Fenofibrate ameliorates nitroglycerin-induced migraine in rats: Role of CGRP/p-CREB/P2X3 and NGF/PKC/ASIC3 signaling pathways.

Migraine, a debilitating neurological condition, significantly affects patients' quality of life. Fenofibrate, a peroxisome proliferator-activated receptor alpha (PPAR-α) agonist approved for managing dyslipidemia, has shown promise in treating neurological disorders. Therefore, this study aims to investigate the protective effects of fenofibrate against nitroglycerin (NTG)-induced chronic migraine in rats. Migraine was induced in rats by administering five intermittent doses of NTG (10 mg/kg, i. p.) on days 1, 3, 5, 7, and 9. Rats were treated with either topiramate (80 mg/kg/day, p. o.), a standard drug, or fenofibrate (100 mg/kg/day, p. o.) from day 1-10. Fenofibrate significantly improved mechanical and thermal hypersensitivity, photophobia, and head grooming compared to topiramate. These effects were associated with reduced serum levels of nitric oxide (NO), calcitonin gene-related peptide (CGRP), and pituitary adenylate cyclase-activating polypeptide (PACAP). Furthermore, fenofibrate down-regulated c-Fos expression in the medulla and medullary pro-inflammatory cytokine contents. Additionally, fenofibrate attenuated NTG-induced histopathological changes in the trigeminal ganglia and trigeminal nucleus caudalis. These effects were associated with the inhibition of CGRP/p-CREB/purinergic 2X receptor 3 (P2X3) and nerve growth factor (NGF)/protein kinase C (PKC)/acid-sensing ion channel 3 (ASIC3) signaling pathways. This study demonstrates that fenofibrate attenuated NTG-induced migraine-like signs in rats. These effects were partially mediated through the inhibition of CGRP/p-CREB/P2X3 and NGF/PKC/ASIC3 signaling pathways. The present study supports the idea that fenofibrate could be an effective candidate for treating migraine headache without significant adverse effects. Future studies should explore its clinical applicability.

The Association Between Preoperative Insulin-Like Growth Factor 1 Levels and the Total Body Weight Loss in Women Post Laparoscopic Sleeve Gastrectomy.

BACKGROUND: Despite the well-described optimal initial clinical response of sleeve gastrectomy (SG) in the treatment of obesity, some patients do not achieve optimal initial clinical response. Insulin-like growth factor-1 (IGF-1) has currently shown an association with post-bariatric surgery weight loss. This study aimed to assess the IGF-1 levels in female patients with obesity, the change after surgery, and their association with the metabolic profile and weight loss after surgery. PATIENTS AND METHODS: This was a prospective study that was conducted on adult female patients who were recruited for SG. The patients underwent clinical and laboratory investigations that included the IGF-1 measurement. At the 1-year follow-up, the same clinical and laboratory measures were repeated. RESULTS: This study included 100 female patients. At the 1-year follow-up, there was a statistically significant reduction in body mass index (BMI) (p < 0.001), fasting HbA1C levels (p < 0.001), and triglycerides (p < 0.001), as well as a statistically significant increase in HDL (p < 0.001) and IGF-1 (p < 0.001). Multiple regression analysis revealed that, among the patients baseline characteristics, the significant predictors for the percentage of total weight loss (%TWL) were the patients' BMI (p < 0.001) and IGF-1 levels (p < 0.001). The ROC curve showed that an IGF1 cutoff value of ≤ 23 ng/ml detected suboptimal initial clinical response, with a sensitivity of 95.35% and a specificity of 100%. CONCLUSION: This study underscores the significant impact of SG on weight loss and metabolic improvements in female patients. Baseline IGF-1 levels emerged as a crucial predictor of optimal initial clinical response.

Berberine loaded thermosensitive lipid nanoparticles: in vitro characterization, in silico study, and in vivo anti-arthritic effect.

Thermoresponsive drug delivery systems have been used to treat diseases that cause hyperthermia or elevated body tissue temperatures, viz., rheumatoid arthritis and different cancers. The aim of the study was to enhance berberine (BER) release using thermosensitive nanostructured lipid carriers (TNLCs) through intra-articular administration for the management of arthritis. TNLCs were prepared using binary mixtures of stearic acid and decanoic acid as solid and liquid lipids, respectively. Lipid mixtures with an optimum melting point were assessed using differential scanning calorimetry studies. In vitro characterization of the BER TNLCs included particle size, zeta potential, entrapment efficiency, and drug release at 37 °C and 41 °C. Joint diameter measurement, real-time polymerase chain reaction (RT-PC) analysis, enzyme-linked immunosorbent assay (ELISA) for inflammatory markers, and histological evaluation of the dissected joints were all performed in vivo on rats with adjuvant-induced arthritis. In vitro characterization revealed negatively charged BER-loaded TNLCs with a spherical shape, particle size less than 500 nm, BER entrapment efficiency up to 79%, and a high drug release rate at an elevated temperature of 41 °C. In silico studies revealed the affinity of BER to different formula components and to the measured biomarkers. In vivo assessment of the optimum TNLCs showed that BER TNLCs were superior to the BER solution suspension regarding their effect on inflammatory biomarkers, joint diameter, and histological studies.

Topical caffeine-loaded nanostructured lipid carriers for enhanced treatment of cellulite: A 32 full factorial design optimization and in vivo evaluation in rats.

The goal of this study was the development and evaluation of semisolid caffeine (CAF) loaded nanostructured lipid carriers (NLCs) for topical treatment of cellulite. CAF-loaded NLC formulations were prepared via high-speed homogenization followed by ultrasonication. A 32 full factorial design was employed for formulation optimization. The total lipid content (%) and the liquid lipid content per total lipids (%) were chosen as factors, whereas particle size (PS), polydispersity index (PDI), zeta potential (|ZP|) and viscosity (VIS) were selected as responses. The design suggested CAF-NLC3 as the optimum formulation consisting of a total lipid content of 15% w/w (palmitic acid and soft paraffin/isopropyl myristate, 7:3 w/w) and a surfactant content of 10% w/w (Tween 80/lecithin, 8:1.2 w/w). CAF-NLC3 revealed PS, PDI, ZP, VIS and CAF content values of 318.8 nm, 0.253, -41.1 mV, 18.0 Pa.s and 97.57%, respectively. It showed a pseudoplastic rheological behavior, acceptable pH value (5.25), good spreadability (1.12 mm2/g) and spherical shape employing transmission electron microscopy. Differential scanning calorimetry and X-ray diffraction demonstrated the amorphization of CAF in CAF-NLC3. CAF-NLC3 remained stable for 3 months at room and refrigeration conditions. A single topical application of CAF-NLC3 on shaved abdominal skins of Wistar rats revealed enhanced skin retention of CAF by 2-fold and 1.4-fold after 4 h when compared with plain CAF gel (CAF-P) and marketed CAF gel (CAF-M), respectively. Furthermore, CAF-NLC3 exhibited a superior anti-cellulite activity in comparison with CAF-P and CAF-M through elevating extracellular matrix components (collagen 1, elastin and hyaluronic acid) and stimulating the brown adipose tissue thermogenesis via up-regulating UCP1 and PPAR-γ expression. In addition, CAF-NLC3 prominently increased lipolysis through HSL activity and decreased pro-inflammatory cytokines such as ICAM-1 and VCAM-1 after 30 days of treatment on a high fat diet-induced cellulite rat model. These findings were further confirmed by histopathological examination supported by morphometric analysis. Therefore, incorporation of CAF in a semisolid NLC formulation would be a promising cosmetic approach for the topical treatment of cellulite.

Epidemiology of postoperative spinal wound infection in the Middle East and North Africa (MENA) region.

Background: Despite the extensive literature on postoperative spinal wound infection, yet to our knowledge, there is no previous study containing combined data from several sites in the Middle East and North Africa (MENA) region. This study aimed to estimate the incidence of surgical site infection (SSI) following spine surgeries, its associated factors, and management. Methods: In a retrospective cohort study, medical records of all patients ≥18 years of age who underwent spine surgery at 6 tertiary referral centers in the MENA region between January 2014 to December 2019 (n=5,872) were examined to collect data on the following: (1) Patient's characteristics, (2) Disease characteristics, (3) Spine surgery approach, and (4) Characteristics of Postoperative SSI. The determinants of postoperative SSI were identified using logistic regression analysis. Receiver operating characteristic (ROC) curve was applied to identify the cut-off of the length of stay in the hospital postoperatively till the infection is likely to occur. Significance was set at p<.05. Results: The overall incidence of SSI was 4.2% (95% CI: 3.72-4.77), in the form of deep (46.4%), superficial (43.1%), dehiscence (9.3%), and organ space (1.2%) infections. After adjusting for all possible confounders, significant predictors of postoperative SSI were; diabetes (OR=2.12, p<.001), smoking (OR=1.66, p=.002), revision surgery (OR=2.20, p<.001), open surgery (OR=2.73, p<.001), perioperative blood transfusion (OR=1.45, p=.033), ASA class III(OR=2.08, p=.002), and ≥4 days length of stay "LOS" (OR= 1.71, p=.001). A cut-off of 4 days was the optimum LOS above which postoperative SSI is more likely to occur, with 0.70 sensitivity, 0.47 specificity, and 0.61 area under the curve. Conclusions: This is the first study that highlighted the incidence of postoperative SSI in spine surgery in the MENA region. Incidence figures are comparable to figures in different areas of the world. Identifying predictors of SSI might help high­risk patients benefit from more intensive wound management.

Quercus coccinea Münchh leaves polyphenols: Appraisal acute lung injury induced by lipopolysaccharide in mice.

Genus Quercus is a well-known source for its polyphenolic content and important biological activity. Plants belonging to the Quercus genus were traditionally used in asthma, inflammatory diseases, wound healing, acute diarrhea, and hemorrhoid. Our work intended to study the polyphenolic profile of the Q. coccinea (QC) leaves and to assess the protective activity of its 80% aqueous methanol extract (AME) against lipopolysaccharide (LPS)-induced acute lung injury (ALI) in mice. Together, the potential molecular mechanism was investigated. Nineteen polyphenolic compounds (1-18), including tannins, flavone, and flavonol glycosides. Phenolic acids and aglycones were purified and identified from the AME of QC leaves. Treatment with AME of QC showed an anti-inflammatory effect evidenced by a remarkable decline in the count of white blood cells and neutrophils which was in harmony with decreasing the levels of high mobility group box-1, nuclear factor kappa B, tumor necrosis factor-α, and interleukin 1 beta. In addition, the antioxidant activity of QC was documented through the significant reduction in malondialdehyde level and elevation of reduced glutathione level and superoxide dismutase activity. Furthermore, the mechanism involved in the pulmonary protective effect of QC involved the downregulation of the TLR4/MyD88 pathway. The AME of QC showed a protective effect against LPS-induced ALI through the powerful anti-inflammatory and antioxidant activities which are linked to its abundancy with polyphenols.

Evaluating the efficacy of Nd:YAG fourth harmonic (266 nm) in comparison with ArF excimer (193 nm) in laser corneal reshaping: ex vivo pilot study.

PURPOSE: Laser corneal reshaping is a common eye surgery utilized to overcome many vision disorders. Different UV laser wavelengths can be effective in the treatment. However, the ArF excimer laser (193 nm) is the most commonly used due to its high absorption in the cornea. In the current study, we investigate the efficacy of applying a solid-state laser (Nd:YAG fourth harmonic at 266 nm) for the corneal reshaping procedure. METHODS: The utilized laser is generated using an optical setup based on a BBO nonlinear crystal which converts the Q-switched laser (532 nm) to its fourth harmonic (266 nm). Different pulse energies were applied with the same number of the shoots on ex vivo rabbit corneas, and the histological effect is studied. Moreover, the possible thermal damage on the treated corneal tissues was inspected via electron microscope. Additionally, the DNA damage on the corneal cells due to the application of the proposed laser was examined and compared with the existing technology (ArF Excimer laser at 193 nm) using the comet assay. RESULTS: The histological examination revealed an appropriate ablation result with the minimum thermal effect at 1.5 mJ and 2.0 mJ. The overall results show that applying 50-shoots of the 1.5-mJ pulse energy using the proposed 266-nm solid-state laser produces the optimum ablation effect with the minimum thermal damage, and almost the same DNA damage occurred using the commercial 193-nm ArF excimer laser. CONCLUSION: Solid-state laser at 266 nm could be a good alternative to the common 193-nm excimer laser for corneal reshaping procedures.

Green Biodegradable Polylactide-Based Polyurethane Triblock Copolymers Reinforced with Cellulose Nanowhiskers.

A novel series of biodegradable polylactide-based triblock polyurethane (TBPU) copolymers covering a wide range of molecular weights and compositions were synthesized for potential use in biomedical applications. This new class of copolymers showed tailored mechanical properties, improved degradation rates, and enhanced cell attachment potential compared to polylactide homopolymer. Triblock copolymers, (TB) PL-PEG-PL, of different compositions were first synthesized from lactide and polyethylene glycol (PEG) via ring-opening polymerization in the presence of tin octoate as the catalyst. After which, polycaprolactone diol (PCL-diol) reacted with TB copolymers using 1,4-butane diisocyanate (BDI) as a nontoxic chain extender to form the final TBPUs. The final composition, molecular weight, thermal properties, hydrophilicity, and biodegradation rates of the obtained TB copolymers, and the corresponding TBPUs were characterized using 1H-NMR, GPC, FTIR, DSC, and SEM, and contact angle measurements. Results obtained from the lower molecular weight series of TBPUs demonstrated potential use in drug delivery and imaging contrast agents due to their high hydrophilicity and degradation rates. On the other hand, the higher molecular weight series of TBPUs exhibited improved hydrophilicity and degradation rates compared to PL-homopolymer. Moreover, they displayed improved tailored mechanical properties suitable for utilization as bone cement, or in regeneration medicinal applications of cartilage, trabecular, and cancellous bone implants. Furthermore, the polymer nanocomposites obtained by reinforcing the TBPU3 matrix with 7% (w/w) bacterial cellulose nanowhiskers (BCNW) displayed a ~16% increase in tensile strength, and 330% in % elongation compared with PL-homo polymer.

Dual-effects of caffeinated hyalurosomes as a nano-cosmeceutical gel counteracting UV-induced skin ageing.

Caffeine (CAF) is a challenging natural bioactive compound with proven antiaging efficacy. However, being hydrophilic hampers its permeation through the skin. Our aim is to develop a novel CAF-loaded nano-cosmeceutical tool counteracting skin photoaging via improving CAF skin permeation using a bioactive nanocarrier. Caffeinated hyalurosomes are novel biocompatible antiaging nanoplatforms designed by immobilization of phospholipid vesicles with a hyaluronan polymer. Physicochemical properties of the selected hyalurosomes formulation showed nano-sized vesicles (210.10 ± 1.87 nm), with high zeta potential (-31.30 ± 1.19 mv), and high encapsulation efficiency (84.60 ± 1.05%). In vitro release results showed outstanding sustained release profile from caffeinated hyalurosomes compared to the CAF-loaded in conventional gel over 24 h. The in-vivo study revealed a photoprotective effect of caffeinated hyalurosomes, reflected from the intact and wrinkling-free skin. Results of biochemical analyses of oxidative stress, pro-inflammatory mediators, and anti-wrinkling markers further confirmed the efficacy of the prepared hyalurosomes compared to the CAF conventional gel. Finally, histopathological examination demonstrated normal histological structures of epidermal layers with minimal inflammatory cell infiltrates in the caffeinated hyalurosomes group compared to the positive control group. Conclusively, caffeinated hyalurosomes successfully achieved enhanced CAF loading and penetration into the skin besides the hydration effect of hyaluronan. Consequently, the developed delivery system presents a promising skin protection nano-platforms via the double effects of both hyaluronan and CAF, hence it guards against skin photodamage.

The role of miRNAs in viral myocarditis, and its possible implication in induction of mRNA-based COVID-19 vaccines-induced myocarditis.

Background: Several reports of unheeded complications secondary to the current mass international rollout of SARS-COV-2 vaccines, one of which is myocarditis occurring with the FDA fully approved vaccine, Pfizer, and others. Main body of the abstract: Certain miRNAs (non-coding RNA sequences) are involved in the pathogenesis in viral myocarditis, and those miRNAs are interestingly upregulated in severe COVID-19. We hypothesize that the use of mRNA-based vaccines may be triggering the release of host miRNAs or that trigger the occurrence of myocarditis. This is based on the finding of altered host miRNA expression promoting virus-induced myocarditis. Short conclusion: In conclusion, miRNAs are likely implicated in myocarditis associated with mRNA vaccines. Our hypothesis suggests the use of miRNA as a biomarker for the diagnosis of mRNA vaccine-induced myocarditis. Additionally, the interplay between viral miRNA and the host immune system could alter inflammatory profiles, hence suggesting the use of therapeutic inhibition to prevent such complications.

Neuroprotective Effect of Artichoke-Based Nanoformulation in Sporadic Alzheimer's Disease Mouse Model: Focus on Antioxidant, Anti-Inflammatory, and Amyloidogenic Pathways.

The vast socio-economic impact of Alzheimer's disease (AD) has prompted the search for new neuroprotective agents with good tolerability and safety profile. With its outstanding role as antioxidant and anti-inflammatory, alongside its anti-acetylcholinesterase activity, the artichoke can be implemented in a multi-targeted approach in AD therapy. Moreover, artichoke agricultural wastes can represent according to the current United Nations Sustainable Development goals an opportunity to produce medicinally valuable phenolic-rich extracts. In this context, the UPLC-ESI-MS/MS phytochemical characterization of artichoke bracts extract revealed the presence of mono- and di-caffeoylquinic acids and apigenin, luteolin, and kaempferol O-glycosides with remarkable total phenolics and flavonoids contents. A broad antioxidant spectrum was established in vitro. Artichoke-loaded, chitosan-coated, solid lipid nanoparticles (SLNs) were prepared and characterized for their size, zeta potential, morphology, entrapment efficiency, release, and ex vivo permeation and showed suitable colloidal characteristics, a controlled release profile, and promising ex vivo permeation, indicating possibly better physicochemical and biopharmaceutical parameters than free artichoke extract. The anti-Alzheimer potential of the extract and prepared SLNs was assessed in vivo in streptozotocin-induced sporadic Alzheimer mice. A great improvement in cognitive functions and spatial memory recovery, in addition to a marked reduction of the inflammatory biomarker TNF-α, ß-amyloid, and tau protein levels, were observed. Significant neuroprotective efficacy in dentate Gyrus sub-regions was achieved in mice treated with free artichoke extract and to a significantly higher extent with artichoke-loaded SLNs. The results clarify the strong potential of artichoke bracts extract as a botanical anti-AD drug and will contribute to altering the future medicinal outlook of artichoke bracts previously regarded as agro-industrial waste.

Development and Evaluation of Novel Leflunomide SPION Bioemulsomes for the Intra-Articular Treatment of Arthritis.

Systemic treatments for rheumatoid arthritis are associated with many side effects. This study aimed to minimize the side effects associated with the systemic administration of leflunomide (LEF) by formulating LEF-loaded emulsomes (EMLs) for intra-articular administration. Additionally, EMLs were loaded with supramagnetic nanoparticles (SPIONs) to enhance joint localization, where a magnet was placed on the joint area after intra-articular administration. Full in vitro characterization, including colloidal characteristics, entrapment efficiency, and in vitro release were conducted besides the in vivo evaluation in rats with adjuvant-induced arthritis. In vivo study included joint diameter measurement, X-ray radiographic analysis, RT-PCR analysis, Western blotting, ELISA for inflammatory markers, and histopathological examination of dissected joints. The particle size and entrapment efficiency of the selected LEF SPION EMLs were 198.2 nm and 83.7%, respectively. The EMLs exhibited sustained release for 24 h. Moreover, in vivo evaluation revealed LEF SPION EMLs to be superior to the LEF suspension, likely due to the increase in LEF solubility by nanoencapsulation that improved the pharmacological effects and the use of SPION that ensured the localization of EMLs in the intra-articular cavity upon administration.

Apigenin attenuates LPS-induced neurotoxicity and cognitive impairment in mice via promoting mitochondrial fusion/mitophagy: role of SIRT3/PINK1/Parkin pathway.

RATIONALE: Alteration of the NAD+ metabolic pathway is proposed to be implicated in lipopolysaccharide (LPS)-induced neurotoxicity and mitochondrial dysfunction in neurodegenerative diseases. Apigenin, a naturally-occurring flavonoid, has been reported to maintain NAD+ levels and to preserve various metabolic functions. OBJECTIVES: This study aimed to explore the effect of apigenin on mitochondrial SIRT3 activity as a mediator through which it could modulate mitochondrial quality control and to protect against intracerebrovascular ICV/LPS-induced neurotoxicity. METHODS: Mice received apigenin (40 mg/kg; p.o) for 7 consecutive days. One hour after the last dose, LPS (12 µg/kg, icv) was administered. RESULTS: Apigenin robustly guarded against neuronal degenerative changes and maintained a normal count of intact neurons in mice hippocampi. Consequently, it inhibited the deleterious effect of LPS on cognitive functions. Apigenin was effective in preserving the NAD+/NADH ratio to boost mitochondrial sirtuin-3 (SIRT3), activity, and ATP production. It conserved normal mitochondrial features via induction of the master regulator of mitochondrial biogenesis, peroxisome proliferator-activated receptor γ (PPARγ) coactivator-1α (PGC-1α), along with mitochondrial transcription factor A (TFAM) and the fusion proteins, mitofusin 2 (MFN2), and optic atrophy-1 (OPA1). Furthermore, it increased phosphatase and tensin homolog (PTEN)-induced putative kinase 1 (PINK1) and parkin expression as well as the microtubule-associated protein 1 light chain 3 II/I ratio (LC3II/I) to induce degradation of unhealthy mitochondria via mitophagy. CONCLUSIONS: These observations reveal the marked neuroprotective potential of apigenin against LPS-induced neurotoxicity through inhibition of NAD+ depletion and activation of SIRT3 to maintain adequate mitochondrial homeostasis and function.

Insights into the role of pERK1/2 signaling in post-cerebral ischemia reperfusion sexual dysfunction in rats.

The purpose of the present study was to investigate the effects of ERK1/2 inhibition on both the amygdala and hippocampal structures, and to investigate its role in regulating memory for sexual information. This study utilized a cerebral ischemia reperfusion (IR) model to produce a stressful brain condition that highlights the possible involvement of a hippocampal GC/pERK1/2/BDNF pathway in the resulting sexual consequences of this ailment. Male Wistar rats were divided into four groups: (1) sham; (2) IR: subjected to 45 min of ischemia followed by 48 h of reperfusion; (3) PD98059: received PD98059 at 0.3 mg/kg, i.p.; (4) IR + PD98059. This study provides new evidence for cerebral IR-induced amygdala injury and the sexual impairments that are associated with motor and cognitive deficits in rats. These findings were correlated with histopathological changes that are defined by extensive neuronal loss in both the hippocampus and the amygdala. The current study postulated that the ERK inhibitor PD98059 could reverse IR-induced injury in the amygdala as well as reversing IR-induced sexual impairments. This hypothesis is supported by the ability of PD98059 to: (1) restore luteinizing hormone and testosterone levels; (2) increase sexual arousal and copulatory performance (as evidenced by modulating mount, intromission, ejaculation latencies, and post-ejaculatory intervals); (3) improve the histological profile in the amygdala that is associated with reduced glutamate levels, c-Fos expression, and elevated gamma aminobutyric acid levels. In conclusion, the present findings introduce pERK1/2 inhibition as a possible strategy for enhancing sexual activity in survivors of IR.

Crosstalk between PI3K/AKT/KLF4 signaling and microglia M1/M2 polarization as a novel mechanistic approach towards flibanserin repositioning in parkinson's disease.

Balancing microglia M1/M2 polarization has been shown as a prospective therapeutic strategy for Parkinson's disease (PD). Various vital signaling pathways are likely to govern the microglial phenotype. The implication of 5HT1A receptors in neurodegenerative disorders has raised interest in exploring the repositioning of flibanserin (Flib), a 5HT1A agonist, as an effective neuroprotective agent for PD. Therefore, this study was designed to assess the ability of Flib to modulate microglia phenotype switching from M1 to M2 via PI3K/AKT downstream targets in a rotenone model of PD. Rats received rotenone (1.5 mg/kg) every other day and were concurrently treated with Flib (40 mg/kg/day) with or without wortmannin (15 µg/kg/day), a PI3K inhibitor, for 21 days. Flib improved the motor perturbations induced by rotenone, as confirmed by the reversion of histopathological damage and tyrosine hydroxylase immunohistochemical alterations in both the striata and substantia nigra. The molecular signaling of Flib was elaborated by inducing striatal AKT phosphorylation and the expression of its substantial target, KLF4. Flib induced STAT6 phosphorylation to promote M2 polarization as demonstrated by the increased CD163++ microglial count with striatal arginase activity. In parallel, it markedly inhibited M1 activation as evidenced by the reduction in CD86++ microglia count with striatal proinflammatory mediators, IL-1ß and iNOS. The pre-administration of wortmannin mostly negated Flib's neuroprotective effects. In conclusion, Flib AKT/ KLF4-dependently amended M1/M2 microglial imbalance to exert a promising neuroprotective effect, highlighting its potential as a revolutionary candidate for conquering PD.

Appraisal on the Wound Healing Potential of Deverra tortuosa DC. and Deverra triradiata Hochst Essential Oil Nanoemulsion Topical Preparation.

Deverra tortuosa (Desf.) DC. and Deverra. triradiata Hochst. ex Bioss are perennial desert shrubs widely used traditionally for many purposes and they are characteristic for their essential oil. The objective of the present study was to investigate the in vivo wound healing activity of the essential oil (EO) of D. tortuosa and D. triradiata through their encapsulation into nanoemulsion. EO nanoemulsion was prepared using an aqueous phase titration method, and nanoemulsion zones were identified through the construction of phase diagrams. The EO was prepared by hydrodistillation (HD), microwave-assisted hydrodistillation (MAHD), and supercritical fluid extraction (SFE) and analyzed using GC/MS. D. tortuosa oil is rich in the non-oxygenated compound, representing 74.54, 73.02, and 41.19% in HD, MADH, and SFE, respectively, and sabinene represents the major monoterpene hydrocarbons. Moreover, D. triradiata is rich in oxygenated compounds being 69.77, 52.87, and 61.69% in HD, MADH, and SFE, respectively, with elemicin and myristicin as major phenylpropanoids. Topical application of the nanoemulsion of D. tortuosa and D. triradiata (1% or 2%) exhibited nearly 100% wound contraction and complete healing at day 16. Moreover, they exhibit significant antioxidant and anti-inflammatory effects and a significant increase in growth factors and hydroxyproline levels. Histopathological examination exhibited complete re-epithelialization accompanied by activated hair follicles and abundant collagen fibers, especially at a concentration of 2%. Therefore, the incorporation of the two Deverra species into nanoemulsion could professionally endorse different stages of wound healing.

The Role of Ethnic Disparities in the Outcomes of Bariatric Surgery: A Systematic Review and Meta-Analysis.

Bariatric surgery is increasingly performed over the past decade for the treatment of morbid obesity. It has beneficial effects on weight reduction, along with diabetes remission. Conflicting results have been reported to evaluate the effect of ethics differences on the outcomes of bariatric surgery. We conducted this meta-analysis to outline the effects of ethnic differences on the outcomes of bariatric surgery, including weight reduction, biochemical variables, diabetes, and hypertension remission. A comprehensive literature search was conducted, using PubMed, Web of Science (ISI), Google Scholar, Popline, Global Health Library (GHL), Virtual Health Library (VHL) including Cochrane database, New York Academy of Medicine (NYAM), and System for Information on Grey Literature in Europe (SIGLE) for studies reporting body mass index (BMI), percentage of excess weight loss (%EWL), waist circumference, hypertension, lipid profile, and diabetes variables. We used the National Heart, Lung, and Blood Institute (NHLBI) tool (Bethesda, MD: NHLBI, National Institutes of Health {NIH}) for quality assessment. Comprehensive Meta-Analysis version 2 software (Englewood, NJ: Biostat, Inc.) was applied to perform the meta-analysis of the variables of interest. We included 23 studies of 71,679 subjects, who underwent bariatric surgery. The majority of the included cases were Whites 55,030 (77%), while 705 (1%) were Asians. The percentages of Blacks, African Americans, Hispanics, and Non-Hispanics were 9.3%, 1.3%, 10.4%, and 1%, respectively. BMI showed no significant difference between Whites vs African American and Hispanic vs Non-Hispanic groups (MD: 0.858; 95% CI: 3.408-1.691; p = 0.509 and MD: 0.455; 95% CI: 2.444-1.554; p = 0.663, respectively). The same result was reported for %EWL, comparing Whites vs African Americans. Lipid biochemical variables, diabetes remission, and hypertension control were significantly more seen among the Asian population. In conclusion, we reported a significant ethnic diversity and reduction in waist circumference, hyperlipidemia, and the associated morbidity one year after bariatric surgery in the Asian population. Further, high-quality prospective studies should focus on the social and psychological ethnic differences associated with obesity.

Noninvasive Capsulotomy for Refractory Depression by Frameless Stereotactic Radiosurgery.

PURPOSE: Effective treatment options for refractory depression are needed. Recent advancements permit both precise ablative radiation and functional neurologic connectome analysis using standard magnetic resonance imaging. We combined these innovations to perform stereotactic radiosurgical capsulotomy for the treatment of medically refractory major depressive disorder and study connectome response using a novel tractography-based approach. METHODS AND MATERIALS: Patients with medically refractory depression were enrolled on a prospective pilot single-arm observational trial from 2020 to 2021 at a single academic tertiary referral center. Bilateral ablation of the anterior limb of the internal capsule was accomplished by mask-based linear accelerator stereotactic radiosurgery. Beck's Depression Inventory measured efficacy. Montreal Cognitive Assessment evaluated cognition. RESULTS: Three patients were enrolled. Depression burden was improved by 88% at 12-month follow-up and by 55% at 18-month follow-up for patient 1 and 2, respectively. Patient 1 discontinued ketamine therapy, and patient 2 discontinued electroconvulsive therapy. Patient 3 reported global improvement in symptoms and function at 3 months. All 3 patients had reduction or resolution of suicidal ideation. No patient experienced cognitive decline or neurologic toxicity, and Montreal Cognitive Assessment score, as well as subjective patient-reported evaluations of concentration and attention, were superior after treatment. Tractography confirmed intended disruption of the cortico-striatal-thalamo-cortical loop with structural reorganization in the connectome. Connectome change was consistent between patients. Observed increases in caudate and putamen connectivity and decreases in thalamic connectivity may explain improved concentration, attention, and depression. The diversity and magnitude of connectome change may correlate with degree of clinical response. CONCLUSIONS: In 3 patients with refractory depression, radiosurgical capsulotomy significantly reduced the burden of depression. Functional connectome reorganization offers neurobiological evidence to support further investigations of the role of radiosurgery in depression.

Gentiopicroside PLGA Nanospheres: Fabrication, in vitro Characterization, Antimicrobial Action, and in vivo Effect for Enhancing Wound Healing in Diabetic Rats.

Purpose: Gentiopicroside (GPS), an adequate bioactive candidate, has a promising approach for enhancing wound healing due to its antioxidant and antimicrobial properties. Its poor aqueous solubility negatively affects oral absorption accompanied by low bioavailability due to intestinal/hepatic first-pass metabolism. Our aim in this study is to fabricate GPS into appropriate nanocarriers (PLGA nanospheres, NSs) to enhance its solubility and hence its oral absorption would be improved. Methods: Normal and ODS silica gel together with Sephadex LH20 column used for isolation of GPS from Gentiana lutea roots. Crude GPS would be further processed for nanospheres fabrication using a single o/w emulsion solvent evaporation technique followed by in vitro optimization study to examine the effect of two formulation variables: polymer (PLGA) and stabilizer (PVA) concentrations on the physical characterizations of prepared NSs. Possible GPS-PLGA chemical and physical interactions have been analyzed using Fourier-transform infrared spectroscopy (FTIR) and differential scanning calorimetry (DSC). The optimum GPS-PLGA NSs have been chosen for antimicrobial study to investigate its inhibitory action on Staphylococcus aureus compared with unloaded GPS NSs. Also, a well-designed in vivo study on streptozotocin-induced diabetic rats has been performed to examine the wound healing effect of GPS-PLGA NSs followed by histological examination of wound incisions at different day intervals throughout the study. Results: The optimum GPS PLGA NSs (F5) with well-controlled particle size (250.10±07.86 nm), relative high entrapment efficiency (83.35±5.71), and the highest % cumulative release (85.79±8.74) have increased the antimicrobial activity as it exhibited a higher inhibitory effect on bacterial growth than free GPS. F5 showed a greater enhancing impact on wound healing and a significant stimulating effect on the synthesis of collagen fibers compared with free GPS. Conclusion: These findings demonstrate that loading GPS into PLGA NSs is considered a promising strategy ensuring optimum GPS delivery for potential management of wounds.

Ethnopharmacological impact of Melaleuca rugulosa (Link) Craven leaves extract on liver inflammation.

ETHNOPHARMACOLOGICAL RELEVANCE: Melaleuca species have been used by many ethnic communities for the management and treatment of several ailments as hemorrhoids, cough, skin infections, rheumatism, sore throat, pain, inflammation, and digestive system malfunctions. However, the detailed mechanistic pharmacological effect of Melaleuca rugulosa (Link) Craven leaves in the management of liver inflammation has not been yet addressed. AIM OF THE STUDY: The present study aimed to evaluate the anti-inflammatory, antioxidant, and antiapoptotic capacities of the aqueous methanol extract of M. rugulosa leaves in relevance to their flavonoid content using an appropriate in vivo model. MATERIALS AND METHODS: The aqueous methanol extract of M. rugulosa leaves was administered to the rats at three non-toxic doses (250, 500, and 1000 mg/kg) for seven days prior to the initiation of liver-injury induced by paracetamol (3 g/kg). Liver enzymes including alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP) were evaluated in serum samples. The oxidative stress markers including reduced glutathione (GSH), malondialdehyde (MDA), and nitric oxide (NO) levels as well as the inflammatory markers such as tumour necrosis factor-alpha (TNF-α) and nuclear factor-kappa B (NF-κB), were assessed in liver homogenate. The results were supported by histopathological and immuno-histochemical studies. The phytochemical investigation of the flavonoid-rich fraction of the aqueous methanol extract was accomplished using different chromatographic and spectroscopic techniques. RESULTS: The aqueous methanol extract of M. rugulosa leaves showed a powerful hepatoprotective activity evidenced by the significant reduction of MDA and NO levels, as well as increasing GSH and catalase activity. Moreover, the extract exhibited anti-inflammatory and antiapoptotic activities witnessed by decreasing TNF-α, NF-κB, iNOS, p-JNK, caspase-3, BAX, and increasing Bcl-2 levels. Moreover, the pretreatment of rats with all doses of M. rugulosa leaves extract showed a significant decrease in liver weight/body weight (LW/BW) ratio, and total bilirubin induced by paracetamol. On the other hand, the chromatographic separation of the flavonoid-rich fraction afforded twenty known flavonoids namely; iso-orientin (1), orientin (2), isovitexin (3), vitexin (4), quercetin-3-O-ß-D-glucuronid methyl ether (5), quercetin-3-O-ß-D-mannuronpyranoside (6), isoquercetin (7), quercitrin (8), kaempferol-3-O-ß-D-mannuronopyranoside (9), kaempferol-7-O-methyl ether-3-O-ß-D-glucopyranoside (10), guaijaverin (11), avicularin (12), kaempferide-3-O-ß-D-glucopyranoside (13), astragalin (14), afzelin (15), luteolin (16), apigenin (17), quercetin (18), kaempferol (19), and catechin (20). CONCLUSION: The aqueous methanol extract of M. rugulosa leaves showed potential hepatoprotective, antioxidant, and anti-inflammatory activities against paracetamol-induced liver inflammation which is correlated at least in part to its considerable phenolic content.