidant and anti-inflammatory properties.

Metabolomic study of the estrogenic and anti-osteoporotic potential of Erythrina bidwillii leaf.

Erythrina bidwillii Lindl., Leguminosae, constitutes a valuable crop for horticulture and medicine; however, it is rarely investigated. Menopause is a crucial transitional period in women's health. Women worldwide consider the use of phytoestrogens as a safe hormone replacement therapy to alleviate detrimental menopausal symptoms. Thus, the discovery of novel phytoestrogens is highly demanded. The present study aimed to investigate, for the first time, the metabolomic profile and the estrogenic potential of E. bidwillii Lindl. leaf. Ultra-performance liquid chromatography-electrospray ionization-tandem mass spectrometry and gas chromatography-mass spectrometry metabolite profiling revealed the prevalence of alkaloids, flavonoids, isoflavonoids and fatty acids. Additionally, five erythrinan alkaloids, cristanine A (1), 8-oxoerythraline (2), (+)-erythrinine (3), (+)-erythraline (4) and 8-oxoerythrinine (5), along with the isoflavonoid genistin (6), were isolated. Erythrina bidwillii leaf extract exhibited significant in vivo estrogenic, anti-osteoporotic, anti-hyperlipidemic, hepatoprotective, and nephroprotective activities, utilizing ovariectomized rat model. Moreover, ethyl acetate and hexane fractions possessed significant in vitro estrogeic potential on MCF-7 cell lines. An in silico study of the isolated metabolites revealed that (+)-erythrinine (3) and 8-oxoerythrinine (5) exhibited the highest affinity for ERα and ERß, respectively, modeling them as potential estrogenic lead metabolites. Therefore, E. bidwillii leaf could be employed as promising hormone replacement therapy for postmenopausal women after thorough clinical trials.

Magnetic targeting of lornoxicam/SPION bilosomes loaded in a thermosensitive in situ hydrogel system for the management of osteoarthritis: Optimization, in vitro, ex vivo, and in vivo studies in rat model via modulation of RANKL/OPG.

Osteoarthritis is a bone and joint condition characterized pathologically by articular cartilage degenerative damage and can develop into a devastating and permanently disabling disorder. This investigation aimed to formulate the anti-inflammatory drug lornoxicam (LOR) into bile salt-enriched vesicles loaded in an in situ forming hydrogel as a potential local treatment of osteoarthritis. This was achieved by formulating LOR-loaded bilosomes that are also loaded with superparamagnetic iron oxide nanoparticles (SPIONs) for intra-muscular (IM) administration to improve joint targeting and localization by applying an external magnet to the joint. A 31.22 full factorial design was employed to develop the bilosomal dispersions and the optimized formula including SPION (LSB) was loaded into a thermosensitive hydrogel. Moreover, in vivo evaluation revealed that the IM administration of LSB combined with the application of an external magnet to the joint reversed carrageen-induced suppression in motor activity and osteoprotegerin by significantly reducing the elevations in mitogen-activated protein kinases, extracellular signal-regulated kinase, and receptor activator of nuclear factor kappa beta/osteoprotegerin expressions. In addition, the histopathological evaluation of knee joint tissues showed a remarkable improvement in the injured joint tissues. The results proved that the developed LSB could be a promising IM drug delivery system for osteoarthritis management.

Immunoregulatory role of hesperidin against ovalbumin (OVA)-induced bronchial asthma and depression in rats.

Links between bronchial asthma and depression have recently become a great subject of interest. The present study was carried out to assess the protective role of hesperidin against ovalbumin (OVA)-induced bronchial asthma that is associated with depression in rats, for this purpose, four groups. Rats were sensitized with intraperitoneal administration of 200 µg OVA/10 mg aluminum hydroxide (Al (OH) 3 for 3 consecutive days then at day 11 followed by intranasal challenge with OVA (1.5 mg/kg) at days 19, 20, and 21. Rats were pretreated with hesperidin (100 & 200 mg/kg) 1h before OVA challenge. At the end of the study, behavioral tests, biochemical indices, and histopathological architectures of lung and brain tissues were evaluated. Our findings showed that hesperidin significantly ameliorated the reduction in motor activity, motor coordination, forced swimming, CD4, CD25 and foxp3, interleukin-10 (IL-10), dopamine, serotonin, and neurotrophin-3 (NT3) as well as alleviated the elevation in transforming growth factor-beta (TGF-ß), tumor necrosis factor-alpha (TNF-α), iL-5, and immunoglobulin E (IgE). In addition, hesperidin reduced cellular infiltration, alveolar sacs damage, the bronchioles wall disruption, and nuclei pyknosis in neuron cells. Finally, hesperidin may provide protection against OVA-induced asthma and depression. This impact could be mediated in part by its anti-inflammatory and immunoregulatory properties.

Utilization of response surface design for development and optimization of rosuvastatin calcium-loaded nano-squarticles for hair growth stimulating VEGF and IGF production: in-vitro and in-vivo evaluation.

INTRODUCTION: Countless individuals experience negative emotions as hair loss pattern affects their self-esteem and well-being. Rosuvastatin calcium (Ca-RUV) was reported to stimulate the growth of the hair in the applied area, hence, it was selected as a potential hair loss treatment drug. SIGNIFICANCE: This study aims to develop and optimize (Ca-RUV) loaded squarticles (SQRs) and assess their ability to deliver and release Ca-RUV in the hair follicle for the promotion of hair growth. METHODS: A response surface design was utilized to study the effect of varying Pluronic® F68 (PF68) and the percentage of liquid lipids within the core of the SQRs and the effects of particle size, entrapment efficiency, and drug released percentage after 24 h (%Q24) were assessed. The optimized formula was subjected to DSC, XRD, and in-vivo evaluation in rats. RESULTS: SQRs stabilized by 0.8% PF68 and contained 37.5% liquid lipids showed an acceptable particle size (250 nm), drug entrapment efficiency (75%), and %Q24 (100%). The in-vivo studies illustrated the ability of the formula to regrow hair in animals after 10 days due to the elevation of the vascular endothelial growth factor (VEGF) and insulin-like growth factor 1 (IGF-1) to their normal values and by 9% and 54%, respectively, relative to standard therapy minoxidil (5%). CONCLUSION: Thus, it can be concluded that the optimized formula of Ca-RUV loaded SQRs showed superior in-vivo results in the promotion of hair growth in a shorter period relative to the marketed product. Therefore, the formula can offer a viable option for the treatment of hair loss.

Explicit mechanistic insights of Prosopis juliflora extract in streptozotocin-induced diabetic rats at the molecular level.

Background: The Ancient system of medicine showed the limelight on the use of herbal remedies and was found to possess minimal side effects and acceptable therapeutic outcomes. In this context, Prosopis juliflora gained importance in managing chronic diseases such as cancer, dermatological diseases, and chronic inflammatory disorders. Hence, P. juliflora was selected for further investigation associated with diabetes and inflammation. Aim: The present study aimed to evaluate the anti-diabetic activity in chemically induced experimental rats and explore the nature of phytocomponents that may produce this activity. Methods: Experimentally, diabetes was induced by a single administration of streptozotocin at 50 mg/kg intraperitoneally in Wistar rats. The animals were treated orally with P. juliflora at low and high doses (200 and 400 mg/kg) for 10 days. Blood collected from the retro-orbital plexus was analyzed for parameters like blood glucose levels, insulin, adiponectin, Keap1 and Nrf2. PPAR-γ, AMPK and GLUT 2 levels were analyzed in the pancreatic tissue. Besides, at the end of the experiment, animals were sacrificed, and the pancreatic tissue sections were subjected for histopathological, morphometrical and immune histochemical exploration. The phytochemical composition of the plant was investigated by GC-MS. Results: The administration of P. juliflora higher dose showed a significant decrease (**p< 0.001) in blood glucose levels with a rise in adiponectin, PPARγ, Keap1, Nrf2, Glut 2, and AMPK significantly (**p< 0.001). The inflammatory cytokine TNFα was also estimated and was found to be lowered significantly (**p< 0.001) in test drug-treated animals. Furthermore, in the pancreatic tissue, the number of Islets, the area, and the number of ß-cells were improved significantly with the sub-chronic treatment of P. juliflora extract. The structure and function of ß-cells were also revamped. Conclusion: The study results demonstrated a significant effect of P. juliflora on glycemic status, inflammatory condition, and the architecture of pancreatic tissue. In the identification and isolation process by GC MS, it was noticed that P. juliflora contained few phytochemical constituents from which it might be considered a promising drug for type 2 diabetes mellitus.

Coating with tripolyphosphate-crosslinked chitosan as a novel approach for enhanced stability of emulsomes following oral administration: Rutin as a model drug with improved anti-hyperlipidemic effect in rats.

The aim of the current study is to preserve the emulsomal vesicles against the harsh condition of gastrointestinal tract (GIT), after oral administration, employing tripolyphosphate (TPP)-crosslinked chitosan as a protective coating layer. Rutin was used as a model drug with evaluation of anti-hyperlipidemic activity in rats. The rutin loaded unmodified emulsomes were prepared using tripalmitin and soybean phosphatidylcholine (SPC), by thin film method. Drug loading for the prepared formulations ranged between 6.80 and 15.50 %. The selected formulation (RT-Emuls-6) comprised tripalmitin and SPC, molar ratio 1:1, and exhibited particle size (PS) and zeta potential (ZP) of 150.40 nm and -35.35 mV, respectively. RT-Emuls-6 was then modified by coating with either solely chitosan (RT-Emuls-6-Ch) or TPP-crosslinked chitosan (RT-Emuls-6-Ch-TPP-1). The latter exhibited PS and ZP values of 269.60 nm and 37.17 mV, respectively. Transmission electron microscopy of RT-Emuls-6-Ch-TPP-1 showed a dense pale greyish layer of a coating layer of chitosan crosslinked with TPP surrounding SPC bilayers. Fourier transform infrared spectroscopy analysis along with X-ray powder diffraction confirmed cross-linking between chitosan and TPP. Stability study in the simulated GIT fluids revealed that the order of rutin retained percentage was RT-Emuls-6-Ch-TPP-1 > RT-Emuls-6-Ch > RT-Emuls-6 (80.02, 50.66 and 44.41 %, respectively for simulated gastric fluid and 63.50, 55.66 and 24.00 %, respectively for simulated intestinal fluid, after 2 h incubation). Anti-hyperlipidemic activity of rutin loaded emulsomes was evaluated, after oral administration, in a high fat diet-induced hyperlipidemia in rats. The order of activity was as follows: RT-Emuls-6-Ch-TPP-1 > RT-Emuls-6-Ch > RT-Emuls-6 > free rutin. These findings revealed the potential of TPP-crosslinked chitosan as a protective coating layer for enhancing the stability of emulsomes against the harsh condition of GIT. RT-Emuls-6-Ch-TPP-1 had a potent anti-hyperlipidemic activity via regulation of lipids, oxidative stress, irisin and uncoupling protein 1.

Cold plasma approach fortifies the topical application of thymoquinone intended for wound healing via up-regulating the levels of TGF-ß, VEGF, and α-SMA in rats.

Wound healing is a series of coordinated events that involve tissue repair and regeneration. Cold atmospheric plasma approach sheds the light on the mechanism that initiates the inflammatory responses throughout the healing cascade. The present study was planned to assess the effect of thymoquinone treated with cold plasma (TQcp) on the rat wound model compared to thymoquinone (TQ). To assess the wound healing potential of TQcp, a full-thickness wound model was used. The induced wound was smeared, starting just after excision, twice daily with TQcp and TQ for 7 days. Our findings revealed that TQcp improved the skin healing potential by augmenting the skin regeneration indices as evidenced by enhancing the new production of hyaluronic acid and collagen type I. TQcp significantly reduced the skin content of tumor necrosis factor- α and inhibited the hypertrophic scarring by up-regulating the skin content of transforming growth factor-beta. Furthermore, TQcp enhanced the levels of interleukin-10, alpha smooth muscle actin and vascular endothelial growth factor, demonstrating a great potential for wound healing that also reflected in the histopathological and ultra-structural picture of the skin. Finally, our results demonstrated that TQcp revealed a significant potential for wound healing than TQ alone.

Reliability of assessing morphologic features with prognostic significance in cytology specimens of epithelioid diffuse pleural mesothelioma and implications for cytopathology reporting.

BACKGROUND: The World Health Organization incorporates morphologic features with prognostic significance in the 2021 classification of epithelioid diffuse pleural mesothelioma (E-DPM). Although cytology specimens are often the first and occasionally the only specimen available for patients with DPM, these features have not yet been investigated in cytology. METHODS: Nuclear atypia, pleomorphic features, necrosis, and architectural patterns were retrospectively assessed in 35 paired cytology and concurrent/consecutive surgical pathology specimens of E-DPM. Agreement between pairs was determined via unweighted κ scores. Discordant cases were re-reviewed to determine the reasons for disagreement. RESULTS: Interpretation of nuclear atypia in cytology was concordant with histology in all cases (κ = 1.000; p < .001). The presence of pleomorphic features and necrosis was concordant in 97.1% (κ = 0.842; p < .001) and 85.7% (κ = 0.481; p = .001) of paired cases, respectively. Assessment of architectural patterns in cytology showed only slight agreement with histology (κ = 0.127; p = .037). In cytology cases (n = 23) with cell block material available, assessment of nuclear atypia and the presence of pleomorphic features showed perfect agreement (κ = 1.000; p < .001, each), the presence of necrosis showed moderate agreement (κ = 0.465; p = .008), and assessment of architectural patterns showed slight agreement (κ = 0.162; p = .15) in paired specimens. Most disagreements were due to sampling differences between cytology and histology specimens. CONCLUSIONS: Although complete nuclear grading of E-DPM is not possible given the unreliability of mitotic counts in cytology, assessment of nuclear atypia in cytology specimens is shown to be reliable. Identification of pleomorphic features and necrosis is also reliable despite occasional sampling issues. Assessment of architectural patterns is more limited in cytology.

Influence of chrysin on D-galactose induced-aging in mice: Up regulation of AMP kinase/liver kinase B1/peroxisome proliferator-activated receptor-γ coactivator 1-α signaling pathway.

Adenosine monophosphate kinase/liver kinase B1/peroxisome proliferator-activated receptor-γ coactivator 1-α (AMPK/LKB1/PGC1α) pathway has a vital role in regulating age-related diseases. It controls neurogenesis, cell proliferation, axon outgrowth, and cellular energy homeostasis. AMPK pathway also regulates mitochondrial synthesis. The current study evaluated the effect of chrysin on D-galactose (D-gal) induced-aging, neuron degeneration, mitochondrial dysfunction, oxidative stress, and neuroinflammation in mice. The mice were allocated randomly into four groups (10 each group): Group 1: normal control group, Group 2: D-gal group, Groups 3 and 4: chrysin (125 and 250 mg/kg, respectively). Groups 2-4 were injected with D-gal (200 mg/kg/day; s.c) for 8 weeks to induce aging. Groups 3 and 4 were orally gavaged every day concurrent with D-gal. At the end of experiment, behavioral, brain biochemical and histopathological changes were monitored. Chrysin administration elevated discrimination ratio in object recognition, Y Maze percentage alternation, locomotor activity and brain contents of AMPK, LKB1, PGC1α, NAD (P)H quinone oxidoreductase 1 (NQO1), heme oxygenase 1 (HO-1), nerve growth factor (NGF) (neurotrophin-3; NT-3), and seretonin as well as reduced brain contents of tumor necrosis factor-alpha (TNF-α), nuclear factor kappa B (NF-κB), advanced glycation end products (AGEs) and glial fibrillary acidic protein (GFAP) compared to D-gal-treated mice. Chrysin also alleviated cerebral cortex and white matter neurons degeneration. Chrysin protects against neurodegeneration, improves mitochondrial autophagy and biogenesis as well as activates antioxidant genes expression. In addition, chrysin ameliorates neuroinflammation and stimulates the release of NGF and serotonin neurotransmitter. So, chrysin has a neuroprotective effect in D-gal induced-aging in mice.

Study of exopolysaccharide produced by Streptomyces rochie strain OF1 and its effect as ameliorative on osteoarthritis in rats via inhibiting TNF-α/COX2 pathway.

BACKGROUND: Carbohydrates are known as the main natural products of life activities. RESULTS: Streptomyces rochie strain OF1 isolated from a mangrove tree produced exopolysaccharide S5 (EPSS5) (14.2 gl-1) containing uronic acid 21.98% sulfate content of 11.65 mg/ml, and a viscosity of 1.35 mm2/s. while total hexose amine content was 24.72%. The high performance liquid chromatography (HPLC) analysis of mono sugars revealed that EPS was composed of manouronic acid, glucuronic acid, xylose, and fructose at a molar ratio of 1.0:0.5:1.0:2.0, respectively. It showed that the whole antioxidant activity was 92.06%. It showed antibacterial activity against Staphylococcus aureus, and E. coli, MRSA and Klebsiella pneumoniae. But, EPSS5 displayed low antifungal activity against Candida albicans. While no antifungal activity has been detected against Aspergillus niger. EPSS5 has antibiofilm action that is noticeable toward S. aureus with an inhibition ratio of biofilm up to 50%. Effect of EPS on serum levels of TNF-α and COX2 by 2 fold and 1.9 fold of EPS reduced serum levels of Tumor necrosis factor-α (TNF-α) by 38%, 12%, 49%, and Cyclooxygenase-2 (COX2) by 61%, 34%, and 62%, respectively. By affected of EPSS5 on arthritis in rats stimulated by carrageenan. CONCLUSIONS: Administration of EPS ameliorated carrageen-induced elevation in inflammatory mediators; TNF-α/COX and suppressed the expressions of metalloproteinase 9 (MMP9) by 68%, 86%, and 75% correspondingly in comparison to the group of carrageenans. Then again, therapy involving a high dose only reduced MMP9 level by 57%, compared to free drug suggesting that EPSS5 is a good inhibitor of the MMP9, as it brought MMP9 back to normal levels via the signaling pathway.

Naringin protects mice from D-galactose-induced lung aging and mitochondrial dysfunction: Implication of SIRT1 pathways.

AIM: Aging is the leading risk factor for diminishing lung function, as well as injury and lung disorder. The target of our research was to examine the potential protective effect of naringin and the possible role of SIRT1 in mice with D-galactose-induced lung aging, by evaluating its effects on antioxidant systems, mitochondrial biogenesis, autophagy, and apoptosis, by referring to the potential involvement of Nrf2/NQO1, LKB1/AMPK/PGC-1α, FOXO1, and P53/caspase-3 signaling. MATERIAL AND METHODS: The mice were randomly sorted into 5 groups (10 each): 1st: normal group received subcutaneous normal saline and intragastric distilled water, 2nd: naringin 300 mg/kg orally, 3rd: D-galactose (200 mg/kg/day) was administered subcutaneously into mice for eight weeks, to accelerate aging, 4th & 5th: oral naringin (150, 300 mg/kg) was given daily concurrently with D-galactose injection for 8 weeks. KEY FINDING: In silico investigation revealed that naringin substantially stimulates the SIRT1 and AMPK molecules. At the molecular level, our findings indicated that treatment with naringin stimulated the mitochondrial biogenesis pathway through regulation of the LKB1/AMPK/PGC-1α signals and upregulated FOXO1-mediated autophagy. Furthermore, naringin exhibited antioxidant properties by activating the Nrf2/NQO1 pathway and inhibiting MDA and AGEs levels. In addition, Naringin ameliorated alveolar spaces destruction and bronchial wall thickening, as well as alleviated P53/caspase-3 apoptosis signaling. SIGNIFICANCE: Naringin exerts protective effects against D-galactose-induced lung aging and enhances longevity by activating SIRT1. SIRT1 regulates various aging-related molecular pathways via restoring pro-oxidant/antioxidant homeostasis, activation of mitochondrial biogenesis, modulating of autophagy and inhibition of apoptosis.

Eplerenone modulates the inflammatory response in monosodium iodoacetate-induced knee osteoarthritis in rats: Involvement of RANKL/OPG axis.

AIMS: Osteoarthritis (OA) is a multifactorial degenerative disease marked by the progressive deterioration of articular cartilage with inflammation of the synovium. OA's main symptoms include pain and function loss. Monosodium Iodoacetate (MIA) experimental model is widely-used for OS induction since it produces symptoms comparable to those occurring in humans. MATERIALS AND METHODS: Thirty-two rats were divided into four groups (n = 8). The 1st group received saline and included the normal-control rats. Groups 2-4 received intra-articular injections of MIA (3 mg/50 µL) in the rats' knee joints to induce OA. Group 2 included the MIA-control rats. Groups 3 and 4 received intra-articular MIA followed by a 14-day oral eplerenone (50 and 100 mg/kg); respectively. KEY FINDINGS: Intra-articular injection of MIA in rats' knee joints caused significant inflammation and pain, elevation of Akt and ERK gene expression in knee joints along with significant alterations in the histological pictures of knee joints and OARSI scores. RANKL/OPG Axis was significantly disrupted. SIGNIFICANCE: Eplerenone treatment produced a significant improvement in motor coordination and spontaneous locomotor activity in rats and modulated the key inflammatory mediators in OA (TNF-α, NF-κß, and IL-6). Eplerenone also suppressed the qRT-PCR gene expression of Akt and ERK in knee joint tissues and improved the histological pictures and OARSI scores of knee joints of treated rats. Eplerenone caused a decline in RANKL concentration accompanied by a rise in OPG concentration thus modulating the RANKL/OPG Axis. Consequently, eplerenone is a candidate for OA therapy due to its potential anti-inflammatory effects.

Neuroprotective effect of secukinumab against rotenone induced Parkinson's disease in rat model: Involvement of IL-17, HMGB-1/TLR4 axis and BDNF/TrKB cascade.

Neuroinflammatory status produced via activation of toll like receptor-4 (TLR-4) and interleukin-17 receptor (IL-17R) is one of the principal mechanisms involved in dopaminergic neuronal loss in Parkinson's disease (PD). Activation of TLR-4 and IL-17R stimulates reactive oxygen species (ROS) and proinflammatory cytokines (IL-17, IL-1ß, TNFα, IL-6) production that augments neurodegeneration and reduces neuro-survival axis (TrKB/Akt/CREB/BDNF). So, reducing IL-17-driven neuroinflammation via secukinumab, monoclonal antibody against IL-17A, may be one of therapeutic approach for PD. Moreover, the aim was extended to delineate the possible neuroprotective mechanism involved against neuronal loss in rotenone induced PD in rats. Rats received 11 subcutaneous injection of rotenone (1.5 mg/kg) every other day for 21 consecutive days and treated with 2 subcutaneous injections of secukinumab (15 mg/kg) on day 9 and 15, one hour after rotenone administration. Treatment with secukinumab improved motor impairment and muscle incoordination induced by rotenone, as verified by open field and rotarod tests. Moreover, secukinumab attenuated neuronal loss and improve histopathological profile. Noteworthy, secukinumab reduces neuro-inflammatory status by hindering the interaction between IL and 17A and IL-17RA together with inhibiting the activation of TLR-4 and its downstream cascade including pS536-NFκB p65, IL-1ß and HMGB-1. Additionally, secukinumab stimulated neuro-survival signalling cascade via activation pY515-TrKB receptor and triggered upsurge in its downstream targets (pS473-Akt/pS133-CREB/BDNF). Furthermore, secukinumab increased striatal tyrosine hydroxylase immunoexpression, the rate limiting step in dopamine biosynthesis, to guard against dopaminergic neuronal loss. In conclusion, secukinumab exerts a neuroprotective effect against rotenone induced neuronal loss via inhibition IL17A/IL17RA interaction and HMGB-1/TLR-4/NF-κBp65/IL1ß signalling cascade, together with activation of TrKB/ Akt/CREB/BDNF axis.

Protective Effects of Cannabis sativa on chemotherapy-induced nausea in a rat: Involvement of CB1 receptors.

Cyclophosphamide is an anticancer and immunosuppressive agent used in the treatment of various malignancies but causing gastrointestinal distress. Cannabis sativa and its derivatives have been used for the treatment of human gastrointestinal disorders. A purpose of this study was to investigate the effect of C. sativa on nausea induced by cyclophosphamide in rats. The rats were divided into four groups (eight animals per group): Group 1: Normal control (saline i.p.). Group 2: Rats received cyclophosphamide (200 mg/kg i.p.) 3 consecutive days. Group 3 and 4: Rats received cyclophosphamide (200 mg/kg i.p.) across Days 1-7, and C. sativa (20 and 40 mg/kg s.c.) was administered on cyclophosphamide days 4-7. We examined intake of kaolin, normal food and changes in body weight, as an indicator of the emetic stimulus. Oxidative stress markers, antioxidant enzymes status, serotonin (5-HT), dopamine, noradrenaline and CB1R levels were evaluated in the intestinal homogenate. Moreover, histopathological study was performed. Results showed that C. sativa ameliorates cyclophosphamide-induced emesis by increasing in body weight and normal diet intake with a decrease in kaolin diet intake after 7 days. Moreover, C. sativa significantly decreases (serotonin) 5-HT, dopamine and noradrenaline, as well as decreasing oxidative stress and inflammation. Administration of C. sativa significantly increased the expression of CB1R in intestinal homogenate. Treatment with C. sativa also improved the histological feature of an intestinal tissue. These results suggested that C. sativa possess antiemetic, antioxidant and anti-inflammatory effects in chemotherapy-induced nausea in rats by activating CB1R.

Fisetin alleviates thioacetamide-induced hepatic fibrosis in rats by inhibiting Wnt/ß-catenin signaling pathway.

BACKGROUND: Liver fibrosis is a chronic wound-healing response to liver injury of various origins and represents a major health problem. OBJECTIVE: The current study endeavored to investigate the repressing effect of fisetin on hepatic fibrosis induced by thioacetamide (TAA) in rats. MATERIALS AND METHODS: Rats were injected with TAA (200 mg/kg) intraperitoneally twice per week for 6 weeks to induce liver fibrosis. Fisetin (50 and 100 mg/kg/day) or silymarin (50 mg/kg/day) were given orally on a daily basis along with TAA. Liver function parameters, oxidative stress, inflammatory and fibrogenic biomarkers as well as wnt3a, ß-catenin, glycogen synthase kinase 3 (GSK-3ß) and cyclin D1 were estimated. Histoapthological and immunohistochemical examinations were performed. RESULTS: Fisetin restored normal liver functions, increased reduced glutathione (GSH) level and decreased malondialdehyde (MDA), as well as inflammatory biomarkers including; tumor necrosis factor-alpha (TNF-α) and interleukin 6 (IL-6). Additionally, it lessened transforming growth factor ß1 (TGF-ß1), collagen I and tissue inhibitor of metalloproteinase-1 (TIMP-1) levels as well as elevated matrix metalloproteinase-9 (MMP-9) hepatic content. Furthermore, fisetin significantly suppressed wnt3a gene expression associated with decreased ß-catenin and increased GSK-3ß levels. Moreover, fisetin decreased the progress of histologic hepatic fibroplasia and diminished hepatic expression of α-SMA and cyclin D1. CONCLUSION: Fisetin curbed liver fibrosis and exhibited superior activity over silymarin through inhibition of hepatic stellate cells (HSCs) activation and proliferation via suppressing the Wnt/ß-catenin pathway, modulating MMP-9 and TIMP-1, and inhibiting multiple profibrogenic factors, besides its antioxidant and anti-inflammatory effects. Therefore, fisetin is a promising therapeutic candidate for hepatic fibrosis.