Effect of icariin in a rat model of colchicine-induced cognitive deficit: role of ß-amyloid proteolytic enzymes.

ABSTRACTThe deposition of ß-amyloid plaques, either due to their over-production or insufficient clearance, is an important pathological process in cognitive impairment and dementia. Icariin (ICA), a flavonoid compound extracted from Epimedium, has recently gained attention for numerous age-related diseases, such as neurodegenerative diseases. We aimed to explore the possible neuro-protective effect of ICA supplementation in colchicine-induced cognitive deficit rat model and exploring its effect on the ß-amyloid proteolytic enzymes. The study included four groups (10 rats each): normal control, untreated colchicine, colchicine + 10 mg/kg ICA, and colchicine + 30 mg/ kg ICA. Results revealed that intra-cerebro-ventricular colchicine injection produced neuronal morphological damage, ß amyloid deposition, and evident cognitive impairment in the behavioral assessment. Icariin supplementation in the two doses for 21 days attenuated neuronal death, reduced the ß amyloid levels, and improved memory consolidation. This was associated with modulation of the proteolytic enzymes (Neprilysin, Matrix Metalloproteinase-2, and insulin-degrading enzyme) concluding that ß-amyloid enzymatic degradation may be the possible therapeutic target for ICA.

Vaccination with Toxoplasma lysate antigen or its encapsulated niosomes form immunomodulates adjuvant-induced arthritis through JAK3 downregulation.

BACKGROUND: Inflammatory autoimmune arthritis like that present in rheumatoid arthritis (RA) is treated by medications with many side effects. This study was a trial to benefit from Toxoplasma immune-modulatory effects on its host to treat arthritis in rat model resembling joints affection of RA. To avoid hazards of infection, Toxoplasma lysate antigen (TLA) was given instead of the whole infection, in addition to giving its encapsulated niosomes form, assuming that it would enhance the effect of TLA alone, to compare effects of both on disease activity with that of prednisolone. METHODS: Swiss albino rats were divided into 6 groups: normal control group and the remaining 5 groups were injected by CFA adjuvant to induce arthritis; one of those groups was the untreated model. Each of the other groups received one of the following (TLA, TLA-encapsulated niosomes, prednisolone or niosomes) for comparison of their results. Inflammatory markers measured at the end of the experiment were: interleukin 17 (IL-17), IL-10 and CRP by ELISA technique; histopathological assessment of the biopsied hind paw joints was done and also, Janus kinase 3 (JAK3) expression was assessed by immunohistochemistry. RESULTS: TLA and TLA-encapsulated niosomes both mitigated the signs of clinical and histopathological arthritis and were having anti-inflammatory effects (decreased CRP, IL-17 and JAK3 expressions, while increased IL-10 levels) with better effects in TLA-encapsulated niosomes-treated RA group, both groups' results were comparable to prednisolone. Niosomes also gave some anti-inflammatory effects but were mild in comparison to TLA and TLA-encapsulated niosomes. CONCLUSION: Vaccination with both TLA and TLA-encapsulated niosomes for the first time in adjuvant-induced arthritis ameliorated the disease through diversion of immune system and JAK3 downregulation. Both vaccinations should be further tested to evaluate the possibility of their introduction for disease treatment and in other autoimmune diseases.

Coenzyme Q10 alleviates testicular endocrine and spermatogenic dysfunction induced by high-fat diet in male Wistar rats: Role of adipokines, oxidative stress and MAPK/ERK/JNK pathway.

The current study investigated the possible protective effects of Coenzyme Q10 (Co Q10 ) on rat model of high-fat diet (HFD) induced testicular dysfunction. Thirty male Wistar rats were allocated randomly into three groups: control, HFD, HFD + Co Q10 (75 mg/kg/day) groups. Animals were sacrificed after 3 months and epididymal sperm suspension, blood, and testes were collected for further analysis. In comparison to the untreated HFD group, the Co Q10 treated group revealed significantly increased serum testosterone, adiponectin levels, and decreased LH, FSH, and leptin levels. In addition, HFD resulted in significant increase in testicular oxidative stress (increased MDA, iNOS, NO, XO & decreased catalase, SOD, GSH) and inflammation (increased pJNK/JNK, pERK/ERK, and p-p38MAPK/MAPK), while Co Q10 was effective to ameliorate these changes. In addition, Co Q10 significantly increased sperm count, motility and viability that were markedly deteriorated by HFD. Regarding testicular ultrastructure, seminiferous tubular diameter and epithelium height were reduced in HFD group and Co Q10 significantly improved these testicular changes. Finally, a significant reduction in spermatogenic cell proliferation was detected by PCNA fluorescent expression and Co Q10 significantly reversed this change. In summary, our results indicated that Co Q10 could suppress testicular dysfunction produced by HFD. This protective effect could be attributed to its antioxidant, anti-inflammatory properties and to its effect on adipokines and spermatogenic cell proliferation. So, Co Q10 may be a promising food supplement to protect against testicular dysfunction induced by HFD.

Trivalent chromium supplementation ameliorates adjuvant induced rheumatoid arthritis through up-regulation of FOXP3 and decrease in synovial Cathepsin G expression.

BACKGROUND: Rheumatoid arthritis (RA) is a known debilitating autoimmune disease. Immune-suppressants that are used for disease treatment have serious side effects, therefore, trivalent chromium (Cr (III)); which has shown evidence of its influences on some inflammatory pathways and cytokines; was used in this study for the first time to be assessed for its therapeutic effect in RA rat model and was compared to prednisolone in a trial to find a treatment with lesser side effects. METHODS: Adult male albino rats were randomly divided into four groups: normal, untreated RA, prednisolone treated RA (1.25 mg/kg/day) and Cr (III) treated RA groups (80 µg/kg/day), induction of RA was done by subcutaneous complete Freund adjuvant injection. Study duration was 4 weeks throughout which arthritis scoring and weight measurement were pursued. Histopathological examination and immunohistochemical FOXP3 assessment were done for joint biopsies. Serum inflammatory markers (interleukin 17, interleukin 10, CRP) and synovial erosive arthritis marker (Cathepsin G) were measured. HDL and non-HDL cholesterol were estimated as well. RESULTS: Cr (III) treatment showed marked clinical and histopathological improvement, also astonishing anti-inflammatory effects (increase in FOXP3 expression and interleukin 10, with decrease in interleukin 17, CRP and synovial Cathepsin G) to the extent that Cr (III) effects on inflammation abolishment were comparable to that of prednisolone and even better at some aspects. Moreover, Cr (III) was protective from side effects, i.e., weight gain and dyslipidemia that were seen with prednisolone treatment. CONCLUSIONS: Cr (III) is promising in treating RA and it lacks some side effects of accustomed immune-modulatory agents including prednisolone. Further experimental studies and clinical trials should be held to see the efficacy of Cr (III) in different doses and to assess its long term side effects when used for rheumatoid arthritis and other autoimmune diseases treatment.

Chitosan-coated nanostructured lipid carriers for effective brain delivery of Tanshinone IIA in Parkinson's disease: interplay between nuclear factor-kappa ß and cathepsin B.

Parkinson's disease (PD) is the second most common progressive neurodegenerative disorder associated with increased oxidative stress, the underlying vital process contributing to cell death. Tanshinone IIA (TAN) is a phytomedicine with a documented activity in treating many CNS disorders, particularly PD owing to its unique anti-inflammatory and antioxidant effect. However, its clinical utility is limited by its poor aqueous solubility, short half-life, and hence low concentration reaching targeted cells. This work aimed to develop a biocompatible chitosan-coated nanostructured lipid carriers (CS-NLCs) for effective brain delivery of TAN for PD management. The proposed nanosystem was successfully prepared using a simple melt-emulsification ultra-sonication method, optimized and characterized both in vitro and in vivo in a rotenone-induced PD rat model. The developed TAN-loaded CS-NLCs (CS-TAN-NLCs) showed good colloidal properties (size ≤ 200 nm, PDI ≤ 0.2, and ζ-potential + 20 mV) and high drug entrapment efficiency (> 97%) with sustained release profile for 24 h. Following intranasal administration, CS-TAN-NLCs succeeded to achieve a remarkable antiparkinsonian and antidepressant effect in diseased animals compared to both the uncoated TAN-NLCs and free TAN suspension as evidenced by the conducted behavioral tests and improved histopathological findings. Furthermore, biochemical evaluation of oxidative stress along with inflammatory markers, nuclear factor-kabba ß (NF-Kß) and cathepsin B further confirmed the potential of the CS-TAN-NLCs in enhancing brain delivery and hence the therapeutic effect of TAN of treatment of PD. Accordingly, CS-TAN-NLCs could be addressed as a promising nano-platform for the effective management of PD.

Brain targeted lactoferrin coated lipid nanocapsules for the combined effects of apocynin and lavender essential oil in PTZ induced seizures.

Apocynin (APO) is a plant derived antioxidant exerting specific NADPH oxidase inhibitory action substantiating its neuroprotective effects in various CNS disorders, including epilepsy. Due to rapid elimination and poor bioavailability, treatment with APO is challenging. Correspondingly, novel APO-loaded lipid nanocapsules (APO-LNC) were formulated and coated with lactoferrin (LF-APO-LNC) to improve br ain targetability and prolong residence time. Lavender oil (LAV) was incorporated into LNC as a bioactive ingredient to act synergistically with APO in alleviating pentylenetetrazol (PTZ)-induced seizures. The optimized LF-APO-LAV/LNC showed a particle size 59.7 ± 4.5 nm with narrow distribution and 6.07 ± 1.6mV zeta potential) with high entrapment efficiency 92 ± 2.4% and sustained release (35% in 72 h). Following subcutaneous administration, LF-APO-LAV/LNC brought about ⁓twofold increase in plasma AUC and MRT compared to APO. A Log BB value of 0.2 ± 0.14 at 90 min reflects increased brain accumulation. In a PTZ-induced seizures rat model, LF-APO-LAV/LNC showed a Modified Racine score of 0.67 ± 0.47 with a significant increase in seizures latency and decrease in duration. Moreover, oxidant/antioxidant capacity and inflammatory markers levels in brain tissue were significantly improved. Histopathological and immunohistochemical assessment of brain tissue sections further supported these findings. The results suggest APO/LAV combination in LF-coated LNC as a promising approach to counteract seizures.

Targeted delivery of budesonide in acetic acid induced colitis: impact on miR-21 and E-cadherin expression.

Inflammatory bowel disease (IBD) is characterized by chronic inflammation along the gastrointestinal tract. For IBD effective treatment, developing an orally administered stable drug delivery system capable of targeting inflammation sites is a key challenge. Herein, we report pH responsive hyaluronic (HA) coated Eudragit S100 (ES) nanoparticles (NPs) for the targeted delivery of budesonide (BUD) (HA-BUD-ES-NPs). HA-BUD-ES-NPs showed good colloidal properties (274.8 ± 2.9 nm and - 24.6 ± 2.8 mV) with high entrapment efficiency (98.3 ± 3.41%) and pH-dependent release profile. The negative potential following incubation in simulated gastrointestinal fluids reflected the stability of HA coat. In vitro studies on Caco-2 cells showed HA-BUD-ES-NPs biocompatibility and enhanced cellular uptake and anti-inflammatory effects as shown by the significant reduction in IL-8 and TNF-α. The oral administration of HA-BUD-ES-NPs in an acetic acid induced colitis rat model significantly mitigated the symptoms of IBD, and improved BUD therapeutic efficacy compared to drug suspension. This was proved via the improvement in disease activity index and ulcer score in addition to refined histopathological findings. Also, the assessment of inflammatory markers, epithelial cadherin, and mi-R21 all reflected the higher efficiency of HA-BUD-ES-NPs compared to free drug and uncoated formulation. We thus suggest that HA-BUD-ES-NPs provide a promising drug delivery platform for the management and site specific treatment of IBD.

Effect of sacubitril/valsartan on cognitive impairment in colchicine-induced Alzheimer's model in rats.

Alzheimer's disease (AD) is a complex neurodegenerative disease. There is epidemiological evidence that heart failure (HF) patients are at higher risk of developing AD, and the impact of sacubitril/valsartan, the first angiotensin receptor-neprilysin inhibitor (ARNI) approved for HF, on cognitive functions is still controversial. To investigate the effect of sacubitril/valsartan on cognitive functions in colchicine-induced AD rat model. Forty adult male Wistar rats were equally allocated into four groups (each of 10 rats): Group I: normal control, Group II: intracerebroventricular injection of colchicine (15 µg/5 µl/bilaterally), Group III: colchicine (15 µg/5 µl/bilaterally, icv) + oral sacubitril/valsartan (100 mg/kg/day) for 25 days, and Group IV: colchicine (15 µg/5 µl/bilaterally, icv) + oral valsartan (50 mg/kg/day) for 25 days. Behavioral assessment was done using Morris water maze and passive avoidance tasks. Biochemically, ß-amyloid (1-40 and 1-42) peptides, oxidative stress (malondialdehyde and superoxide dismutase) and inflammatory (tumor necrosis factor-alpha) parameters were measured in hippocampus and prefrontal cortex. Sacubitril/valsartan exaggerated colchicine-induced cognitive impairment in both Morris water maze and passive avoidance tasks and was associated with significant increase in ß-amyloid accumulation, oxidative stress, and inflammation versus valsartan. Sacubitril/valsartan caused deleterious effect on cognitive impairment and biochemical alterations in colchicine-induced AD rat model. Hence, special caution should be taken following long-term intake of ARNI on cognitive functions.

HR LC-MS/MS metabolomic profiling of Yucca aloifolia fruit and the potential neuroprotective effect on rotenone-induced Parkinson's disease in rats.

Yucca aloifolia L. fruit (Yucca or Spanish bayonet, family Asparagaceae) is recognized for its purplish red color reflecting its anthocyanin content, which has a powerful antioxidant activity. This study aimed to investigate yucca (YA) fruit extract's protective effect on Parkinson's disease (PD). In vitro study, the anti-inflammatory activity of yucca fruit extracts was explored by measuring tumor necrosis factor receptor 2 (TNF-R2) and nuclear factor kappa B (NF-KB) to choose the most effective extract. Afterward, a detailed in vivo investigation of the protective effect of the most active extract on rotenone-induced PD was performed on male albino Wister rats. First, the safety of the extract in two different doses (50 and 100 mg/kg in 0.9% saline orally) was confirmed by a toxicological study. The rats were divided into four groups: 1) normal control (NC); 2) rotenone group; and third and fourth groups received 50 and 100 mg/kg yucca extract, respectively. The neurobehavioral and locomotor activities of the rats were tested by rotarod, open field, and forced swim tests. Striatal dopamine, renal and liver functions, and oxidative stress markers were assessed. Western blot analysis of brain tissue samples was performed for p-AMPK, Wnt3a, and ß-catenin. Histopathological examination of striatal tissue samples was performed by light and electron microscopy (EM). The metabolites of the active extract were characterized using high-resolution LC-MS/MS, and the results showed the prevalence of anthocyanins, saponins, phenolics, and choline. Biochemical and histopathological tests revealed a dose-dependent improvement with oral Yucca extract. The current study suggests a possible neuroprotective effect of the acidified 50% ethanol extract (YA-C) of the edible Yucca fruit, making it a promising therapeutic target for PD.

Tanshinone IIA loaded bioactive nanoemulsion for alleviation of lipopolysaccharide induced acute lung injury via inhibition of endothelial glycocalyx shedding.

Acute lung injury (ALI) and its more serious form; acute respiratory distress syndrome are major causes of COVID-19 related mortality. Finding new therapeutic targets for ALI is thus of great interest. This work aimed to prepare a biocompatible nanoformulation for effective pulmonary delivery of the herbal drug; tanshinone-IIA (TSIIA) for ALI management. A nanoemulsion (NE) formulation based on bioactive natural ingredients; rhamnolipid biosurfactant and tea-tree oil, was developed using a simple ultrasonication technique, optimized by varying oil concentration and surfactant:oil ratio. The selected TSIIA-NE formulation showed 105.7 nm diameter and a PDI âˆ¼ 0.3. EE exceeded 98 % with biphasic sustained drug release and good stability over 3-months. In-vivo efficacy was evaluated in lipopolysaccharide (LPS)-induced ALI model. TSIIA-NE (30 µg/kg) was administered once intratracheally 2 h after LPS instillation. Evaluation was performed 7days post-treatment. Pulmonary function assessment, inflammatory, oxidative stress and glycocalyx shedding markers analysis in addition to histopathological examination of lung tissue were performed. When compared to untreated rats, in-vivo efficacy study demonstrated 1.4 and 1.9-fold increases in tidal volume and minute respiratory volume, respectively, with 32 % drop in wet/dry lung weight ratio and improved levels of arterial blood gases. Lung histopathology and biochemical analysis of different biomarkers in tissue homogenate and bronchoalveolar lavage fluid indicated that treatment may ameliorate LPS-induced ALI symptoms thorough anti-oxidative, anti-inflammatory effects and inhibition of glycocalyx degradation. TSIIA-NE efficacy was superior to free medication and blank-NE. The enhanced efficacy of TSIIA bioactive nanoemulsion significantly suggests the pharmacotherapeutic potential of bioactive TSIIA-NE as a promising nanoplatform for ALI.