The Impact of Early-Life Recurrent Otitis Media in Children on the Psychological Well-Being of Caregivers.

AIM: Children with early-life recurrent otitis media (OM) will often endure pain, sleep disturbances, and other developmental setbacks that impact the surrounding family system. The aim of this study was to investigate the psychological well-being and family functioning of caregivers of children with early-life recurrent OM (rOM). METHODS: Data from a longitudinal pregnancy cohort were used to categorize children into two groups: those with a history of recurrent OM (rOM group) and those without a history of rOM (reference group) by the age of 3 years. The psychological well-being of caregivers and the family functioning status were assessed using the Affect Balance Scale and the General Functioning Scale of the McMaster Family Assessment Device (FAD-GF), respectively, at the three-, five-, and eight-year follow-up appointments. Multiple linear regression models were used to analyze the data and were adjusted for potential confounding variables. RESULTS: There were significant associations between having a child with an early history of rOM and the Affect Balance Scale of caregivers for the negative affects subscale at the three- (p < 0.001) and five- (p = 0.018) year follow-ups, and the Affect Balance subscale at the three-year (p = 0.007) and the five-year follow-ups (p = 0.047). There were no significant associations measured during the 8-year follow-up period for the FAD-GF. CONCLUSION: The findings of this study further highlight the impact of caring for a child with rOM in early childhood on caregivers' psychological well-being in the first five years of a child's life. The impact, however, did not appear to influence the longer-term functioning of the family as a whole. LEVEL OF EVIDENCE: 3 Laryngoscope, 134:1445-1449, 2024.

Warfarin and bisphosphontes interaction in patients undergoing total knee arthroplasty.

Background: Patients undergoing knee arthroplasty (TKA) surgery need anticoagulant therapy, mainly warfarin for prevention of venous thromboembolism (VTE). Warfarin is mainly eliminated by renal glomerular filtration where 92 % of warfarin is excreted in urine. Warfarin overdose may lead to significant bleeding and warfarin underdosing may cause VTE and other complications. Thus, international normalized ratio (INR) monitoring is crucial in TKA patients taking warfarin. Great interest has been expressed in bisphosphonate to reduce periprosthetic osteoporosis in patients undergoing total joint arthroplasty. Many human case reports and cohort studies proved bisphosphonates induced impaired renal function. Objectives: The main goal of the current study is to examine the pharmacodynamin effect of bisphosphonates on warfarin excretion and clinical effects in patients undergoing TKA surgery. Methods: Fifty patients undergoing TKA were recruited in the current study. Twenty five patients were given warfarin and twenty five patients were given warfarin and bisphosphonates starting three days after surgery. INR, major bleeding events and minor bleeding events were followed up in all recruited patients for one month after surgery. Results: warfarin plus zoledronic acid group had significantly higher percent of post INR greater than 4 (p = 0.022) and significantly higher percent of minor bleeding events (p = 0.041) than warfarin only group. Conclusion: Concomitant administration of bisphosphonates may increase warfarin bleeding adverse effects in elderly patient undergoing TKA.

The Impact of Waiting Times on Behavioral Outcomes for Children with Otitis Media: Results from an Urban Ear, Nose, and Throat Telehealth Service.

Aim: Children with otitis media (OM) experience long waiting times to access Australia's public hospitals due to limited capacity. The aim of this article is to utilize an Ear, Nose, and Throat (ENT) telehealth service (the Ear Portal) to examine whether delayed access to specialist care is associated with poorer behavioral outcomes for children with OM. Methods: Participants in the study included 45 children who were referred to ENT specialists due to recurrent and persistent OM. Children were triaged as semiurgent with a target time-to-assessment of 90 days or nonurgent with a target time-to-assessment of 365 days. The behavioral outcomes of children were assessed using the parent report Strengths and Difficulties Questionnaire (SDQ). Descriptive statistics and adjusted multiple linear regression models were used to compare children who received access to the service within the time-to-assessment target of their triage category ("on-boundary"; n = 17) and outside the time-to-assessment target ("off-boundary"; n = 28). Spearman correlation analysis was used to explore the relationship between the internalizing, externalizing, and total SDQ scores as a function of waiting times in days. Results: Borderline or abnormal SDQ scores ranged from 24.4% to 42.2% across the study participants. The regression analysis showed a statistically significant association between the off-boundary group and higher scores (i.e., poorer) on the peer, emotional, conduct, internalizing, and total problems subscales. Further, lengthy waiting times were significantly correlated with higher internalizing problems. These findings indicate that longer waiting times may lead to poorer behavioral outcomes for children with OM.Clinical Trial Registration: (ACTRN1269000039189p). Conclusion: Children with recurrent and persistent OM referred to ENT outpatient care were found to have significantly more behavioral difficulties if their waiting times exceeded the recommended timeframes for their triaged referrals. Additionally, they experienced more internalizing problems that correlated with longer waiting times. This highlights the calls for alterations in current clinical practice given the lengthy waiting times in Australia's public hospitals.

Seroprevalence of herpes simplex virus type 1 and type 2 among the migrant workers in Qatar.

BACKGROUND: Limited data exists on herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) infections in migrant populations. This study investigated HSV-1 and HSV-2 seroprevalences and associations among craft and manual workers (CMWs) in Qatar who constitute 60% of Qatar's population. METHODS: A national population-based cross-sectional seroprevalence survey was conducted on the CMW population, all men, between July 26 and September 9, 2020. 2,612 sera were tested for anti-HSV-1 IgG antibodies using HerpeSelect 1 ELISA IgG kits and for anti-HSV-2 IgG antibodies using HerpeSelect 2 ELISA IgG kits (Focus Diagnostics, USA). Univariable and multivariable logistic regression analyses were conducted to identify associations with HSV-1 and HSV-2 infections. RESULTS: Serological testing identified 2,171 sera as positive, 403 as negative, and 38 as equivocal for HSV-1 antibodies, and 300 sera as positive, 2,250 as negative, and 62 as equivocal for HSV-2 antibodies. HSV-1 and HSV-2 seroprevalences among CMWs were estimated at 84.2% (95% CI 82.8-85.6%) and 11.4% (95% CI 10.1-12.6%), respectively. HSV-1 infection was associated with nationality, educational attainment, and occupation. HSV-2 infection was associated with age, nationality, and educational attainment. CONCLUSIONS: Over 80% of CMWs are infected with HSV-1 and over 10% are infected with HSV-2. The findings highlight the need for sexual health programs to tackle sexually transmitted infections among the CMW population.

The association between otitis media in early childhood with later behaviour and attention problems: A longitudinal pregnancy cohort.

OBJECTIVES: The present study aims to investigate the association between an early history of recurrent otitis media (OM) with or without ventilation tube insertion (VTI) and later behavioural problems in childhood and adolescence. METHODS: Parental reports in a longitudinal pregnancy cohort were used to classify children into three groups; recurrent OM without VTI (rOM group; n = 276), recurrent OM with VTI (VTI group; n = 62), and no history of early-life recurrent OM as a reference group (n = 1485). The Child Behaviour Checklist (CBCL) was administered at ages 5, 8, 10, and 13 years and data were analysed for psychological wellbeing. Mixed-effects regression modelling was used to investigate the associations between a history of rOM and CBCL T-scores across all ages for rOM and VTI groups compared to the reference group. All analyses were controlled for a wide range of confounding variables. RESULTS: The analyses revealed a significant association between recurrent OM and behavioural problems. While there was a general decline in scores (i.e. improvement) observed over the duration of the follow-up period, children in the rOM group displayed significantly higher scores for internalising and externalising behaviours at ages five, eight and 10 years. Attention scores were significantly higher across all ages in the rOM group. A transient increase in internalising behaviour was observed in the VTI group at ages eight and 10 years. Logistic regression models showed an increased overall likelihood for the rOM group only to fall within the abnormal clinical range for internalising and externalising behaviours. CONCLUSION: Early-life recurrent OM with and without VTI was associated with increased behavioural and attention problems in early and late childhood. This suggests that recurrent OM can have a significant impact on children's behaviour and attention that can persist into early adolescence.

On the Mechanical Behaviour of Biomimetic Cornstalk-Inspired Lightweight Structures.

This paper presents an investigation on the stiffness and energy absorption capabilities of three proposed biomimetic structures based on the internal architecture of a cornstalk. 3D printing was used to manufacture specimens using a tough and impact-resistant thermoplastic material, acrylonitrile butadiene styrene (ABS). The structural stiffness, maximum stress, densification strain, and energy absorption were extracted from the compression tests performed at a strain rate of 10-3 s-1. A numerical model was developed to analyse the behaviour of the biomimetic structures under compression loading. Further, a damage examination was conducted through optical microscopy and profilometry. The results showed that the cornstalk-inspired biomimetic structure exhibited a superior specific energy absorption (SEA) capability that was three times higher than that of the other core designs as reported in the literature.

Medicinal plants with antimalarial activities mediated via glycogen synthase kinase-3 beta (GSK3ß) inhibition.

Many of the therapeutic effects of plant extracts and bioactive compounds appear related to their immunomodulatory effects and impact on the host immune system. The immune response is desirable to mitigate established infections and, in the case of severe malaria, is a feasible approach to dealing with the overwhelming cytokine response. Glycogen synthase kinase-3 (GSK3), a Ser/Thr kinase that is a central regulator of the cytokine response, is a promising antimalarial drug target. In this review, we discussed our ongoing research projects, which include assessing the antimalarial activities of medicinal plants and their bioactive compounds, immunomodulatory activities mediated by GSK3, and the potential inflammatory pathway involved in malarial infection.

Phycosynthesis of Silver Nanoparticles Using Cladophora Glomerata and Evaluation of Their Ability to Inhibit the Proliferation of MCF-7 and L20B Cell Lines.

BACKGROUND: Nanotechnology is receiving greater attention these days as a result of its applications in numerous industrial, medical, and environmental fields. OBJECTIVE: To synthesize silver nanoparticles with a green alga, Cladophora glomerata, and determine their inhibitory activity against tumor cell (MCF-7) and transgenic mouse cell (L20B) lines. MATERIALS AND METHODS: Methanol extract was prepared from Cladophora glomerata and used as a safe factory for the synthesis of silver nanoparticles (AgNPs). UV-visible spectrophotometer, X-ray diffraction, scanning electron microscopy, and EDX analyses were used to characterize the biosynthesized AgNPs. The anti-tumor activity of the phycosynthesized AgNPs was tested against the MCF-7 and L20B cell lines. Furthermore, the bioactive compounds in the algal extract were determined by gas chromatography-mass spectroscopy (GC-MS). RESULTS: The phycosynthesis produced clusters of spherical and polydispersed cuboidal pure AgNPs with an average size of 32 nm. The phycosynthesized AgNPs possess anti-cancer and anti-tumor activities on the MCF-7 and L20B cell lines, with significant anti-proliferation percentages of 52.8 and 65.8%, respectively, after 48 hours of treatment with 100 µg/ml AgNPs. Both treated cell lines showed a significant change in cellular shape and tissue detachment. The GC-MS analysis revealed the presence of a high proportion of octadecanoic acid (47.59%) and hexadecanoic acid (14.97%). CONCLUSION: Cladophora glomerata contains chemicals that improve the stabilization and reduction properties of the nanoparticles. It can be used as a safe, local, and natural source for the synthesis of AgNPs and can also be used as a benign factory for many other metal nanoparticles. The phycosynthesized AgNPs have anti-cancer and anti-tumor activities on the test cell lines and provide an insight into the potential for using them as a trend in cancer nanotherapy.
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Autoimmunity in Human CE: Correlative with The Fertility Status of The CE Cyst.

Cystic echinococcosis is speculated to exert several immune-evasion strategies involving autoimmune-phenomena. We evaluated the hypothesizes that the prevalence of autoantibodies increases in the sera of CE patients that may evidence the association between the parasite and autoimmune diseases. Sera from 63 subjects at distinct types of CE cyst fertility were investigated for antinuclear antibodies (ANA), and anti-CCP antibodies. Plasma levels and cellular production of IL-17A cytokine were specifically defined as being assumed to prime for autoimmunity. Healthy-controls were age and gender-matched to test sera. ANA expressions inside the surgically removed metacestode and adventitial layer were also assayed. Out of 63 patients, 35 % had fertile highly viable cysts (group-1), 41 % had fertile low viable cysts (group-2) and 24 % had non-fertile cysts (group-3). A four-fold increase in ANA sera-levels was detected in group-1 compared with their controls (p-value 0.001) while anti-CCP levels were of insignificant differences. In group-2 and group-3, no significant differences were detected between ANA and anti-CCP sera-levels in CE patients and their controls. IL-17A sera-levels in group-1 and group- 2 were significantly higher than their healthy-controls while being of insignificant differences in group-3, p-value= 0.300. No association was detected between sera-levels of IL-17A and ANA as well as anti-CCP antibodies. Interestingly, relative IL-17A cellular expression associated positive ANA deposition in the parasite cells and adventitial layer. Collectively, based on the parasite fertility, IL-17A and ANA seemed to be involved in the host immune defenses against CE. There is no association between CE and anti-CCP antibodies.

Steroids from Diplazium esculentum: Antiplasmodial activity and molecular docking studies to investigate their binding modes.

Diplazium esculentum is an edible fern commonly consumed by the local community in Malaysia either as food or medicine. Isolation work on the ethyl acetate extract of the stem of D. esculentum resulted in the purification of two steroids, subsequently identified as stigmasterol (compound 1) and ergosterol5,8-endoperoxide (compound 2). Upon further testing, compound 2 displayed strong inhibitory activity against the Plasmodium falciparum 3D7 (chloroquine-sensitive) strain, with an IC50 of 4.27±1.15 µM, while compound 1 was inactive. In silico data revealed that compound 2 showed good binding affinity to P. falciparum-Sarco endoplasmic reticulum calcium-dependent ATPase (PfATP6); however, compound 1 did not show an antiplasmodial effect due to the lack of a peroxide moiety in the chemical structure. Our data suggested that the antiplasmodial activity of compound 2 from D. esculentum might be due to the inhibition of PfATP6, which resulted in both in vitro and in silico inhibitory properties.

Steroids from Diplazium esculentum: Antiplasmodial activity and molecular docking studies to investigate their binding modes

@#Diplazium esculentum is an edible fern commonly consumed by the local community in Malaysia either as food or medicine. Isolation work on the ethyl acetate extract of the stem of D. esculentum resulted in the purification of two steroids, subsequently identified as stigmasterol (compound 1) and ergosterol5,8-endoperoxide (compound 2). Upon further testing, compound 2 displayed strong inhibitory activity against the Plasmodium falciparum 3D7 (chloroquine-sensitive) strain, with an IC50 of 4.27±1.15 µM, while compound 1 was inactive. In silico data revealed that compound 2 showed good binding affinity to P. falciparum-Sarco endoplasmic reticulum calcium-dependent ATPase (PfATP6); however, compound 1 did not show an antiplasmodial effect due to the lack of a peroxide moiety in the chemical structure. Our data suggested that the antiplasmodial activity of compound 2 from D. esculentum might be due to the inhibition of PfATP6, which resulted in both in vitro and in silico inhibitory properties.

Medicinal plants with antimalarial activities mediated via glycogen synthase kinase-3 beta (GSK3β) inhibition

@#Many of the therapeutic effects of plant extracts and bioactive compounds appear related to their immunomodulatory effects and impact on the host immune system. The immune response is desirable to mitigate established infections and, in the case of severe malaria, is a feasible approach to dealing with the overwhelming cytokine response. Glycogen synthase kinase-3 (GSK3), a Ser/Thr kinase that is a central regulator of the cytokine response, is a promising antimalarial drug target. In this review, we discussed our ongoing research projects, which include assessing the antimalarial activities of medicinal plants and their bioactive compounds, immunomodulatory activities mediated by GSK3, and the potential inflammatory pathway involved in malarial infection.

A Three-Dimensional Finite Element Analysis of Displacement and Stress Distributions of Unilateral and Bilateral Cleft Lips by Using Developed Pre-Surgical Treatment Architecture.

Cleft lips and cleft palates are the most common birth defects in newborns. Pre-surgical correction of unilateral and bilateral cleft lips and palates has been the subject of interest of many previous works. This condition has necessitated the evolution of many surgical and non-surgical techniques to mitigate the problem of this deformity in children. In this study, we proposed a new architecture that can be used instead of the conventional pre-surgical treatment. The proposed architecture has mechanical and electronic parts. This architecture was adopted to apply external stress to the cleft bones and cleft edges using an airbag that is located in the mechanical part. The amount of air in the airbag can be controlled by an available control unit in the electronic part. The effect of external stress on the cleft bones and the cleft edges was analyzed by using the finite element analysis (FEA) method. The FEA study aimed to analyze the displacement, amount of tensile and compressive forces, and Von Mises stress distributions on the cleft bones, cleft edges, nasal septum, and superior alveolar part of the maxillary jaw of unilateral and bilateral cleft models during pre-surgical treatment with the novel architecture. The results show that displacement and stress affected the clefts of both models. Displacement had a significant effect of gradually bringing the clefts closer to each other and returning them to the posterior. The analysis also investigated the effects of stress on the cleft bone and cleft edge. It was found from the results that the stresses helped to bring the incisions closer to the most appropriate position for plastic surgeons. The results prove that the positive and negative X-displacements move in the opposite direction, which means that the cleft edges gradually converge toward each other. Moreover, the negative Z-displacement affected the movement of cleft bones and cleft edges from outside to inside and gradually returned them to a suitable position. The findings show that the proposed architecture can be contributed to the pre-surgical treatment of the unilateral and bilateral clefts as an alternative to the traditional method.

SARS-CoV-2 Infection Is at Herd Immunity in the Majority Segment of the Population of Qatar.

BACKGROUND: Qatar experienced a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) epidemic that disproportionately affected the craft and manual worker (CMW) population, who comprise 60% of the total population. This study aimed to assess ever and/or current infection prevalence in this population. METHODS: A cross-sectional population-based survey was conducted during July 26 to September 09, 2020, to assess both anti-SARS-CoV-2 positivity through serological testing and current infection positivity through polymerase chain reaction (PCR) testing. Associations with antibody and PCR positivity were identified through regression analyses. RESULTS: The study included 2641 participants, 69.3% of whom were <40 years of age. Anti-SARS-CoV-2 positivity was 55.3% (95% CI, 53.3%-57.3%) and was significantly associated with nationality, geographic location, educational attainment, occupation, and previous infection diagnosis. PCR positivity was 11.3% (95% CI, 9.9%-12.8%) and was significantly associated with nationality, geographic location, occupation, contact with an infected person, and reporting 2 or more symptoms. Infection positivity (antibody and/or PCR positive) was 60.6% (95% CI, 58.6%-62.5%). The proportion of antibody-positive CMWs who had a prior SARS-CoV-2 diagnosis was 9.3% (95% CI, 7.9%-11.0%). Only seven infections were ever severe, and only 1 was ever critical-an infection severity rate of 0.5% (95% CI, 0.2%-1.0%). CONCLUSIONS: Six in every 10 CMWs in Qatar have been infected, suggestive of reaching the herd immunity threshold. Infection severity was low, with only 1 in every 200 infections progressing to be severe or critical. Only 1 in every 10 infections had been previously diagnosed, which is suggestive of mostly asymptomatic or mild infections.

The Anticancer Properties of Artemisia aucheri Boiss Extract on HT29 Colon Cancer Cells.

BACKGROUND: Colon cancer is one of the most common cancers in the world, and efforts toward its treatment have not been completely successful. In recent years, more attention has been focused on herbal medicine (HM) due to their anticancer and cytotoxic properties. This study investigated the anticancer and antioxidant effects of Artemisia aucheri (A. aucheri) Boiss extract against HT29 colon cancer cells compared with HEK239 natural cells. METHODS: This study was performed on human HT29 colon cancer cells. Various doses of 0, 10, 100, 500, and 1000 µg/ml of A. aucheri extract were subjected to cells at specified time intervals. After treatment, the trypan blue test was employed to determine the viability of the cells. MTT and annexin tests were used to determine cell viability and the apoptosis induced by the extract. Malondialdehyde (MDA) testing was applied to investigate the antioxidant properties of the extract on fatty acids. Data analysis was performed using SPSS version 22. One-way ANOVA and paired comparison tests were employed for data analysis. RESULTS: The highest cytotoxicity effect of A. aucheri extract was observed at 1000 µg/ml (80.63 ± 3.66) being dose-dependent compared with the control in both cell lines (p < 0.001). Additionally, the survival rate of HT29 (IC50 = 57.88 µg/ml) and HEK (IC50 = 295 µg/ml) cancer cells decreased with increasing concentration of A. aucheri (the lowest cell viability was at 1000 µg/ml). Furthermore, the induction of membrane lipid peroxidation was significantly higher in HT29 compared with the control (p < 0.001). Another cytotoxic mechanism for the extract was the induction of apoptosis being significantly higher in HT29 colon cancer cells compared with the control group (p < 0.001). CONCLUSION: Cytotoxic effects of A. aucheri extract were dose-dependent. This HM exerted cytotoxic effects against HT29 cells through the induction of membrane lipid peroxidation and apoptosis.

Seroprevalence of SARS-CoV-2 infection in the craft and manual worker population of Qatar

BackgroundQatar experienced a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) epidemic that disproportionately affected the craft and manual worker (CMW) population who comprise 60% of the total population. This study aimed to assess the proportions of ever and/or current infection in this population. MethodsA cross-sectional population-based survey was conducted during July 26-September 09, 2020 to assess both anti-SARS-CoV-2 positivity through serological testing and polymerase chain reaction (PCR) positivity through PCR testing. Associations with antibody and PCR positivity were identified through regression analyses. ResultsStudy included 2,641 participants, 69.3% of whom were <40 years of age. Anti-SARS-CoV-2 positivity was estimated at 55.3% (95% CI: 53.3-57.3%) and was significantly associated with nationality, geographic location, educational attainment, occupation, presence of symptoms in the two weeks preceding the survey, and previous infection diagnosis. PCR positivity was assessed at 11.3% (95% CI: 9.9-12.8%) and was significantly associated with geographic location, contact with an infected person, and reporting two or more symptoms. Infection positivity (antibody and/or PCR positive) was assessed at 60.6% (95% CI: 9.9-12.8%). The proportion of antibody-positive CMWs that had a prior SARS-CoV-2 diagnosis was 9.3% (95% CI: 7.9-11.0%). Only seven infections were ever severe and one was ever critical--an infection severity rate of 0.5% (95% CI: 0.2-1.0%). ConclusionsSix in every 10 CMWs have been infected, suggestive of reaching the herd immunity threshold. Infection severity was low with only one in every 200 infections progressing to be severe or critical. Only one in every 10 infections had been previously diagnosed suggestive of mostly asymptomatic or minimally mild infections.

Efficacy of Mushroom Metabolites (Pleurotus ostreatus) as A Natural Product for the Suppression of Broomrape Growth (Orobanche crenata Forsk) in Faba Bean Plants.

Broomrape parasitism on faba bean (Vicia faba L.) is the most destructive factor for this crop in Egypt. Pot experiments were conducted during the two successive seasons 2017/2018 and 2018/2019 to study the mitigation of broomrape stress on faba bean using a ten-fold dilution of 10% (w/v) spent mushroom substrate extract (SMSE) of Pleurotus ostreatus and the same dilution of culture filtrate of mushroom (MCF) grown in potato dextrose broth (PDB) at a rate of 48 l hectare-1 compared with the commercial herbicide Roundup (Glyphosate 48% emulsifiable concentrate) at a rate of 144 cm3 ha-1 on the two varieties (Misr3 and Sakha3) cultivated in broomrape-infested soil. The treatments include the use of mushroom products as foliar spray and/or soil amendment in addition to Roundup spraying as a recommended treatment. Using Gas Chromatography-Mass Spectrometry (GC-MS) spectroscopy, our results indicate that the major components of the two mushroom products were bioactive compounds such as polyphenol and high molecular weight aliphatic and aromatic hydrocarbons that may interfere with parasite and host metabolism. These results indicated that SMSE of P. ostreatus and MCF of the same mushroom grown in potato dextrose broth (PDB) gave the best control of broomrape, and increased plant height, root length, leaf area, chlorophyll concentration, relative water content and seed yield (g plant-1), as well as anatomical characters of leaves in the two faba bean varieties (Misr3 and Sakha3), such as upper and lower epidermis, palisade tissue, spongy tissue and vascular bundles. Additionally, electrolyte leakage was decreased in the treated plants compared to control plants and the plants treated with Roundup (glyphosate) because of the important role of SMSE and MCF in the improvement of faba bean water status.

GSK3ß: A plausible molecular target in the cytokinemodulating effect of exogenous insulin in a murine model of malarial infection.

Malaria is a life-threatening disease caused by the Plasmodium sp. parasite. Infection results in heightened pro-inflammatory response which contributes to the pathophysiology of the disease. To mitigate the overwhelming cytokine response, host-directed therapy is a plausible approach. Glycogen synthase kinase-3ß (GSK3ß), a serine/threonine kinase plays a pivotal role in the regulation of inflammatory response during pathogenic infections. The present study was conducted to investigate the chemo-suppressive and cytokine-modulating effects of insulin administration in malaria-infected mice and the involvement of GSK3ß. Intraperitoneal administrations of 0.3 and 0.5 U/kg body weight insulin each for four consecutive days into Plasmodium berghei NK65 (PbN)-infected mice resulted in chemo-suppression exceeding 60% and improved median survival time of infected mice (20.5 days and 19 days respectively compared to 15.5 days for non-treated control). Western analysis revealed that pGSK3ß (Ser9) intensity in brain samples from insulin-treated (0.3 and 0.5 U/kg body weight) infected mice each were 0.6 and 2.2 times respectively than that in control. In liver samples, pGSK3ß (Ser9) intensity from insulin-treated infected mice were significantly higher (4.8 and 16.1 fold for 0.3 and 0.5 U/kg bw respectively) than that in control. Insulin administration decreased both brain and liver pNF-κB p65 (Ser536) intensities (to 0.8 and 0.6 times for 0.3 U/kg bw insulin; and to 0.2 and 0.1 times for 0.5 U/kg bw insulin respectively compared to control). Insulin treatment (0.5 U/kg bw) also significantly decreased the serum levels of pro-inflammatory cytokines (TNF-α (3.3 times) and IFN-γ (4.9 times)) whilst significantly increasing the levels of anti-inflammatory cytokines (IL-4 (4.9 fold) and IL-10 (2.1 fold)) in PbN-infected mice. Results from this study demonstrated that the cytokinemodulating effects of insulin at least in part involve inhibition of GSK3ß and consequent inhibition of the activation of NF-κB p65 suggesting insulin as a potential adjunctive therapeutic for malaria.

GSK3β: A plausible molecular target in the cytokinemodulating effect of exogenous insulin in a murine model of malarial infection

@# Malaria is a life-threatening disease caused by the Plasmodium sp. parasite. Infection results in heightened pro-inflammatory response which contributes to the pathophysiology of the disease. To mitigate the overwhelming cytokine response, host-directed therapy is a plausible approach. Glycogen synthase kinase-3β (GSK3β), a serine/threonine kinase plays a pivotal role in the regulation of inflammatory response during pathogenic infections. The present study was conducted to investigate the chemo-suppressive and cytokine-modulating effects of insulin administration in malaria-infected mice and the involvement of GSK3β. Intraperitoneal administrations of 0.3 and 0.5 U/kg body weight insulin each for four consecutive days into Plasmodium berghei NK65 (PbN)-infected mice resulted in chemo-suppression exceeding 60% and improved median survival time of infected mice (20.5 days and 19 days respectively compared to 15.5 days for non-treated control). Western analysis revealed that pGSK3β (Ser9) intensity in brain samples from insulin-treated (0.3 and 0.5 U/kg body weight) infected mice each were 0.6 and 2.2 times respectively than that in control. In liver samples, pGSK3β (Ser9) intensity from insulin-treated infected mice were significantly higher (4.8 and 16.1 fold for 0.3 and 0.5 U/kg bw respectively) than that in control. Insulin administration decreased both brain and liver pNF-κB p65 (Ser536) intensities (to 0.8 and 0.6 times for 0.3 U/kg bw insulin; and to 0.2 and 0.1 times for 0.5 U/kg bw insulin respectively compared to control). Insulin treatment (0.5 U/kg bw) also significantly decreased the serum levels of pro-inflammatory cytokines (TNF-α (3.3 times) and IFN-γ (4.9 times)) whilst significantly increasing the levels of anti-inflammatory cytokines (IL-4 (4.9 fold) and IL-10 (2.1 fold)) in PbN-infected mice. Results from this study demonstrated that the cytokinemodulating effects of insulin at least in part involve inhibition of GSK3β and consequent inhibition of the activation of NF-κB p65 suggesting insulin as a potential adjunctive therapeutic for malaria.