Honokiol-Loaded Methoxy Poly (Ethylene Glycol) Polycaprolactone Micelles for the Treatment of Age-Related Macular Degeneration.

Age-related macular degeneration (AMD), a multifactorial age-related retinal hypoxic disorder resulting in irreversible loss of vision, is the foremost cause of blindness in the United States. Current treatment strategies involve multiple intraocular injections of antivascular endothelial growth factor (VEGF) agents into the vitreous of eye. In addition to the challenges of drug localization and targeted delivery, the need of frequent injections into the eye raises patient compliance issues, and thus call for development of sustained drug delivery systems. In this study, a sustained drug delivery system was prepared by loading an antihypoxia-induced factor (HIF) agent, honokiol (HON), into methoxy poly (ethylene glycol) polycaprolactone (MPEG-PCL) polymer. These HON-MPEG-PCL micelles were characterized by evaluating size, ζ potential, in vitro drug release profile, and morphology by transmission electron microscopy. The cytotoxic nature of developed micelles was assessed on human retinal pigment epithelial cell line (ARPE-19) cells by cytotoxicity assay. The cellular uptake and HIF and VEGF expression levels were determined in in vitro settings. Micelles formed had a particle size of 30.8 ± 0.8 nm with the poly dispersity index of 0.19 ± 0.0004 and ζ potential was found to be -5.46 ± 0.49 mv. Entrapment efficiency was calculated to be 64 ± 0.135%. In vitro drug release showed sustained release of drug from the formulation. Result from in vitro cytotoxicity study confirmed noncytotoxic nature of HON-MPEG-PCL micelles compared to HON drug solution. Furthermore, enzyme-linked immunosorbent assay studies performed showed the periodic downregulation of HIF and VEGF, which are major growth factors involved in underlying mechanism of AMD. The results showed successful development of HON-MPEG-PCL micelles, which may be useful for the effective treatment of AMD.

The Role of Inflammation in Breast and Prostate Cancer Metastasis to Bone.

Tumor metastasis to bone is a common event in multiple forms of malignancy. Inflammation holds essential functions in homeostasis as a defense mechanism against infections and is a strategy to repair injured tissue and to adapt to stress conditions. However, exaggerated and/or persistent (chronic) inflammation may eventually become maladaptive and evoke diseases such as autoimmunity, diabetes, inflammatory tissue damage, fibrosis, and cancer. In fact, inflammation is now considered a hallmark of malignancy with prognostic relevance. Emerging studies have revealed a central involvement of inflammation in several steps of the metastatic cascade of bone-homing tumor cells through supporting their survival, migration, invasion, and growth. The mechanisms by which inflammation favors these steps involve activation of epithelial-to-mesenchymal transition (EMT), chemokine-mediated homing of tumor cells, local activation of osteoclastogenesis, and a positive feedback amplification of the protumorigenic inflammation loop between tumor and resident cells. In this review, we summarize established and evolving concepts of inflammation-driven tumorigenesis, with a special focus on bone metastasis.

Nanodelivery of Resveratrol-Loaded PLGA Nanoparticles for Age-Related Macular Degeneration.

Age-related macular degeneration, precisely neovascular form, is the leading cause of vision loss and the key treatment includes intravitreal injections of anti-vascular endothelial growth factor (anti-VEGF) agents. A method to increase local concentration of drug at posterior segment of the eye and to reduce the frequency of intravitreal injections is an unmet need. Resveratrol, a naturally occurring antioxidant and anti-inflammatory polyphenol, was loaded in PLGA polymeric nanoparticles to study their sustained release property and effectiveness in reducing expression of VEGF protein in vitro. Nanoparticles were characterized using FTIR, DSC, size, encapsulation efficiency, TEM, and in vitro drug release studies. Using MTT assay, the cytotoxicity of formulation was evaluated on ARPE-19 cells. The cellular uptake and VEGF expression levels were also evaluated in in vitro settings. The optimized formulation had a particle size of 102.7 nm with - 47.30 mV of zeta potential. Entrapment efficiency was found to be 65.21%. The cell viability results suggested compatibility of developed formulation. Cellular uptake and VEGF expression levels for the formulated nanoparticles specified that the developed formulation showed potential cellular uptake and had displayed anti-angiogenic property by inhibiting VEGF expression in vitro. The results showed successful development of resveratrol-loaded nanoparticles which may be used for neovascular AMD treatment alone or in combination with anti-VEGF agents.

Repeated exposure of pyriproxyfen to pregnant female mice causes developmental abnormalities in prenatal pups.

The continuous exposure to conventional pesticides leads to severe health and environmental issues especially at prenatal stage during developmental period. Herein, we aimed to investigate the anomalies due to repeated exposure of pyriproxyfen in pregnant female mice and their neonates. Twenty-four pregnant female mice were repeatedly administered with pyriproxyfen at 30, 100, 300, and 1000 mg/kg by oral gauge from gestation day (GD) 7 to gestation day 17 and six females were given distilled water in the control group. All the live pups were euthanized at postnatal day (PND) 7 and their organs (heart, liver, kidney, and brain) were dissected out, weighed, and assessed for further histopathological examinations. The results exhibited a significant (P < 0.001) decrease in the body weight gain of all treated pregnant mice in comparison to the controls and a significant increase in the gestational length was observed in group IV (P < 0.01) and group V (P < 0.001). In addition, no live pups were born in groups IV and V and one pregnant female mouse was also found dead in both treatments. The body weights of the pups were significantly decreased in group II (P < 0.05) and group III (P < 0.001) and the relative organ (liver, heart, and kidney) weight of the pups was increased significantly (P < 0.001, P < 0.01, P < 0.05) due to prenatal exposure in group II as compared to group I. The relative brain weights of the pups were decreased significantly (P < 0.001) in groups II and III as compared to group I. The liver, kidney, heart, and brain sections exhibited various histological alterations in groups II and III by hematoxylin and eosin staining. Furthermore, immunohistochemical staining of the coronal sections of pup's brain showed significant (P < 0.001) reduction in cortical radial thickness and total neural count in group II and III as compared to group I. Therefore, the prenatal exposure to pyriproxyfen provoked the damage to various organs in mice offspring and an increase in fetal death at higher doses.

Corrigendum to "Predicting entropy generation in flow of non-Newtonian flow due to a stretching sheet with chemically reactive species" [Comput. Methods Prog. Biol. 187 (2020) 105246].

This is the corrigendum to our recent published research article [1] in which the analysis of non-Newtonian fluid (Williamson model) is presented in the presence of entropy generation by a stretched surface. Total entropy rate is discussed via thermodynamics second law. The results are arranged for nonlinear ODE's through Rung Kutta integration technique with shooting method. In this communication [1] some minor typing errors are noted which is occurred during the writing and typing of momentum, energy and entropy generation. Therefore, we have rewritten the above mentioned equations in correct form in this corrigendum. Note that the updated version of manuscript does not affect the scientific and physical validity of the paper.

Predicting entropy generation in flow of non-Newtonian flow due to a stretching sheet with chemically reactive species.

BACKGROUND: We have studied the steady Darcy Forchheimer MHD generalized non-Newtonian flow of an incompressible non-linear stretched surface in the presence chemical reactive species. Darcy Forchheimer effect and chemically reactive species are considered under entropy generation. Entropy generation analysis has been essentially applied in engineering procedure in order to improve the theoretical and mathematical evaluation problems. METHOD: To approximate the entropy generation rate, the leading nonlinear equations are solved numerically by using Rung Kutta integration technique with shooting method. RESULTS: Next using the reproduction date, the entropy generation results are discussed by using theoretical and mathematical approaches. The numerical results acquired for different physical mechanism are exposing through graphs and tables. CONCLUSIONS: The physical effects of nanomaterials, skin friction coefficient, heat transfer, mass transfer and entropy generation have been illustrated for different values of involved parameters such as the Weissenberg number, magnetic field parameter, porous medium parameter, the Darcy parameter, the Lewis number, thermophoresis diffusion, the Brownian motion parameter, chemical reaction parameter and the Prandtl number. The numerical results acquired for different physical mechanism are exposing through graphs and tables.

NADPH oxidase 4 mediates the protective effects of physical activity against obesity-induced vascular dysfunction.

AIMS: Physical activity is one of the most potent strategies to prevent endothelial dysfunction. Recent evidence suggests vaso-protective properties of hydrogen peroxide (H2O2) produced by main endothelial NADPH oxidase isoform 4 (Nox4) in the vasculature. Therefore, we hypothesized that Nox4 connects physical activity with vaso-protective effects. METHODS AND RESULTS: Analysis of the endothelial function using Mulvany Myograph showed endothelial dysfunction in wild-type (WT) as well as in C57BL/6J/ Nox4-/- (Nox4-/-) mice after 20 weeks on high-fat diet (HFD). Access to running wheels during the HFD prevented endothelial dysfunction in WT but not in Nox4-/- mice. Mechanistically, exercise led to an increased H2O2 release in the aorta of WT mice with increased phosphorylation of eNOS pathway member AKT serine/threonine kinase 1 (AKT1). Both H2O2 release and phosphorylation of AKT1 were diminished in aortas of Nox4-/- mice. Deletion of Nox4 also resulted in lower intracellular calcium release proven by reduced phenylephrine-mediated contraction, whilst potassium-induced contraction was not affected. H2O2 scavenger catalase reduced phenylephrine-induced contraction in WT mice. Supplementing H2O2 increased phenylephrine-induced contraction in Nox4-/- mice. Exercise-induced peroxisome proliferative-activated receptor gamma, coactivator 1 alpha (Ppargc1a), as key regulator of mitochondria biogenesis in WT but not Nox4-/- mice. Furthermore, exercise-induced citrate synthase activity and mitochondria mass were reduced in the absence of Nox4. Thus, Nox4-/- mice became less active and ran less compared with WT mice. CONCLUSIONS: Nox4 derived H2O2 plays a key role in exercise-induced adaptations of eNOS and Ppargc1a pathway and intracellular calcium release. Hence, loss of Nox4 diminished physical activity performance and vascular protective effects of exercise.

An investigation on some toxic effects of pyriproxyfen in adult male mice.

OBJECTIVES: Pyriproxyfen as an insect growth regulator is widely used globally for pest management. There are reports on adverse effects of insecticides such as organ toxicity, endocrine disruptions, and teratogenicity in animals and humans. We aimed to investigate reproductive toxicity of pyriproxyfen in adult male mice. MATERIALS AND METHODS: 48 male Swiss albino mice were divided into eight groups and received the different 1200, 600, 320, 200, 100, 40, 20, 0 mg/kg/day doses orally, and body weights were accessed for 28 consecutive days. In the end, mice were sacrificed, testes were dissected and weighed. Probable testicular tissue alterations were examined by histopathological studies. In addition, the diameter of seminiferous tubules and Leydig cells distribution were assessed in all experimental and control groups. RESULTS: Pyriproxyfen treatment caused significant (P<0.05) reduction in body and organ weights in mice. However, the shrinkage and displacement of seminiferous tubules, reduced lumen diameter, and vacuolization occurred in seminiferous tubules in higher doses exposed animals in comparison to controls. The relative testis weights, mean diameter of seminiferous tubules, and Leydig cells distribution remained unchanged at low doses. CONCLUSION: These findings reveal that pyriproxyfen caused reduction in body weight gain as well as damage to the testicular architecture in mice and thus may potentially interfere with spermatogenesis. Findings in an outbred strain of mice can be extrapolated fairly reliably to the human model. The chemical can thus be further exploited to study its effects on impairment of fertility and as an endocrine disruptor.

A Commentary on Telerehabilitation Services in Pakistan: Current Trends and Future Possibilities.

A 2014 World Health Organization (WHO) study reported that almost 27 million people with disability live in Pakistan with fewer than one allied rehabilitation professional per 10,000 people. The current study sought to determine the attitudes toward telerehabilitation via a survey administered to 329 Pakistani rehabilitation professionals. Study results indicate that rehabilitation professionals in Pakistan are knowledgeable about telerehabilitation and Information and Communication Technology (ICT), and are receptive to employing telerehabilitation programs and applications. Therefore, we can infer that the future of telerehabilitation can be bright in Pakistan but requires the attention of policy makers and non-government organizations to launch an appropriate program nationwide. The authors suggest that a range of telerehabilitation services (e.g., consultation, assessment, and therapy) could alleviate the shortage of rehabilitation personnel in Pakistan.

Teaching strategies and academic performances of undergraduates in quaid-I-azam medical college, bahawalpur.

OBJECTIVE: to assess the outcomes and competencies of medical undergraduates regarding their learning abilities after introducing Clinical Presentation Curriculum (CPC) instead of Traditional Curriculum in Quaid-i-Azam Medical College, Bahawalpur. DESIGN: a cross-sectional comparative study. PLACE AND DURATION OF STUDY: 3rd and 4th year MBBS class during session 2004-2005 at Quaid-i-Azam Medical College (QMC), Bahawalpur. SUBJECTS AND METHODS: Five hundred students of 3rd year and 4th year MBBS who were taught for 176 and 172 hours respectively, appeared in 20 tests during session 2004-2005, were included in the study. Students were taught pathology according to Traditional Curricular model for 88 and 86 hours, respectively during college hours. Ten class tests each of 3rd and 4th year MBBS were taken and scores recorded. In the next step, the same group of students were taught in accordance with CPC model for 88 and 86 hours respectively in college hours. Ten class tests each were taken and scores recorded. A standardized questionnaire was given to all 500 students after finishing with each curricular model and then the results were compared on SPSS 8.0 regarding their study trends, thinking abilities, intellectual skills and liking of CPC. Chi-square test was used to get significance values and percentages were used for the evaluation of differences. RESULTS: This study detected the positive effects of CPC model not only on study trends and thought process but also had the beneficial effects on learning potential of students in QMC where traditional curriculum was being followed for teaching students. When compared with traditional curricula, CPC model significantly ( p =< 0.01) improved the learning methods to improve knowledge and intellectual skills e.g; group discussions, internet use, reading latest and relevant journals and visits to wards and concerned teachers. Academic performances of these students significantly (p =< 0.01) improved regarding their class test attendance, class room attendance and marks obtained in tests when compared with traditional curricula. Similarly, there was significant (p =< 0.01) increase in divergent thinkers. CONCLUSION: CPC, introduced in 3rd and 4th year MBBS of QMC, Bahawalpur, with traditional curriculum, significantly improved the academic performance, learning behaviour and intellectual skills of students.

Estrogen replacement therapy for depression in perimenopausal women.

OBJECTIVE: To determine the effect of a four-week course of oral estrogen therapy on depression in aging women. DESIGN: Quasi experimental. PLACE AND DURATION OF STUDY: The OPD, Bahawal Victoria Hospital, Bahawalpur, from September 2000 to January 2004. PATIENTS AND METHODS: Forty-two depressed women (aged 42-57) who were either perimenopausal (n = 20) or postmenopausal (n = 22) received open label treatment with oral estrogen tablets (1.25 mg/day) for 4 weeks. The Montgomery-Asberg Depression Rating Scale and the Beck Depression Inventory were used to assess depressive symptoms, the Greene Climacteric Scale was used to assess menopause-related symptoms, and the Clinical Global Impression(CGI) was used to assess global clinical improvement in these women at baseline and after treatment. Remission of depression was defined as a score < 10 on the Montgomery-Asberg Depression Rating Scale and a score < or = 2 on the CGI at week 4. RESULTS: The women who completed the study had a median Montgomery-Asberg Depression Rating Scale score of 20 (range = 15-32) at study entry and 11.50 (range = 10-31.0) at week 4 (z = -3.43, p < 0.01). This improvement was consistent with that reported by the women themselves on the Beck Depression Inventory (rs = 0.86, n = 20, p < 0.01). The improvement measured by CGI scores was also significant (p < 0.01). Remission of depression was noted in 5 of the 40 women (after 1 year) who completed the study. Anti-depressant response was not associated with severity or subtypes of depression at study entry or with concomitant improvement in menopause-related symptoms. CONCLUSION: Perimenopausal and postmenopausal women benefit from short-term use of estrogen therapy. Antidepressant effect of estrogen therapy is independent of improvement in menopause-related symptoms.

Effect of pregnancy on diabetic nephropathy and retinopathy.

OBJECTIVE: To determine whether pregnancy worsens renal function in women with diabetic nephropathy and the effect of pregnancy on diabetic retinopathy. DESIGN: Cross-sectional analytical study. PLACE AND DURATION OF STUDY: The study was conducted in OPD, Bahawal Victoria Hospital, Bahawalpur from September 1997 to June 2003. SUBJECTS AND METHODS: Thirty-five patients (aged 20-36 years ) identified with diabetic nephropathy and moderate to severe renal dysfunction(creatinine [Cr] > 1.4 mg/dl) at pregnancy onset by retrospective chart review. Alterations in glomerular filtration rate (GFR) were estimated. An equal number of non-pregnant premenopausal type I diabetic women with similar degrees of renal dysfunction served as controls for non-pregnant rate of decline of renal function and potential contributing factors. Student's t-test and repeated measures analysis of variance were analyzed. RESULTS: Mean serum Cr rose from 1.8 mg/dl prepregnancy to 2.5 mg/dl in the third trimester. Renal function was stable in 27%, showed transient worsening in pregnancy in 27%, and demonstrated a permanent decline in 45%. Proteinuria increased in pregnancy in 79%. Exacerbation of hypertension or pre-eclampsia occurred in 73% and 71% of these showed acceleration of disease during the pregnancy. All the patients had diabetic retinopathy, though proliferative retinopathy was diagnosed and treated in only 54.5.% prepregnancy. The retinopathy progressed, requiring laser therapy, in 45.4%. Macular edema was noted in 6 of the patients. Other diabetic complications included peripheral and autonomic neuropathy in 8 patients. CONCLUSION: Pregnancy induced progression is seen in the decline of renal functions. Patients with diabetic nephropathy were found to have a > 40% chance of accelerated progression of their disease as a result of pregnancy. Forty-five percent of the patients had permanent decline in GFR in association with pregnancy.