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Rajiv Bajracharya,* Kshitis Chandra Baral,* Sang Hoon Lee, Jae Geun Song, Hyo-Kyung Han College of Pharmacy, Dongguk University-Seoul, Goyang, Korea*These authors contributed equally to this workCorrespondence: Hyo-Kyung Han, College of Pharmacy, Dongguk University-Seoul, Dongguk-ro-32, Ilsan-Donggu, Goyang, Korea, Tel +82-31-961-5217, Fax +82-31-961-5206, Email hkhan@dongguk.eduPurpose: Oral administration, although convenient and preferred for treating colorectal cancer (CRC), faces challenges due to limited CRC-related intestinal positioning and a dense mucus barrier. In the present study, a gold-nanoparticle decorated–organometallic phyllosilicate nanocomposite (AC-Au), with a pH-dependent surface coating, was employed for more effective oral delivery of anticancer drugs to treat CRC.Methods: The organometallic AC-Au was synthesized using the in-situ sol-gel method. Subsequently, methotrexate (MTX) was loaded into AC-Au, and the complex (AC-Au/MTX) was surface-coated with poly (methacrylic acid-co-methyl methacrylate) (1:2), a pH-dependent polymer (E/AC-Au /MTX). The in vitro characteristics of nanoparticles were examined using various analytical methods. In vivo efficacy studies were also conducted using an HCT-116 orthotopic colorectal cancer model.Results: AC-Au emerged as a spherical nanoparticle with a mean size of 26.5 ± 0.43 nm, displaying a positive charge over the pH range of 2– 10. Both the uncoated and coated drug–loaded nanocomplexes (AC-Au/MTX and E/AC-Au/MTX) were fabricated with high entrapment efficiency (> 80%). Various analyses, including ultraviolet-visible spectroscopy, X-ray powder diffraction, transmission electron microscopy, and energy dispersive X-ray spectroscopy, confirmed the formation of the nanocomplexes. While AC-Au/MTX achieved rapid and extensive drug release at the pH range of 1.2– 7.4, E/AC-Au/MTX exhibited pH-dependent drug release, with approximately 23% at pH 1.2 and 74% at pH 7.4. Relative to free MTX, the AC-Au-based nanocomplex significantly enhanced the cytotoxicity of MTX in HCT-116 cells. Furthermore, orally administered E/AC-Au/MTX significantly improved the anti-tumor activity of MTX in an HCT-116 orthotopic colorectal cancer model, resulting in approximately 60% suppression of tumor mass compared with the positive control.Conclusion: The organometallic AC-Au nanocomplex coated with a pH-dependent polymer has the potential to be an effective colonic drug delivery system of MTX, enhancing in vivo efficacy against colorectal cancer.Keywords: methotrexate, aminoclay, gold nanoparticle, colonic delivery, cytotoxicity

Kshitis Chandra Baral, Rajiv Bajracharya, Sang Hoon Lee, Hyo-Kyung Han BK21 FOUR Team and Integrated Research Institute for Drug Development, College of Pharmacy, Dongguk University-Seoul, Goyang, 10326, KoreaCorrespondence: Hyo-Kyung HanBK21 FOUR Team, College of Pharmacy, Dongguk University-Seoul, Dongguk-ro-32, Ilsan-Donggu, Goyang, 10326, KoreaTel +82-31-961-5217Fax +82-31-961-5206Email hkhan@dongguk.eduAbstract: Probiotics have demonstrated their high potential to treat and/or prevent various diseases including neurodegenerative disorders, cancers, cardiovascular diseases, and inflammatory diseases. Probiotics are also effective against multidrug-resistant pathogens and help maintain a balanced gut microbiota ecosystem. Accordingly, the global market of probiotics is growing rapidly, and research efforts to develop probiotics into therapeutic adjuvants are gaining momentum. However, because probiotics are living microorganisms, many biological and biopharmaceutical barriers limit their clinical application. Probiotics may lose their activity in the harsh gastric conditions of the stomach or in the presence of bile salts. Moreover, they easily lose their viability under thermal or oxidative stress during their preparation and storage. Therefore, stable formulations of probiotics are required to overcome the various physicochemical, biopharmaceutical, and biological barriers and to maximize their therapeutic effectiveness and clinical applicability. This review provides an overview of the pharmaceutical applications of probiotics and covers recent formulation approaches to optimize the delivery of probiotics with particular emphasis on various dosage forms and formulation technologies.Keywords: probiotic, therapeutic adjuvant, formulation, drug delivery system, gut microbiota

Introduction: Functional performance measures (grip strength, Short Physical Performance Battery (SPPB), and 3-meter gait speed) represent underlying disease progression and predict mortality. However, there is little information regarding whether these measures assessed at 2-months post-hip fracture predict long-term mortality (10-year follow-up). Methods: To address this gap, a longitudinal analysis of Baltimore Hip Studies-7 cohort, with mortality verified by National Death Index, was conducted. Mean difference in 2-month functional performance measures (n = 242, men n = 121, female n = 121) among those who survived and did not survive over 10 years was determined using t-test. Prediction of mortality by these measures, overall and by sex, was estimated using cox proportional hazard models, for which Hazard ratios (HR) with 95% confidence intervals (CI) were estimated. Results: We found that, gait speed [0.47 (standard deviation, SD = 0.39) versus 0.31(SD = 0.27)] and SPPB score [4.89(SD = 3.31) versus 2.83(SD = 2.24)] were significantly higher at 2 months among those surviving compared to those who did not. Adjusting for covariates, functional performance predicted long-term mortality in men and women. Increase in gait speed by 0.1m/s predicted 15% decrease in mortality for men [HR = 0.85(0.55-0.96)] and 17% for women [HR = 0.83 (0.74-0.93)]. Increase in SPPB by 1 unit predicted decrease in mortality by 14% for men [HR = 0.86(0.77-0.95)] and 17% for women [HR = 0.83(0.74-0.93). Increase in grip strength by 1 kg predicted 5% decrease in mortality for men [HR = 0.94 (0.92-0.97)] and 9% for women [HR = 0.90 (0.86-0.95)]. Conclusion: Functional performance measured at 2-months post-hip fracture predicted long-term mortality. Those with poor functional performance at 2-months can be referred for further assessment to optimize their care to promote survival. [ABSTRACT FROM AUTHOR]

Introduction: Mortality after hip fracture remains high, approximately 30% in the first three months. Males are known to have worse mortality outcomes overall and among hip fracture patients compared to females. Infection and Alzheimer's disease and related dementia (ADRD) are among the top three causes of death among hip fracture patients. This study aimed to measure sex differences in survival time and mortality risk among hip fracture patients who died of infection- or cognition-related causes of death (COD). Methods: Patients, age 65 and older, were recruited within 15 days of hospitalization for surgical repair of hip fracture (2006-2011). COD and date of death were derived from the National Death Index (December 2018). Complete cases(N = 330; 145 Male, 155 Female) were assessed using Cox Proportional Hazards models to determine the adjusted Hazard Ratio(HR) for all-cause and cause-specific mortality risk by patient sex; adjusted for age, education, comorbidities, depression, and American Society of Anesthesiologists Physical Status Rating. Results: The sample was majority white with a mean age of 80.8 (7.7) years, and approximately 50% female. There was not a significant age difference between males and females. Median overall survival time was 46.7 months (42.3 males, 54.6 females). Of the 267 reported deaths 62 (30 male, 32 female) were cognition-related, and 38 (25 male, 13 female) were infection-related with 6 (4 male, 2 female) cross-over cases. Median survival time for cognition-related COD was 54.2 months (43.8 male, 61.7 female) and was 25.3 months for infection-related COD(17.0 male, 54.6 female). Males had significantly greater risk of all-cause mortality (HR = 4.8, 95% CL: 2.5, 9.4). Males were also at increased risk for cognition-(HR = 1.60, 95% CL: 1.2, 2.2) and infection-related COD (HR = 1.5, 95% CL: 1.1, 2.1) in both crude and adjusted analyses. Conclusion: Known sex differences in mortality risk after hip fracture remain. Within the most common causes of death there are increased risks of mortality for males compared to females after hip fracture. While males had increased mortality risk in all conditions, median time to death was noticeably shorter for infection-related COD. These findings continue to highlight the negative outcomes for males after hip fracture. Despite the increased risk there are positive aspects to this work including that median time to death was still multiple months after the initial fracture and could mean that there is room for survival extending measures to be employed. [ABSTRACT FROM AUTHOR]

Introduction: Physical performance measures are the cornerstone for identifying older adults at a greater risk of poor outcomes like hospitalization and disability. However, the utility of physical performance measures to predict recovery after a sudden mobility disablement such as hip fracture is unclear. The objective of this analysis was to assess whether physical performance at 2 months post hip fracture can predict functional recovery one year post fracture independent of variables available from the medical chart and self-report. Methods: The study population includes participants enrolled in the Baltimore Hip Studies7th cohort (n = 339). The study endpoint was participants' self-reported ability to walk one block. Candidate predictors of this endpoint were: 1) physical performance [Short Physical Performance Battery (SPPB), gait speed, and grip strength], 2) medical abstract variables [sex, age, ASA (American Society of Anesthesiologist) physical status rating, fracture type, surgery procedure, and comorbidities], and 3) self-reported walking (ability to walk 10 feet and 1 block pre-fracture and at 2 months). The most important predictors of functional recovery at 12 months were identified by two different methods: (1) Logistic regression followed by area under the ROC curve and Hosmer and Lemeshow goodness-of-fit test for discrimination and calibration, respectively, and (2) Classification and Regression Tree Analysis. Results: The analytic sample comprised 162 participants with complete data. Mean age was 81 years. In the fully adjusted model only 2-month SPPB score (OR = 1.59, CI = 1.25-2.02), self-reported pre-fracture ability to walk a block (OR = 4.35, CI = 1.44-13.11), and 2-month ability to walk 10 feet (OR = 3.24, CI = 1.29-8.14) predicted ability to walk a block at 12 months. The model performed well with an area under ROC curve of 0.88 and had a good fit (Hosmer and Lemeshow Chi-square p-value = 0.77). The CART model showed that individuals with a 2-month SPPB score ≥ 3 had a 71% probability of being able to walk a block at 12 months compared to only 15% probability for those who score less than 3. Conclusion: Measuring SPPB at 2 months post hip fracture in the clinical setting may facilitate a more accurate assessment of long-term functional recovery compared to typical medical status variables. [ABSTRACT FROM AUTHOR]

Introduction: Gestational hypertension and preeclampsia are the most common types of hypertensive disorder in pregnancy and these conditions are associated with adverse maternal and fetal outcomes. This study aims to determine the differences in pregnancy outcomes in women with gestational hypertension and preeclampsia., Methods: A retrospective study was done at The Paropakar Maternity and Women's Hospital, a tertiary level hospital, in the Kathmandu, Nepal. Pregnant women who had given birth at the hospital between September 17 and December 18 of 2017 were included. Data were obtained from the non-digitalized hospital records. The adjusted odds ratio (AOR) and 95% confidence interval were computed using logistic regression analysis. Multivariable analysis of pregnancy outcomes (cesarean sections, low birth weight, and preterm birth) was adjusted for maternal age, parity, twin birth, gestational age, calcium supplementation, and maternal co-morbidity., Results: Preeclampsia was strongly associated with cesarean section compared to normal pregnancies (OR = 8.11, p<0.001). Whereas the odds of cesarean section among women with gestational hypertension was almost 2 times (OR = 1.89, p<0.001). Preterm birth was not significantly associated with gestational hypertension but was associated with preeclampsia (OR = 3.39, p<0.001). Gestational hypertension and preeclampsia were not associated with low birth weight., Conclusion: In Nepal, women who develop preeclampsia seem at higher risk of having adverse pregnancy outcomes than women with gestational hypertension. These findings should be considered by national health authorities and other health organizations when setting new priorities to improve pregnancy outcomes., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Das et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Severe respiratory infections can result in acute respiratory distress syndrome (ARDS) 1 . There are no effective pharmacological therapies that have been shown to improve outcomes for patients with ARDS. Although the host inflammatory response limits spread of and eventually clears the pathogen, immunopathology is a major contributor to tissue damage and ARDS 1,2 . Here we demonstrate that respiratory viral infection induces distinct fibroblast activation states, which we term extracellular matrix (ECM)-synthesizing, damage-responsive and interferon-responsive states. We provide evidence that excess activity of damage-responsive lung fibroblasts drives lethal immunopathology during severe influenza virus infection. By producing ECM-remodelling enzymes-in particular the ECM protease ADAMTS4-and inflammatory cytokines, damage-responsive fibroblasts modify the lung microenvironment to promote robust immune cell infiltration at the expense of lung function. In three cohorts of human participants, the levels of ADAMTS4 in the lower respiratory tract were associated with the severity of infection with seasonal or avian influenza virus. A therapeutic agent that targets the ECM protease activity of damage-responsive lung fibroblasts could provide a promising approach to preserving lung function and improving clinical outcomes following severe respiratory infections.

Adipokines secreted from adipose tissue are key regulators of metabolism in animals. Adiponectin, one of the adipokines, modulates pancreatic beta cell function to maintain energy homeostasis. Recently, significant conservation between Drosophila melanogaster and mammalian metabolism has been discovered. Drosophila insulin like peptides (Dilps) regulate energy metabolism similarly to mammalian insulin. However, in Drosophila, the regulatory mechanism of insulin producing cells (IPCs) by adipokine signaling is largely unknown. Here, we describe the discovery of the Drosophila adiponectin receptor and its function in IPCs. Drosophila adiponectin receptor (dAdipoR) has high homology with the human adiponectin receptor 1. The dAdipoR antibody staining revealed that dAdipoR was expressed in IPCs of larval and adult brains. IPC- specific dAdipoR inhibition (Dilp2>dAdipoR-Ri) showed the increased sugar level in the hemolymph and the elevated triglyceride level in whole body. Dilps mRNA levels in the Dilp2>dAdipoR-Ri flies were similar with those of controls. However, in the Dilp2>dAdipoR-Ri flies, Dilp2 protein was accumulated in IPCs, the level of circulating Dilp2 was decreased, and insulin signaling was reduced in the fat body. In ex vivo fly brain culture with the human adiponectin, Dilp2 was secreted from IPCs. These results indicate that adiponectin receptor in insulin producing cells regulates insulin secretion and controls glucose and lipid metabolism in Drosophila melanogaster. This study demonstrates a new adipokine signaling in Drosophila and provides insights for the mammalian adiponectin receptor function in pancreatic beta cells, which could be useful for therapeutic application.