Unlocking the potential of edible Ulva sp. seaweeds: Metabolomic profiling, neuroprotective mechanisms, and implications for Parkinson's disease management.

Green seaweed (Ulva sp.) is frequently used as a food component and nutraceutical agent because of its high polysaccharide and natural fiber content in Asian countries. This study investigates both metabolomic profiling of Ulva sp. and the neuroprotective efficacy of its ethanol extract and its underlying mechanisms in a rotenone-induced rat model of neurodegeneration, mimicking Parkinson's disease (PD) in humans. Metabolomic profiling of Ulva sp. extract was done using liquid chromatography high resolution electrospray ionization mass spectrometry and led to the identification of 22 compounds belonging to different chemical classes.Catenin Beta Additionally, this study demonstrated the neuroprotective properties against rotenone-induced PD, which was achieved through the suppression of elevated levels of tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), and IL-6 together with the inhibition of reactive oxygen species (ROS) generation, apoptosis, inflammatory mediators, and the phosphoinositide 3-kinases/serine/threonine protein kinase (PI3K/AKT) pathway. Using a protein-protein interaction network, AKT1, GAPDH, TNF-α, IL-6, caspase 3, signal transducer and activator of transcription 3, Catenin Beta 1, epidermal growth factor receptor, B-cell lymphoma -2, and HSP90AA1 were identified as the top 10 most significant genes. Finally, molecular docking results showed that compounds 1, 3, and 7 might possess a promising anti-parkinsonism effect by binding to active sites of selected hub genes. Therefore, it is hypothesized that the Ulva sp. extract has the potential to be further developed as a potential therapeutic agent for the treatment of PD.

Wound Restorative Power of Halimeda macroloba/ Mesenchymal Stem Cells in Immunocompromised Rats via Downregulating Inflammatory/Immune Cross Talk.

Impaired skin wound healing is still a major challenge, especially with immunocompromised patients who express delayed healing and are susceptible to infections. Injection of rat-derived bone marrow mesenchymal stem cells (BMMSCs) via the tail vein accelerates cutaneous wound healing via their paracrine activity. The present work aimed to investigate the combined wound-healing potential of BMMSCs and Halimeda macroloba algae extract in immunocompromised rats. High-resolution liquid chromatography-mass spectrometry (HR-LC-MS) investigation of the extract revealed the presence of variant phytochemicals, mostly phenolics, and terpenoids, known for their angiogenic, collagen-stimulating, anti-inflammatory, and antioxidant properties. The BMMSCs were isolated and characterized for CD markers, where they showed a positive expression of CD90 by 98.21% and CD105 by 97.1%. Twelve days after inducing immunocompromise (40 mg/kg hydrocortisone daily), a circular excision was created in the dorsal skin of rats and the treatments were continued for 16 days. The studied groups were sampled on days 4, 8, 12, and 16 after wounding. The gross/histopathological results revealed that the wound closure (99%), thickness, density of new epidermis and dermis, and skin elasticity in the healed wounds were considerably higher in the BMMSCs/Halimeda group than the control group (p < 0.05). RT-PCR gene expression analysis revealed that the BMMSCs/Halimeda extract combination had perfectly attenuated oxidative stress, proinflammatory cytokines, and NF-KB activation at day 16 of wounding. The combination holds promise for regenerative medicine, representing a revolutionary step in the wound healing of immunocompromised patients, with still a need for safety assessments and further clinical trials.

Co-administration of Thymoquinone and Propolis in Liposomal Formulations as a Potential Approach for Treatment of Acetic Acid-Induced Ulcerative Colitis: Physiological and Histopathological Analysis.

A severe form of autoimmune-mediated inflammatory bowel disease (IBD) is termed as ulcerative colitis (UC) which ultimately results in significant mucosal damage and ulceration. Herbal remedies may be employed as an alternative for treatment of UC instead of conventional medications such as Sulfasalazine. Promising natural remedies for the treatment of IBD, including colitis, are propolis extract (PP) and thymoquinone (TQ). This study is aimed at assessing the potential of liposomal formulations of TQ and Egyptian PP in combination therapy on improving their therapeutic efficacy against ulcerative colitis in order to maximize the potential of their beneficial clinical effects. Clinical, biochemical, and histological evaluations of colonic mucosal damage and inflammation were evaluated. The results exhibited a significant increase in tissue MDA, TNFα, and nitrite levels with activation of caspase-3 in the acetic acid-induced colitis group, which is predominantly downregulated in the treatment groups. The prepared formulations of TQ and PP revealed liposomal vesicles in a nanoscale size (192 ± 20.3 and 98.2 ± 20.3 nm, respectively) and accepted stability indicated with a zeta potential of 19.3 ± 0.11 and 17.1 ± 0.25 mV, respectively. They showed an entrapment efficiency of 85.3 ± 12.6% and 69.3 ± 11.8%, respectively. At comparable doses, combination therapy with thymoquinone liposomes and propolis liposomes considerably outperformed free TQ and free PP in reducing inflammation of UC as shown in the present study by clinical, biochemical, and histological evaluations.

Follicular dendritic cells.

Follicular dendritic cells (FDCs) are unique accessory immune cells that contribute to the regulation of humoral immunity. They are multitasker cells essential for the organization and maintenance of the lymphoid architecture, induction of germinal center reaction, production of B memory cells, and protection from autoimmune disorders. They perform their activities through both antigen-driven and chemical signaling to B cells. FDCs play a crucial role in the physiological regulation of the immune response. Dis-regulation of this immune response results when FDCs retain antigens for years. This provides a constant antigenic stimulation for B cells resulting in the development of immune disorders. Antigen trapped on FDCs is resistant to therapeutic intervention causing chronicity and recurrences. Beyond their physiological immunoregulatory functions, FDCs are involved in the pathogenesis of several immune-related disorders including HIV/AIDS, prion diseases, chronic inflammatory, and autoimmune disorders. FDCs have also been recently implicated in rare neoplasms of lymphoid and hematopoietic tissues. Understanding FDC biology is essential for better control of humoral immunity and opens the gate for therapeutic management of FDC-mediated immune disorders. Thus, the biology of FDCs has become a hot research area in the last couple of decades. In this review, we aim to provide a comprehensive overview of FDCs and their role in physiological and pathological conditions.

The Potential of Corchorus olitorius Seeds Buccal Films for Treatment of Recurrent Minor Aphthous Ulcerations in Human Volunteers.

Aphthous ulcers are very common disorders among different age groups and are very noxious and painful. The incidence of aphthous ulcer recurrence is very high and it may even last for a maximum of 6 days and usually, patients cannot stand its pain. This study aims to prepare a buccoadhesive fast dissolving film containing Corchorus olitorius seed extract to treat recurrent minor aphthous ulceration (RMAU) in addition to clinical experiments on human volunteers. An excision wound model was used to assess the in vivo wound healing potential of Corchorus olitorius L. seed extract, with a focus on wound healing molecular targets such as TGF-, TNF-, and IL-1. In addition, metabolomic profiling using HR-LCMS for the crude extract of Corchorus olitorius seeds was explored. Moreover, molecular docking experiments were performed to elucidate the binding confirmation of the isolated compounds with three molecular targets (TNF-α, IL-1ß, and GSK3). Additionally, the in vitro antioxidant potential of C. olitorius seed extract using both H2O2 and superoxide radical scavenging activity was examined. Clinical experiments on human volunteers revealed the efficiency of the prepared C. olitorius seeds buccal fast dissolving film (CoBFDF) in relieving pain and wound healing of RMAU. Moreover, the wound healing results revealed that C. olitorius seed extract enhanced wound closure rates (p ≤ 0.001), elevated TGF-ß levels and significantly downregulated TNF-α and IL-1ß in comparison to the Mebo-treated group. The phenotypical results were supported by biochemical and histopathological findings, while metabolomic profiling using HR-LCMS for the crude extract of Corchorus olitorius seeds yielded a total of 21 compounds belonging to diverse chemical classes. Finally, this study highlights the potential of C. olitorius seed extract in wound repair uncovering the most probable mechanisms of action using in silico analysis.

Physiological and structural changes of the lung tissue in male albino rat exposed to immobilization stress.

In case of a life-threatening, stressful event, the body prepares for an emergency. Indeed, the lung is unique in which alveolar cells are constantly exposed to physical and chemical stresses. This study aimed to study the impact of immobilization stress on the blood-air barrier and how it initiate and maintain an inflammatory response, plus determining the resolution of lung inflammation and repair. There was a significant increase in the plasma levels of stress markers "corticosterone and catecholamines" with a decrease in surfactant protein A (a lung-injury marker). Chronic stress produced a significant increase in the pulmonary oxidative and inflammatory markers malondialdehyde, tumor necrosis factor α, and induced nitric oxide synthase when compared with that of acute stress. Both stresses provoked marked pulmonary morphological and ultrastructural changes with a significant increase in caspase-3 immunoexpression. There was increasing evidence of lung's capacity for repair. This process involved edema resolution, cell proliferation, and tissue remodeling in improving the lung-injury, oxidative, and inflammatory markers.

Possible protective effects of vanillin against stress-induced seminiferous tubule injury via modulation of Nrf2 and ZO1.

Around 20% of the human population is distressed. Previous studies have looked into the relationship between restraint immobilization stress (IS) and sexual behavior in male rats. The current study aimed to provide a brief explanation of the mechanisms that generated testicular injury with chronic IS and an attempt to evaluate the mechanisms and effects of vanillin as a novel protective agent. Forty-eight adult male albino rats were divided into six groups: control, vanillin-treated, chronic 2-h IS, 2-h stressed-vanillin-treated, chronic 6-h IS, and 6-h stressed-vanillin treated. The rats were sacrificed, and blood samples were collected for biochemical study. The testes were processed for biochemical and histological study, as well as histological Johnsen score. The results showed that prolonged IS increased both corticosterone and TNF-α levels as well as decreased testosterone, luteinizing hormone, catalase, and Nrf2 levels. This effect was more pronounced after 6 h of IS compared to 2 h. It also induced various testicular injuries with weak ZO-1 and CD34 immunoreactions. On the contrary, vanillin improved all mentioned biochemical and histological alternations induced by stress. Additionally, computational molecular docking analyses were conducted on the compound vanillin within the active site of Zona Occludens-1 (PDB ID: 2JWE). The results demonstrated remarkable docking scores and binding affinity, corroborating its potential protective efficacy. It could be concluded that vanillin is a promising treatment alternative for protecting testicular tissue from the harmful effects of IS via its antioxidant and anti-inflammatory properties.

Neuroprotective effect of quercetin nanoparticles: A possible prophylactic effect in cerebellar neurodegenerative disorders.

Memory deficit, anxiety, coordination deficit and depression are common neurological disorders attributed to aluminum (Al) buildup in the nervous system. Quercetin nanoparticles (QNPs) are a newly developed effective neuroprotectant. We aimed to investigate the potential protective and therapeutic effects of QNPs in Al induced toxicity in rat cerebellum. A rat model of Al-induced cerebellar damage was created by AlCl3 (100 mg/kg) administration orally for 42 days. QNPs (30 mg/kg) was administered for 42-days as a prophylactic (along with AlCl3 administration) or therapeutic for 42-days (following AlCl3 induced cerebellar damage). Cerebellar tissues were assessed for structural and molecular changes. The results showed that Al induced profound cerebellar structural and molecular changes, including neuronal damage, astrogliosis and tyrosine hydroxylase downregulation. Prophylactic QNPs significantly reduced Al induced cerebellar neuronal degeneration. QNPs is a promising neuroprotectant that can be used in elderly and vulnerable subjects to protect against neurological deterioration. It could be a promising new line for therapeutic intervention in neurodegenerative diseases.

Potential protective effect of 3,3'-methylenebis(1-ethyl-4-hydroxyquinolin-2(1H)-one) against bleomycin-induced lung injury in male albino rat via modulation of Nrf2 pathway: biochemical, histological, and immunohistochemical study.

Acute lung injury is a serious condition accounting for the majority of acute respiratory failure. Bleomycin (BLM) is an antibiotic that was first described as a chemotherapeutic agent. 3,3'-methylenebis(1-ethyl-4-hydroxyquinolin-2(1H)-one) was reported to have anti-inflammatory, anti-apoptotic, and anti-oxidative properties. The current work aimed to assess the possible protective effects and the mechanism of protection of 3,3'-methylenebis-(1-ethyl-4-hydroxyquinolin-2(1H)-one) on BLM-induced lung injury in addition to the effect and underlying mechanisms of nuclear factor-erythroid-related factor 2 pathway against this injury. Rats were equally divided into four groups: control group, BLM group, 1-ethyl-4-hydroxyquinolin-2(1H)-one-treated group, and BLM with 1-ethyl-4-hydroxyquinolin-2(1H)-one-treated group. At the end of the work, the blood samples were proceeded for biochemical study. Lung specimens were obtained for biochemical, histological, and immunohistochemical study. The results exhibited a significant increase in both malondialdehyde and tumor necrotic factor-α with a significant decrease in glutathione, superoxide dismutase, IL 10, surfactant protein A, and nuclear factor erythroid 2-related factor 2 in BLM group. The lung histological results showed various morphological changes in the form of disturbed architecture, inflammatory cell infiltration, and intraluminal debris. This group also displayed a significant increase in the mean surface area fraction of anti-cleaved caspase 3, while group IV exhibited amelioration in the previously mentioned parameters and histological alternations that were induced by BLM. It could be concluded that 3,3'-methylenebis(1-ethyl-4-hydroxyquinolin-2(1H)-one) has anti-oxidative, anti-inflammatory, and anti-apoptotic protective effects against BLM-induced lung injury.

Vitis vinifera leaf extract liposomal Carbopol gel preparation's potential wound healing and antibacterial benefits: in vivo, phytochemical, and computational investigation.

Vitis vinifera Egyptian edible leaf extract loaded on a soybean lecithin, cholesterol, and Carbopol gel preparation (VVL-liposomal gel) was prepared to maximize the in vivo wound healing and anti-MRSA activities for the crude extract, using an excision wound model and focusing on TLR-2, MCP-1, CXCL-1, CXCL-2, IL-6 and IL-1ß, and MRSA (wound infection model, and peritonitis infection model). VVL-liposomal gel was stable with significant drug entrapment efficiency reaching 88% ± 3, zeta potential value ranging from -50 to -63, and a size range of 50-200 µm nm in diameter. The in vivo evaluation proved the ability of VVL-liposomal gel to gradually release the drugs in a sustained manner with greater complete wound healing effect and tissue repair after 7 days of administration, with a significant decrease in bacterial count compared with the crude extract. Phytochemical investigation of the crude extract of the leaves yielded fourteen compounds: two new stilbenes (1, 2), along with twelve known ones (3-14). Furthermore, a computational study was conducted to identify the genes and possible pathways responsible for the anti-MRSA activity of the isolated compounds, and inverse docking was used to identify the most likely molecular targets that could mediate the extract's antibacterial activity. Gyr-B was discovered to be the best target for compounds 1 and 2. Hence, VVL-liposomal gel can be used as a novel anti-dermatophytic agent with potent wound healing and anti-MRSA capacity, paving the way for future clinical research.

Wound Healing and Antioxidant Capabilities of Zizyphus mauritiana Fruits: In-Vitro, In-Vivo, and Molecular Modeling Study.

LC-HRMS-assisted chemical profiling of Zizyphus mauritiana fruit extract (ZFE) led to the dereplication of 28 metabolites. Furthermore, wound healing activity of ZFE in 24 adult male New Zealand Dutch strain albino rabbits was investigated in-vivo supported by histopathological investigation. Additionally, the molecular mechanism was studied through different in-vitro investigations as well as, studying both relative gene expression and relative protein expression patterns. Moreover, the antioxidant activity of ZFE extract was examined using two in-vitro assays including hydrogen peroxide and superoxide radical scavenging activities that showed promising antioxidant potential. Topical application of the extract on excision wounds showed a significant increase in the wound healing rate (p < 0.001) in comparison to the untreated and MEBO®-treated groups, enhancing TGF-ß1, VEGF, Type I collagen expression, and suppressing inflammatory markers (TNF-α and IL-1ß). Moreover, an in silico molecular docking against TNFα, TGFBR1, and IL-1ß showed that some of the molecules identified in ZFE can bind to the three wound-healing related protein actives sites. Additionally, PASS computational calculation of antioxidant activity revealed potential activity of three phenolic compounds (Pa score > 0.5). Consequently, ZFE may be a potential alternative medication helping wound healing owing to its antioxidant and anti-inflammatory activities.

Metformin-loaded ethosomes with promoted anti-proliferative activity in melanoma cell line B16, and wound healing aptitude: Development, characterization and in vivo evaluation.

The present work deals with the development of metformin-loaded ethosomes for localized treatment of melanoma and wound healing. Different ethosomal formulations were prepared using different concentrations of ethanol adopting injection technique. The developed formulations were investigated for entrapment efficiency, ex-vivo skin permeation, vesicle size, morphology and permeation kinetics. The optimized formulation was loaded in 5 % carbomer gel that was evaluated for skin permeation, cytotoxic effect against melanoma mice B16 cell line and for wound healing action. Ethosomes having 30 % v/v ethanol displayed superior entrapment for metformin % (55.3 ± 0.07); and a highly efficient permeation via mice skin (85.8 ± 3.7). The related carbomer ethosomal gel exhibited higher skin permeation compared to the untreated metformin gel (P < 0.001). The metformin ethosomes had a substantial antiproliferative activity against melanoma B16 cells compared to corresponding metformin solution as shown by the lower IC50 values (56.45 ± 1.47 and 887.3 ± 23.2, respectively, P < 0.05) and tumour cell viability (P < 0.05). The ethosomal system had a significant wound healing action in mice (80.5 ± 1.9%) that was superior to that of the marketed product Mebo® ointment (56 ± 1 %), P < 0.05. This ethosomal system demonstrated outstanding induction of the mRNA levels of growth factors (IGF-1, FGF-1, PDGF-B and TGF-ß) that are essential in the healing process. Those findings were supported by histopathologic examination of wound sections of different treated groups. Thus, the study proved that metformin ethosomes as a promising drug delivery system and a conceivable therapeutic approach for treatment of melanoma and wound healing.

Wound Healing and Antioxidant Properties of Launaea procumbens Supported by Metabolomic Profiling and Molecular Docking.

Wounds adversely affect people's quality of life and have psychological, social, and economic impacts. Herbal remedies of Launaea procumbens (LP) are used to treat wounds. In an excision wound model, topical application of LP significantly promoted wound closure (on day 14, LP-treated animals had the highest percentages of wound closure in comparison with the other groups, as the wound was entirely closed with a closure percentage of 100%, p < 0.05). Histological analysis revealed a considerable rise in the number of fibroblasts, the amount of collagen, and its cross-linking in LP-treated wounds. Gene expression patterns showed significant elevation of TGF-ß levels (2.1-fold change after 7 days treatment and 2.7-fold change in 14 days treatment) and downregulation of the inflammatory TNF-α and IL-1ß levels in LP-treated wounds. Regarding in vitro antioxidant activity, LP extract significantly diminished the formation of H2O2 radical (IC50 = 171.6 µg/mL) and scavenged the superoxide radical (IC50 of 286.7 µg/mL), indicating antioxidant potential in a dose-dependent manner. Dereplication of the secondary metabolites using LC-HRMS resulted in the annotation of 16 metabolites. The identified compounds were docked against important wound-healing targets, including vascular endothelial growth factor (VEGF), collagen α-1, tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), and transforming growth factor-ß (TGF-ß). Among dereplicated compounds, luteolin 8-C-glucoside (orientin) demonstrated binding potential to four investigated targets (VEGF, interleukin 1ß, TNF-α, and collagen α-1). To conclude, Launaea procumbens extract could be regarded as a promising topical therapy to promote wound healing in excisional wounds, and luteolin 8-C-glucoside (orientin), one of its constituents, is a potential wound-healing drug lead.

Mechanistic Wound Healing and Antioxidant Potential of Moringa oleifera Seeds Extract Supported by Metabolic Profiling, In Silico Network Design, Molecular Docking, and In Vivo Studies.

Moringa oleifera Lam. (Moringaceae) is an adaptable plant with promising phytoconstituents, interesting medicinal uses, and nutritional importance. Chemical profiling of M. oleifera seeds assisted by LC-HRMS (HPLC system coupled to a high resolution mass detector) led to the dereplication of 19 metabolites. Additionally, the wound healing potential of M. oleifera seed extract was investigated in male New Zealand Dutch strain albino rabbits and supported by histopathological examinations. Moreover, the molecular mechanisms were investigated via different in vitro investigations and through analyzing the relative gene and protein expression patterns. When compared to the untreated and MEBO®-treated groups, topical administration of M. oleifera extract on excision wounds resulted in a substantial increase in wound healing rate (p < 0.001), elevating TGF-ß1, VEGF, Type I collagen relative expression, and reducing inflammatory markers such as IL-1ß and TNF-α. In vitro antioxidant assays showed that the extract displayed strong scavenging effects to peroxides and superoxide free radicals. In silico studies using a molecular docking approach against TNF-α, TGFBR1, and IL-1ß showed that some metabolites in M. oleifera seed extract can bind to the active sites of three wound-healing related proteins. Protein−protein interaction (PPI) and compound−protein interaction (CPI) networks were constructed as well. Quercetin, caffeic acid, and kaempferol showed the highest connectivity with the putative proteins. In silico drug likeness studies revealed that almost all compounds comply with both Lipinski's and Veber's rule. According to the previous findings, an in vitro study was carried out on the pure compounds, including quercetin, kaempferol, and caffeic acid (identified from M. oleifera) to validate the proposed approach and to verify their potential effectiveness. Their inhibitory potential was evaluated against the pro-inflammatory cytokine IL-6 and against the endopeptidase MMPs (matrix metalloproteinases) subtype I and II, with highest activity being observed for kaempferol. Hence, M. oleifera seeds could be a promising source of bioactive compounds with potential antioxidant and wound healing capabilities.

The Wound-Healing Potential of Olea europaea L. Cv. Arbequina Leaves Extract: An Integrated In Vitro, In Silico, and In Vivo Investigation.

Olea europaea L. Cv. Arbequina (OEA) (Oleaceae) is an olive variety species that has received little attention. Besides our previous work for the chemical profiling of OEA leaves using LC−HRESIMS, an additional 23 compounds are identified. An excision wound model is used to measure wound healing action. Wounds are provided with OEA (2% w/v) or MEBO® cream (marketed treatment). The wound closure rate related to vehicle-treated wounds is significantly increased by OEA. Comparing to vehicle wound tissues, significant levels of TGF-ß in OEA and MEBO® (p < 0.05) are displayed by gene expression patterns, with the most significant levels in OEA-treated wounds. Proinflammatory TNF-α and IL-1ß levels are substantially reduced in OEA-treated wounds. The capability of several lignan-related compounds to interact with MMP-1 is revealed by extensive in silico investigation of the major OEA compounds (i.e., inverse docking, molecular dynamics simulation, and ΔG calculation), and their role in the wound-healing process is also characterized. The potential of OEA as a potent MMP-1 inhibitor is shown in subsequent in vitro testing (IC50 = 88.0 ± 0.1 nM). In conclusion, OEA is introduced as an interesting therapeutic candidate that can effectively manage wound healing because of its anti-inflammatory and antioxidant properties.

Muscle adaptation to sleeve gastrectomy: Potential role of nutritional supplementation and physical exercise.

Skeletal muscle is metabolically and functionally flexible and contractile under normal conditions. Obesity is a risk factor that causes metabolic disorders and reduces muscle contractility. Sleeve gastrectomy (SG) has been used for surgical correction of obesity. This work aimed to investigate how obesity and its surgical correction affects skeletal muscle and the possible role of nutritional supplementation and physical exercise. Adult male albino rats were randomly divided into five groups, 8 rats per group: group Ia (control non-obese), group Ib (control obese), group II (post-operative, SG), group III (post SG + nutritional supplementation) and group IV (post SG + nutritional supplementation + physical exercise). SG resulted in cellular and metabolic degenerative disorders in the muscle including wasting, weakness and fibrosis with elevated inflammatory, oxidative and injury markers. Nutritional supplementation induced the post SG muscle regeneration indicated by high expression of insulin growth factor-1 (IGF-1) and myogenin and low expression of transforming growth factor beta 1 (TGF-ß1). Interestingly, it improved the metabolic state of the muscle by reducing the oxidative stress, inflammatory and muscle injury markers and delaying the onset of fatigue. What is more, physical exercise along with nutritional supplementation resulted in further improvement of the muscle metabolic state and function. In conclusion, nutritional supplementations together with physical exercise after SG are essential for preserving muscle mass and contractility and improving its metabolic and functional status.

Differential synovial tissue expression of TLRs in seropositive and seronegative rheumatoid arthritis: A preliminary report.

Toll-like receptors (TLRs) are known to have an important role in triggering the innate immune response and in priming antigen-specific adaptive immunity and inflammation. The differences in synovial tissue expression of the TLRs between seronegative and seropositive rheumatoid arthritis (RA) were examined from 9 seropositive RA, 5 seronegative RA and 4 osteoarthritis (OA) patients. Synovitis status was assessed using Krenn's scoring and TLR 1-9 expression by immunohistochemistry. Tissue citrulline content was analysed by HPLC method. In RA TLR expression was generally higher than in OA. TLR2 expression was higher in both seronegative and seropositive RA compared to OA. TLR 1, 4 and 8 expressions were higher in seropositive RA than in seronegative RA or in OA. For TLRs 3, 5, 6, 7 and 9 local differences of expression were found between groups. TLR 1-9 expression correlated with the synovitis grade. No statistical difference was found in synovial tissue citrulline content between the groups. In seropositive RA, the TLR repertoire in the synovial tissue differs from seronegative RA and could explain differences in disease outcomes. The high expression of protein sensing (TLR1, TLR2 and TLR4) and nucleic acid sensing TLRs (TLR7, TLR8 and TLR9) in the seropositive RA could make the synovium primed for reacting to citrullinated proteins and nucleic acids that could be released to extracellular space in formation of neutrophil extracellular traps. This reactivity could be augmented by Fc receptor activation by anti-citrullinated protein antibody immunocomplexes associated with seropositive RA.

Neuroprotective effect of quercetin nanoparticles: A possible prophylactic and therapeutic role in alzheimer's disease.

BACKGROUND: Alzheimer's disease (AD) is the most common cause of dementia in elderly. Quercetin is a well-known flavonoid with low bioavailability. Recently, quercetin nanoparticles (QNPs) has been shown to have a better bioavailability. AIMS: This study aimed to investigate the protective and therapeutic effects of QNPs in Aluminum chloride (AlCl3) induced animal model of AD. MATERIALS AND METHODS: AD was induced in rats by oral administration of AlCl3 (100 mg/kg/day) for 42 days. QNPs (30 mg/kg) was given along with AlCl3 in the prophylactic group and following AD induction in the treated group. Hippocampi were harvested for assessments of the structural and ultrastructural changes using histological and histochemical approaches. RESULTS AND DISCUSSION: AD hippocampi showed a prominent structural and ultrastructural disorders both neuronal and extraneuronal. Including neuronal degeneration, formation of APs and NFTs, downregulation of tyrosine hydroxylase (TH), astrogliosis and inhibition of the proliferative activity (all P ≤ 0.05). Electron microscopy showed signs of neuronal degeneration with microglia and astrocyte activation and disruption of myelination and Blood Brain Barrier (BBB). Interestingly, QNPs administration remarkably reduced the neuronal degenerative changes, APs and NFTs formation (all P ≤ 0.05). Furthermore, it showed signs of regeneration (all P ≤ 0.05) and upregulation of TH. The effect was profound in the prophylactic group. Thus, QNPs reduced the damaging effect of AlCl3 on hippocampal neurons at the molecular, cellular and subcellular levels. CONCLUSION: For the best of our knowledge this is the first study to show a prophylactic and therapeutic effect for QNPs in AD model. This might open the gate for further research and provide a new line for therapeutic intervention in AD.

Mutual inter-regulation between iNOS and TGF-ß1: Possible molecular and cellular mechanisms of iNOS in wound healing.

Abnormal wound healing with excessive scarring is a major health problem with socioeconomic and psychological impacts. In human, chronic wounds and scarring are associated with upregulation of the inducible nitric oxide synthase (iNOS). Recently, we have shown physiological regulation of iNOS in wound healing. Here, we sought to investigate the possible mechanistic role of iNOS in wound healing using biochemical and immunohistochemical assays. We found: (a) iNOS is the main source of wound nitric oxide (NO), (b) NOS inhibition in the wound, downregulated iNOS protein, mRNA and enzymatic activity, and reduced wound NO, and (c) iNOS inhibition resulted in delayed healing at early time points, and excessive scarring at late time points. Furthermore, molecular and cellular analysis of the wound showed that iNOS inhibition significantly (P < 0.05) increased TGF-ß1 mRNA and protein levels, fibroblasts and collagen deposition. These latter findings suggest that iNOS might be exerting its action in the wound by signaling through TGF-ß1 that activates wound fibroblasts to produce excessive collagen. Our current findings provide further support that iNOS is crucial for physiological wound healing, and suggest that dysregulation of iNOS during the inflammatory phase impairs healing, and results in disfiguring post-healing scarring. Thus, the mutual feedback regulation between iNOS and TGF-ß1 at the gene, protein and functional levels might be the mechanism through which iNOS regulates the healing. Monitoring and maintenance of wound NO levels might be important for healing and avoiding long-term complications in susceptible people including patients with diabetic wounds, venous ulcers or keloid prone.