Significant Protection Research Articles

UV radiation-induced peptides in frog skin confer protection against cutaneous photodamage through suppressing MAPK signaling.

Overexposure to ultraviolet light (UV) has become a major dermatological problem since the intensity of ultraviolet radiation is increasing. As an adaption to outside environments, amphibians gained an excellent peptide-based defense system in their naked skin from secular evolution. Here, we first determined the adaptation and resistance of the dark-spotted frogs (Pelophylax nigromaculatus) to constant ultraviolet B (UVB) exposure. Subsequently, peptidomics of frog skin identified a series of novel peptides in response to UVB. These UV-induced frog skin peptides (UIFSPs) conferred significant protection against UVB-induced death and senescence in skin cells. Moreover, the protective effects of UIFSPs were boosted by coupling with the transcription trans-activating (TAT) protein transduction domain. In vivo, TAT-conjugated UIFSPs mitigated skin photodamage and accelerated wound healing. Transcriptomic profiling revealed that multiple pathways were modulated by TAT-conjugated UIFSPs, including small GTPase/Ras signaling and MAPK signaling. Importantly, pharmacological activation of MAPK kinases counteracted UIFSP-induced decrease in cell death after UVB exposure. Taken together, our findings provide evidence for the potential preventive and therapeutic significance of UIFSPs in UV-induced skin damage by antagonizing MAPK signaling pathways. In addition, these results suggest a practicable alternative in which potential therapeutic agents can be mined from organisms with a fascinating ability to adapt.

Estimated Effectiveness of the BNT162b2 XBB Vaccine Against COVID-19

Data describing the early additional protection afforded by the recently recommended BNT162b2 XBB vaccine (Pfizer-BioNTech; 2023-2024 formulation) are limited. To estimate the association between receipt of the BNT162b2 XBB vaccine and medically attended COVID-19 outcomes among US adults 18 years and older. This test-negative case-control study was performed to estimate the effectiveness of the BNT162b2 XBB vaccine against COVID-19-associated hospitalization and emergency department (ED) or urgent care (UC) encounters among adults in the Kaiser Permanente Southern California health system between October 10, 2023, and December 10, 2023. Cases were those presenting with an acute respiratory illness and who had a positive SARS-CoV-2 polymerase chain reaction test; controls had an acute respiratory illness but tested negative for SARS-CoV-2. The primary exposure was receipt of the BNT162b2 XBB vaccine compared with not receiving an XBB vaccine of any kind, regardless of prior COVID-19 vaccination or SARS-CoV-2 infection history. Receipt of prior (non-XBB) versions of COVID-19 vaccines was also compared with being unvaccinated to estimate remaining protection from older vaccines. Analyses for cases and controls were conducted separately for COVID-19 hospital admissions and ED/UC encounters. Adjusted odds ratios and 95% CIs were estimated from multivariable logistic regression models that were adjusted for patient demographic and clinical characteristics. Estimation of vaccine effectiveness was calculated as 1 - odds ratio × 100%. Among 2854 cases and 15 345 controls (median [IQR] age, 56 [37-72] years; 10 658 [58.6%] female), adjusted estimation of effectiveness of the BNT162b2 XBB vaccine received a median of 34 days prior vs not having received an XBB vaccine of any kind was 62% (95% CI, 32%-79%) against COVID-19 hospitalization and 58% (95% CI, 48%-67%) for ED/UC visits. Compared with being unvaccinated, those who had received only older versions of COVID-19 vaccines did not show statistically significant reduced risk of COVID-19 outcomes, including hospital admission. Findings of this case-control study reaffirm current recommendations for broad age-based use of annually updated COVID-19 vaccines given that (1) the BNT162b2 XBB vaccine provided statistically significant additional protection against a range of COVID-19 outcomes and (2) older versions of COVID-19 vaccines offered little, if any, long-term protection, including against hospital admission, regardless of the number or type of prior doses received.

The effect of Fluoride varnish and Silver Diamine Fluoride in prevention of enamel demineralization around orthodontic bracket through UV illumination: An in vitro study

Brief Background The present in vitro study evaluated the effectiveness of Fluoride Vanish and Silver Diamine Fluoride in preventing enamel demineralization around orthodontic brackets, using a UV light on a group of extracted teeth with bonded brackets. Materials and Methods In this study, 30 samples of extracted human permanent teeth with bonded orthodontic brackets were separated into control group I (no fluoride varnish), experimental group II (fluoride varnish was applied), and experimental group III (fluoride varnish with SDF) to examine the preventive effects of fluoride on enamel demineralization. Teeth were subjected to three demineralization cycles in a standard demineralization solution. Enamel demineralization was measured according to the index of Gorelick et al. in all three groups at baseline, after the first and second demineralization cycles under UV light. Results Statistically significant differences were observed between the control group and the FV group after the first demineralization cycle. (p value< 0.0001) No significant difference was found between baseline readings and after two demineralization cycles in the FV+SDF group. Summary and conclusion Fluoride varnish, along with SDF, is effective in reducing enamel demineralization. During the bonding appointment, the initial application of fluoride varnish around the orthodontic bracket can offer significant protection against white spot lesions (WSL). The development of WSL next to brackets can be avoided with regular professional applications of an FV during treatment with fixed orthodontic appliances. Key Words Enamel Demineralization; Fluoride Varnish; Orthodontic Brackets; Silver Diamine Fluoride.

Acute microtubule changes linked to DMD pathology are insufficient to impair contractile function or enhance contraction-induced injury in healthy muscle.

Duchenne muscular dystrophy (DMD) is marked by the genetic deficiency of the dystrophin protein in striated muscle whose consequence is a cascade of cellular changes that predispose the susceptibility to contraction injury central to DMD pathology. Recent evidence identified the proliferation of microtubules enriched in post-translationally modified tubulin as a consequence of dystrophins absence that increases the passive mechanics of the muscle fiber and the excess mechanotransduction elicited reactive oxygen species and calcium signals that promote contraction injury. Motivated by evidence that acutely normalizing the disease microtubule alterations reduced contraction injury in murine DMD muscle ( mdx ), here we sought the direct impact of these microtubule alterations independent of dystrophins absence and the multitude of other changes consequent to dystrophic disease. To this end we used acute pharmacologic (epithiolone-D, EpoD; 4 hours) or genetic (vashohibin-2 and small vasohibin binding protein overexpression via AAV9; 2 weeks) strategies to effectively model the proliferation of detyrosination enriched microtubules in the mdx muscle. Quantifying in vivo nerve evoked plantarflexor function we find no alteration in peak torque nor contraction kinetics in WT mice modeling these DMD relevant MT alterations. Quantifying the susceptibility to eccentric contraction injury we show EpoD treatment proffered a small but significant protection from contraction injury while VASH/SVBP had no discernable impact. We conclude that the disease dependent MT alterations act in concert with additional cellular changes to predispose contraction injury in DMD.

Young adults with SLD and/or ADHD conscripted for military service: risk, resources, and resilience

ABSTRACT This study explored multisystem protective/risk factors for explaining resilience/adjustment in emerging adults with/without neurodevelopmental disorders facing the transition to a stressful non-academic context, mandatory military service. Participants were 904 conscripts (498 males, 55%) ages 18–25 years (M = 18.70, SD = .77) in four groups, with ADHD or SLD or comorbid ADHD+SLD or typical development (TD). Data collection tapped multiple information sources. Youngsters’ multidimensional protective/risk variables spanned three levels: (a) individual level – formally diagnosed disorders (SLD, ADHD, or ADHD+SLD), ego-resiliency, sense of coherence, attachment patterns; (b) family level – family cohesion/adaptability; and (c) community/system level – youngsters’ appraisal of their commander as a secure extrafamilial attachment figure. Youngsters’ five resilience/adjustment measures comprised: positive/negative affect, vocational-institutional satisfaction, social adaptation, and commander-rated overall functioning. MANOVAs yielded significant group differences on youngsters’ protective/risk factors and resilience measures. Regression analyses revealed significant risk posed by ADHD and/or SLD and significant protection offered by ego-resiliency, sense of coherence, attachment patterns, family cohesion, and commander as a ‘secure base’ – for explaining youngsters’ resilience. Discussion focused on factors’ unique protective/risk value for explaining resilient functioning in ADHD, SLD, comorbid, and TD emerging adults, while facing highly demanding environment.

Carbamazepine in osteoarthritis treatment: A novel approach targeting Nav1.7 channels.

Osteoarthritis (OA) presents a growing health concern, with substantial societal and healthcare burdens. Current management focuses on symptom relief, lacking disease-modifying options. Emerging research suggests the sodium channel Nav1.7 as a pivotal target in OA treatment. Preclinical studies demonstrate carbamazepine's efficacy in Nav1.7 blockade, offering significant joint protection in animal models. However, human trials are needed to validate these findings. Carbamazepine's repurposing holds promise for OA management, potentially revolutionizing treatment paradigms. Further research is essential to bridge the gap between preclinical evidence and clinical application, offering hope for improved OA management and enhanced patient quality of life.

Ameliorating effects of Clerodendrum viscosum leaves on lead‐induced hepatotoxicity

AbstractLead (Pb), a common toxicant is ubiquitously present in the environment. Chronic Pb exposure affects almost every organ system of human body including liver. Clerodendrum viscosum is a medicinal plant and its leaves are known to have hepatoprotective, anti‐inflammatory, and anti‐hyperglycemic activities. However, the protective effect of C. viscosum leaves against Pb‐induced hepatotoxicity is yet to be studied. Therefore, this study was designed to assess the protective effect of the aqueous extract of C. viscosum leaf (Cle) against Pb‐induced hepatotoxicity in experimental mice. Pb‐acetate was given to Pb and Pb + Cle groups interperitoneally, and Cle was supplemented to Cle and Pb + Cle groups by oral gavage. Serum biomarkers of liver function—butyrylcholinesterase (BChE), alkaline phosphatase (ALP), aspartate aminotransferase (AST), and alanine transaminase (ALT), antioxidant enzyme activities in hepatic tissue—superoxide dismutase (SOD), reduced glutathione reductase (rGR) and catalase (CAT), levels of transcription factor—nuclear factor erythroid 2‐related factor 2 (Nrf2), and inflammatory marker—interleukin‐6 (IL‐6) were analyzed. Additionally, histological analyses of hepatic tissues of all groups of experimental mice were performed. Pb‐treatment significantly increased ALP, AST, and ALT activities and decreased BChE activity compared to control mice. The antioxidant enzyme (SOD, rGR, and CAT) activities and expression of Nrf2 level were significantly (p < .05) decreased, while IL‐6 level was significantly (p < .05) increased in the hepatic tissue homogenates of Pb‐treated mice compared to the control group. Furthermore, histological examination revealed the disruption of hepatic tissue integrity in Pb‐treated mice. Notably, supplementation of Cle provided significant protection against the changes in the activities of liver function biomarkers and antioxidant enzymes, levels of Nrf2 and IL‐6, and disruption of hepatic tissue by Pb. Taken together the present study suggests that Cle ameliorates the hepatic toxicity caused by Pb.

Corylus avellana cultivar “Tonda di Giffoni”, source of antioxidant diarylheptanoids: Biological evaluation and molecular docking analysis

Hazelnut “Tonda di Giffoni” (Corylus avellana L.) is a PGI (Protected Geographical Indication) product of the Campania region, Southern Italy, marked for its processing quality which guarantees origin, typical features, high physicochemical quality, and organoleptic properties. Previous investigations on hazelnut and its byproducts revealed the presence of diarylheptanoid derivatives, natural compounds with antioxidant properties. With the aim of exploring the nutraceutical properties of hazelnut diarylheptanoids, the antioxidant properties of giffonins E (1), H (2), and J (3), three cyclic diaryletherheptanoids, and carpinontriol B (4), a cyclic diarylheptanoid, were investigated. Tested compounds showed significant protection against hydrogen peroxide (H2O2)-induced cytotoxic damage in human neuroblastoma and embryonic kidney cell lines. Compounds 1–4 were also able to prevent oxidative stress by decreasing reactive oxygen species (ROS) production and levels of lipid peroxidation, and attenuating cell apoptosis (caspase-3 activity).Moreover, considering that the nuclear factor erythroid 2-related factor 2 (Nrf2) is responsible for regulating an extensive panel of antioxidant enzymes, the capability of these natural products to disrupt the interaction between Kelch-like ECH-associated protein 1 (Keap1), thereby activating the Nrf2-mediated pathway, was evaluated by molecular docking experiments and in vitro tests.The Western blot analysis revealed that giffonin H and carpinontriol B had an indirect antioxidant action, as evidenced by a significant rise in the translocated protein following their administration.

The prevalence of neural tube defects and their prevention by folic acid supplementation

Background & AimsFolate is crucial for the development of the fetal neurological system. Moroccan Health authorities promote Folic acid (FA) supplementation, before and during pregnancy, as a significant protection against fetal neural tube defects (NTDs). Thus, the current study aims to investigate the effect of FA supplementation guidelines on NTDs prevalence and to assess the health professionals' (HPs) knowledge, attitude, and practice (KAP) regarding FA supplementation in Morocco. MethodsTo assess the prevalence of NTDs, epidemiological data were collected from local and regional medical facilities and enhanced through a literature study. In addition, an auto-administered questionnaire was implemented to evaluate KAP among HPs on the FA supplementation national program. ResultsThe study results showed that from 2017 to 2023, the national prevalence rate of NTDs ranged from 4.26 to 21 per 10,000 live births, according to the region. Lack of information about FA supplementation is evident among HPs; while, 13.7% of the participants confused FA with vitamin B12; merely 50% recognized the significance of FA; and 11.9% had no idea which foods contained the most folate. Consequently, HPs' attitude and practice towards FA supplementation were deemed inadequate. Additionally, only 35.8% of respondents stated that they occasionally inquire about their patients' nutrition, 55.9% do not prescribe FA, and 44.1% are unwilling to report cases of NTDs. ConclusionNTDs remain a serious public health problem in Morocco. Despite the significant incidence of these diseases, HPs' knowledge, attitudes and practices in terms of prevention present gaps and inadequacies. According to the results of this study, the preparation of specific training sessions and the start of preconception consultations constitute an urgent and important issue.

2D Catalytic Niobium Carbide MXenzyme for Ameliorating Noise‐Induced Hearing Loss

AbstractNoise‐induced hearing loss (NIHL), a prevalent sensory disability affecting a majority of the global population, is dominantly induced by mitochondrial dysfunction and oxidative stress, but no effective therapeutic strategy is available. Herein, the potential of a 2D catalytic niobium carbide (Nb2C) MXenzyme is investigated as a nanomedicine for treating NIHL by scavenging reactive oxygen species (ROS). The findings reveal that 2D Nb2C MXenzyme effectively eliminates free radicals, resulting in a substantial reduction of ROS in House Ear Institute‐Organ of Corti 1 (HEI‐OC1) cells treated with hydrogen peroxide (H2O2). Additionally, the 2D Nb2C MXenzyme demonstrates significant protection on hair cells by preventing cytotoxicity and apoptosis induced by H2O2. In vivo experiments further support the efficacy of the 2D Nb2C MXenzyme in restoring hearing impairment caused by extensive noise exposure. Specifically, it restores the raised amplitude of Wave I in auditory brainstem response (ABR) records and promotes the recovery of damaged ribbon synapses in inner hair cells. Notably, the therapeutic effect of the 2D Nb2C MXenzyme is attributed to its ability to suppress cochlear oxidative stress evidenced by immunohistochemical analysis. This research provides a new approach for treating hearing loss‐related ear diseases by utilizing catalytic biomaterials and nanomedicine with enzyme‐mimicking properties.

Impact of interleukin-1 gene polymorphisms on the severity of COVID-19

The severity of Coronavirus Disease 2019 (COVID-19) has been closely linked to an exacerbated proinflammatory response and cytokine storm. Interleukin-1 (IL-1), a pivotal proinflammatory cytokine, plays a crucial role in the development of acute respiratory distress syndrome (ARDS) and multiorgan dysfunction. Single nucleotide polymorphisms within the IL-1 gene have been shown to modulate IL-1 cytokine levels. This study aimed to investigate the association of IL-1 gene polymorphisms (IL-1 + 3953C > T, IL-1β -511 T > C, and IL-1Ra) with the severity of COVID-19. Genotyping of IL-1 gene polymorphisms (IL-1 + 3953C > T, IL-1β -511 T > C) were performed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP), while IL-1Ra genotyping was done by Random Amplification of Polymorphic DNA (RAPD). PCR-RFLP data were validated through Sanger sequencing (SeqStudio Genetic Analyzer). Data analysis was carried out by SPSS-v21 and SHesis (online version). The frequency of the T allele of the IL-1 + 3953C > T polymorphism was found to be higher in mild cases as compared to severe cases, demonstrating a significant protective effect against COVID-19 severity (P = 0.001). However, no significant associations were observed for IL-1β -511 T > C and IL-1Ra polymorphisms (P > 0.05). In haplotype analysis (between IL-1 + 3953C > T, and IL-1β -511 T > C gene polymorphisms), individual with CT haplotype showed a higher risk of severity (OR = 1.8, P = 0.001), while individuals with TT haplotype showed significant protection against severity (P = 0.001). Our findings suggest that the T allele of IL-1β + 3953C > T polymorphism may confer protective effect against the severity of COVID-19.

Surprising and novel multivariate sequential patterns using odds ratio for temporal evolution in healthcare

BackgroundPattern mining techniques are helpful tools when extracting new knowledge in real practice, but the overwhelming number of patterns is still a limiting factor in the health-care domain. Current efforts concerning the definition of measures of interest for patterns are focused on reducing the number of patterns and quantifying their relevance (utility/usefulness). However, although the temporal dimension plays a key role in medical records, few efforts have been made to extract temporal knowledge about the patient’s evolution from multivariate sequential patterns.MethodsIn this paper, we propose a method to extract a new type of patterns in the clinical domain called Jumping Diagnostic Odds Ratio Sequential Patterns (JDORSP). The aim of this method is to employ the odds ratio to identify a concise set of sequential patterns that represent a patient’s state with a statistically significant protection factor (i.e., a pattern associated with patients that survive) and those extensions whose evolution suddenly changes the patient’s clinical state, thus making the sequential patterns a statistically significant risk factor (i.e., a pattern associated with patients that do not survive), or vice versa.ResultsThe results of our experiments highlight that our method reduces the number of sequential patterns obtained with state-of-the-art pattern reduction methods by over 95%. Only by achieving this drastic reduction can medical experts carry out a comprehensive clinical evaluation of the patterns that might be considered medical knowledge regarding the temporal evolution of the patients. We have evaluated the surprisingness and relevance of the sequential patterns with clinicians, and the most interesting fact is the high surprisingness of the extensions of the patterns that become a protection factor, that is, the patients that recover after several days of being at high risk of dying.ConclusionsOur proposed method with which to extract JDORSP generates a set of interpretable multivariate sequential patterns with new knowledge regarding the temporal evolution of the patients. The number of patterns is greatly reduced when compared to those generated by other methods and measures of interest. An additional advantage of this method is that it does not require any parameters or thresholds, and that the reduced number of patterns allows a manual evaluation.

Neuro-protective and redox potential of troxerutin against cypermethrin-induced neurotoxicity and oxidative stress in mice

The present study was designed to evaluate the protective efficacy of troxerutin against cypermethrin-induced behavioral defects, motor function abnormalities, and oxidative stress in mice. Twenty-four adult female albino mice were randomly divided into four equal groups. The first group served as control, the second group was treated with cypermethrin (20 mg/kg b.w) intraperitoneally at day 21, and the remaining two groups were orally supplemented with TRX (150, 300 mg/kg b.w) for 20 days and with cypermethrin (20 mg/kg b.w) intraperitoneally at day 21. Behavior activities recorded after cypermethrin exposure showed significantly impaired motor function (p≤0.05) as evidenced by the beam balance and pole test. The cypermethrin was also found to cause significant memory dysfunction. Moreover, the oxidative stress in terms of increased tissue malondialdehyde level (p≤0.05) was recorded in the cypermethrin group. The antioxidant activities of catalase and glutathione peroxidase were decreased (p≤0.05) after cypermethrin exposure. Troxerutin supplementation significantly improved the cypermethrin- -induced motor impairment and memory dysfunction. The supplementation of troxerutin significantly restored the redox status. Troxerutin attenuates the neurotoxic and behavioral deficits caused by cypermethrin. Furthermore, troxerutin also provides significant protection against cypermethrin-induced oxidative stress by improving the oxidative stress markers.

Duration of Protection and Humoral Immune Response in Nile Tilapia (Oreochromis niloticus L.) Vaccinated against Streptococcus agalactiae.

Streptococcosis caused by Streptococcus agalactiae (S. agalactiae) is a major bacterial disease affecting the production of Nile tilapia (Oreochromis niloticus L.), causing significant economic losses due to mortality in the growing phase. Vaccination is the most effective method for preventing streptococcosis on Nile tilapia farms. In Brazil, the major tilapia-producing regions have long production cycles (6-10 months) and harvest tilapias weighing over 900 g for fillet production. Thus, data on the duration of the humoral immune response and protection in farmed tilapia have not been reported or are poorly described. Furthermore, the efficiency of serological testing for the long-term monitoring of immune responses induced by vaccination against S. agalactiae has never been addressed. This study evaluated the duration of protection and humoral immune response induced in Nile tilapia vaccinated against S. agalactiae until 300 days post-vaccination (dpv). The immunization trial was composed of two groups: vaccinated (Vac), vaccinated intraperitoneally with a commercial vaccine, and unvaccinated (NonVac) group, injected fish with sterile saline solution. At 15, 30, 150, 180, 210, and 300 dpv, blood sampling was conducted to detect anti-S. agalactiae IgM antibodies using indirect Enzyme-Linked Immunosorbent Assay (ELISA), and the fish were challenged with pathogenic S. agalactiae to determine the duration of vaccine protection through relative percentage survival (RPS). Spearman's rank correlation was performed between the ELISA optical density (OD) of vaccinated tilapia and the duration of vaccine protection (RPS). The mean cumulative mortality in NonVac and Vac groups ranged from 65 to 90% and less than 35%, respectively. The average RPS was 71, 93, 94, 70, 86, and 67% at 15, 30, 150, 180, 210, and 300 dpv, respectively. RPS revealed that the vaccine provided protection from 15 to 300 dpv. The specific anti-S. agalactiae IgM antibody levels were significantly higher in the Vac group than that non-Vac group up to 180 dpv. The vaccinated fish exhibited significant protection for up to 10 months after vaccination. There was a positive correlation between the antibody response and RPS. This study revealed that a single dose of commercial vaccine administered to Nile tilapia can confer long-term protection against S. agalactiae and that indirect ELISA can monitor the duration of the humoral immune response for up to six months following vaccination. Finally, vaccine protection over six months can be associated with other components of the fish immune system beyond the humoral immune response by IgM antibodies.

Tau modulation through AAV9 therapy augments Akt/Erk survival signalling in glaucoma mitigating the retinal degenerative phenotype

The microtubule-associated protein Tau is a key player in various neurodegenerative conditions, including Alzheimer's disease (AD) and Tauopathies, where its hyperphosphorylation disrupts neuronal microtubular lattice stability. Glaucoma, a neurodegenerative disorder affecting the retina, leads to irreversible vision loss by damaging retinal ganglion cells and the optic nerve, often associated with increased intraocular pressure. Prior studies have indicated Tau expression and phosphorylation alterations in the retina in both AD and glaucoma, yet the causative or downstream nature of Tau protein changes in these pathologies remains unclear. This study investigates the impact of Tau protein modulation on retinal neurons under normal and experimental glaucoma conditions. Employing AAV9-mediated gene therapy for Tau overexpression and knockdown, both manipulations were found to adversely affect retinal structural and functional measures as well as neuroprotective Akt/Erk survival signalling in healthy conditions. In the experimental glaucoma model, Tau overexpression intensified inner retinal degeneration, while Tau silencing provided significant protection against these degenerative changes. These findings underscore the critical role of endogenous Tau protein levels in preserving retinal integrity and emphasize the therapeutic potential of targeting Tau in glaucoma pathology.

Reproductive and fetal toxicity studies of histamine H3 receptor antagonist DL76 used in mice to prevent maximal electroshock-induced seizure.

Introduction: Brain histamine is considered an endogenous anticonvulsant and histamine H1 receptor. H1R antagonists have, in earlier studies, been found to induce convulsions. Moreover, research during the last twodecades has provided more information concerning the anticonvulsant activities of histamine H3R (H3R) antagonists investigated in a variety of animal epilepsy models. Methods: Therefore, the in vivo anticonvulsant effect of the H3R antagonist DL76, with proven high in vitro affinity, in vitro selectivity profile, and high in vivo antagonist potency in mice against maximal electroshock (MES)-induced seizures in mice, was assessed. Valproic acid (VPA) was used as a reference antiepileptic drug (AED). In addition, DL76 was tested for its reproductive and fetal toxicity in the same animal species. Results and discussion: Our observations showed that acute systemic administration (intraperitoneal; i.p.) of DL76 (7.5mg/kg, 15mg/kg, 30mg/kg, and 60mg/kg, i.p.) provided significant and dose-dependent protection against MES-induced seizures in female and male mice. Moreover, the DL76-provided protective effects were comparable to those offered by the VPA and were reversed when animals were co-administered the CNS-penetrant selective H3R agonist R-(α)-methylhistamine (RAM, 10mg/kg, i.p.). Furthermore, the administration of single (7.5mg/kg, 15mg/kg, 30mg/kg, or 60mg/kg, i.p.) or multiple doses (3 × 15mg/kg, i.p.) of H3R antagonist DL76 on gestation days (GD) 8 or 13 failed to affect the maternal body weight of mice when compared with the control mice group. No significant alterations were detected in the average number of implantations and resorptions between the control and DL76-treated groups at the early stages of gestation and the organogenesis period. In addition, no significant differences in the occurrence of skeletal abnormalities, urogenital abnormalities, exencephaly, exomphalos, facial clefts, and caudal malformations were observed. The only significant abnormalities witnessed in the treated groups of mice were in the length of long bones and body length. In conclusion, the novel H3R antagonist DL76 protected test animals against MES-induced seizures and had a low incidence of reproductive and fetal malformation with decreased long bone lengths in vivo, signifying the potential therapeutic value of H3R antagonist DL76 for future preclinical as well as clinical development for use in the management of epilepsy.

Selected phytocannabinoids inhibit SN-38- and cytokine-evoked increases in epithelial permeability and improve intestinal barrier function in vitro

Irinotecan use is linked to the development of gastrointestinal toxicity and inflammation, or gastrointestinal mucositis. Selected phytocannabinoids have been ascribed anti-inflammatory effects in models of gastrointestinal inflammation, associated with maintaining epithelial barrier function. We characterised the mucoprotective capacity of the phytocannabinoids: cannabidiol, cannabigerol, cannabichromene and cannabidivarin in a cell-based model of intestinal epithelial stress occurring in mucositis.Transepithelial electrical resistance (TEER) was measured to determine changes in epithelial permeability in the presence of SN-38 (5 μM) or the pro-inflammatory cytokines TNFα and IL-1β (each at 100 ng/mL), alone or with concomitant treatment with each of the phytocannabinoids (1 μM). The DCFDA assay was used to determine the ROS-scavenging ability of each phytocannabinoid following treatment with the lipid peroxidant tbhp (200 μM).Each phytocannabinoid provided significant protection against cytokine-evoked increases in epithelial permeability. Cannabidiol, cannabidivarin and cannabigerol were also able to significantly inhibit SN-38-evoked increases in permeability. None of the tested phytocannabinoids inhibited tbhp-induced ROS generation.These results highlight a novel role for cannabidiol, cannabidivarin and cannabigerol as inhibitors of SN-38-evoked increases in epithelial permeability and support the rationale for the further development of novel phytocannabinoids as supportive therapeutics in the management of irinotecan-associated mucositis.

The Science behind Ashwagandha: A Review of its Therapeutic Potential

Ashwagandha, scientifically known as Withania somnifera, holds a prominent place in Ayurvedic medicine. It has served as a rejuvenating tonic, nootropic, and a potent natural adaptogen. This herb extract has been widely employed for overall health and specific health conditions. It boasts a rich history of over 3,000 years of use in Ayurvedic and indigenous medicinal systems on the Indian subcontinent. One of its key attributes is the presence of bioactive compounds called withanolides, with withaferin-A and withanolide-D being particularly noteworthy. In experimental studies, Ashwagandha has demonstrated its ability to enhance endurance in rats during swimming tests and shield against stress-induced changes in adrenal gland components like ascorbic acid and cortisol. Pre-treatment with Ashwagandha has exhibited significant protection against stress-induced gastric ulcers. Moreover, it has shown anti-tumor effects on CHO cell carcinoma and was effective against lung adenoma induced by urethane in mice. In some instances, Ashwagandha has been used to manage conditions like uterine fibroids and dermatosarcoma with long-term treatment. It has also demonstrated cognitive enhancement, proving beneficial for children with memory deficits and elderly individuals experiencing memory loss. Additionally, Ashwagandha has shown promise in addressing neurodegenerative diseases such as Parkinson's, Huntington's, and Alzheimer's. Its anxiolytic properties, as well as its ability to boost energy levels and support mitochondrial health, make it a valuable natural remedy. Furthermore, it serves as an anti-inflammatory and antiarthritic agent, finding application in clinical cases of Rheumatoid and Osteoarthritis.

Development of 4-phenylbutyric acid microsponge gel formulations for the treatment of lewisite-mediated skin injury.

Lewisite, a chemical warfare agent, causes skin blisters, erythema, edema, and inflammation, requiring mitigation strategies in case of accidental or deliberate exposure. 4-phenyl butyric acid (4-PBA), a chemical chaperone, reduces endoplasmic reticulum stress and skin inflammation. The study aimed to encapsulate 4-PBA in microsponges for effective, sustained delivery against lewisite injury. Porous microsponges in a topical gel would potentially sustain delivery and improve residence time on the skin. Microsponges were developed using the quasi-emulsion solvent diffusion method with Eudragit RS100. Optimized formulation showed 10.58%w/w drug loading was incorporated in a carboxymethylcellulose (CMC) and Carbopol gel for in vitro release and permeation testing using dermatomed human skin. A sustained release was obtained from all vehicles in the release study, and IVPT results showed that compared to the control (41.52 ± 2.54µg/sq.cm), a sustained permeation profile with a reduced delivery was observed for microsponges in PBS (14.16 ± 1.23µg/sq.cm) along with Carbopol 980 gel (12.55 ± 1.41µg/sq.cm), and CMC gel (10.09 ± 1.23µg/sq.cm) at 24h. Optimized formulation showed significant protection against lewisite surrogate phenyl arsine oxide (PAO) challenged skin injury in Ptch1+/-/SKH-1 hairless mice at gross and molecular levels. A reduction in Draize score by 29%, a reduction in skin bifold thickness by 8%, a significant reduction in levels of IL-1β, IL6, and GM-CSF by 54%, 30%, and 55%, respectively, and a reduction in apoptosis by 31% was observed. Thus, the translational feasibility of 4-PBA microsponges for effective, sustained delivery against lewisite skin injury is demonstrated.

EXPLORING THE PHOTOPROTECTIVE POTENTIAL OF CALENDULA OFFICINALIS L. ESSENTIAL OIL IN SKINCARE

The study investigated the potential of Calendula officinalis L. essential oil in skincare formulations with sun protection properties. A comprehensive methodology encompassed extraction, characterization, formulation, and evaluation of the oil’s efficacy. Physicochemical parameters assessment indicated favorable results, with GC-MS analysis identifying twenty-two compounds, notably 1,8 cineole and α-pinene, with antioxidant properties suggesting UVB protection. Formulation of stable oil-in-water creams containing 1-5% Calendula oil exhibited no phase separation and maintained viscosity, highlighting robust physical stability. In vitro SPF testing demonstrated significant sun protection activity, particularly in formulations with higher oil concentrations. The study supports Calendula-based formulations as promising natural alternatives for sun protection in cosmetics, offering a sustainable approach without synthetic additives.