Effects of Cannabidiol, ∆9-Tetrahydrocannabinol, and WIN 55-212-22 on the Viability of Canine and Human Non-Hodgkin Lymphoma Cell Lines.

In our previous study, we demonstrated the impact of overexpression of CB1 and CB2 cannabinoid receptors and the inhibitory effect of endocannabinoids (2-arachidonoylglycerol (2-AG) and Anandamide (AEA)) on canine (Canis lupus familiaris) and human (Homo sapiens) non-Hodgkin lymphoma (NHL) cell lines' viability compared to cells treated with a vehicle. The purpose of this study was to demonstrate the anti-cancer effects of the phytocannabinoids, cannabidiol (CBD) and ∆9-tetrahydrocannabinol (THC), and the synthetic cannabinoid WIN 55-212-22 (WIN) in canine and human lymphoma cell lines and to compare their inhibitory effect to that of endocannabinoids. We used malignant canine B-cell lymphoma (BCL) (1771 and CLB-L1) and T-cell lymphoma (TCL) (CL-1) cell lines, and human BCL cell line (RAMOS). Our cell viability assay results demonstrated, compared to the controls, a biphasic effect (concentration range from 0.5 µM to 50 µM) with a significant reduction in cancer viability for both phytocannabinoids and the synthetic cannabinoid. However, the decrease in cell viability in the TCL CL-1 line was limited to CBD. The results of the biochemical analysis using the 1771 BCL cell line revealed a significant increase in markers of oxidative stress, inflammation, and apoptosis, and a decrease in markers of mitochondrial function in cells treated with the exogenous cannabinoids compared to the control. Based on the IC50 values, CBD was the most potent phytocannabinoid in reducing lymphoma cell viability in 1771, Ramos, and CL-1. Previously, we demonstrated the endocannabinoid AEA to be more potent than 2-AG. Our study suggests that future studies should use CBD and AEA for further cannabinoid testing as they might reduce tumor burden in malignant NHL of canines and humans.

Evaluate the in vitro effect of anthracycline and alkylating cytophosphane chemotherapeutics on dopaminergic neurons.

BACKGROUND: Iatrogenesis is an inevitable global threat to healthcare that drastically increases morbidity and mortality. Cancer is a fatal pathological condition that affects people of different ages, sexes, and races around the world. In addition to the detrimental cancer pathology, one of the most common contraindications and challenges observed in cancer patients is severe adverse drug effects and hypersensitivity reactions induced by chemotherapy. Chemotherapy-induced cognitive neurotoxicity is clinically referred to as Chemotherapy-induced cognitive impairment (CICI), chemobrain, or chemofog. In addition to CICI, chemotherapy also causes neuropsychiatric issues, mental disorders, hyperarousal states, and movement disorders. A synergistic chemotherapy regimen of Doxorubicin (Anthracycline-DOX) and Cyclophosphamide (Alkylating Cytophosphane-CPS) is indicated for the management of various cancers (breast cancer, lymphoma, and leukemia). Nevertheless, there are limited research studies on Doxorubicin and Cyclophosphamide's pharmacodynamic and toxicological effects on dopaminergic neuronal function. AIM: This study evaluated the dopaminergic neurotoxic effects of Doxorubicin and Cyclophosphamide. METHODS AND RESULTS: Doxorubicin and Cyclophosphamide were incubated with dopaminergic (N27) neurons. Neuronal viability was assessed using an MTT assay. The effect of Doxorubicin and Cyclophosphamide on various prooxidants, antioxidants, mitochondrial Complex-I & IV activities, and BAX expression were evaluated by Spectroscopic, Fluorometric, and RT-PCR methods, respectively. Prism-V software (La Jolla, CA, USA) was used for statistical analysis. Chemotherapeutics dose-dependently inhibited the proliferation of the dopaminergic neurons. The dopaminergic neurotoxic mechanism of Doxorubicin and Cyclophosphamide was attributed to a significant increase in prooxidants, a decrease in antioxidants, and augmented apoptosis without affecting mitochondrial function. CONCLUSION: This is one of the first reports that reveal Doxorubicin and Cyclophosphamide induce significant dopaminergic neurotoxicity. Thus, Chemotherapy-induced adverse drug reaction issues substantially persist during and after treatment and sometimes never be completely resolved clinically. Consequently, failure to adopt adequate patient care measures for cancer patients treated with certain chemotherapeutics might substantially raise the incidence of numerous movement disorders.

Cellular interactions in tumor microenvironment during breast cancer progression: new frontiers and implications for novel therapeutics.

The breast cancer tumor microenvironment (TME) is dynamic, with various immune and non-immune cells interacting to regulate tumor progression and anti-tumor immunity. It is now evident that the cells within the TME significantly contribute to breast cancer progression and resistance to various conventional and newly developed anti-tumor therapies. Both immune and non-immune cells in the TME play critical roles in tumor onset, uncontrolled proliferation, metastasis, immune evasion, and resistance to anti-tumor therapies. Consequently, molecular and cellular components of breast TME have emerged as promising therapeutic targets for developing novel treatments. The breast TME primarily comprises cancer cells, stromal cells, vasculature, and infiltrating immune cells. Currently, numerous clinical trials targeting specific TME components of breast cancer are underway. However, the complexity of the TME and its impact on the evasion of anti-tumor immunity necessitate further research to develop novel and improved breast cancer therapies. The multifaceted nature of breast TME cells arises from their phenotypic and functional plasticity, which endows them with both pro and anti-tumor roles during tumor progression. In this review, we discuss current understanding and recent advances in the pro and anti-tumoral functions of TME cells and their implications for developing safe and effective therapies to control breast cancer progress.

An evaluation of the combination effect of zoledronate and chemotherapeutic agents in canine osteosarcoma cells.

Introduction: Osteosarcoma (OSA) is an aggressive form of bone cancer in both dogs and humans. The treatment options for metastatic (stage III) OSA are currently limited and the prognosis is poor. Zoledronate, a second generation amino-bisphosphonate, is commonly used for palliation of cancer induced bone pain. Zoledronate has also demonstrated anti-cancer properties and possibly enhances the cytotoxicity of doxorubicin in a canine histiocytosis cell line and human prostatic cancer cell line. The goal of this study was to evaluate the combination effect of zoledronate and various chemotherapeutic drugs in canine OSA cells. Methods: Canine OSA cell line (D17), cells from two canine primary OSAs, and MDCK, a canine kidney cell line, were used to evaluate the therapeutic potential of these drugs. Carboplatin, doxorubicin, vinorelbine, toceranib, and isophosphoramide mustard (active metabolite of ifosfamide) were used as chemotherapeutic agents. First, cells were treated with either zoledronate or chemotherapy drug alone for 72 hours. Cell viability was assessed using CellTiter Glo and IC5, IC10, IC20, and IC50 were calculated. Second, cells were treated with a combination of zoledronate and each chemotherapeutic agent at their IC5, IC10, IC20, and IC50 concentrations. After 72 hours, cell viability was assessed by CellTiter Glo. Results and discussion: Zoledronate, carboplatin, doxorubicin, vinorelbine, and isophosphoramide mustard showed concentration dependent decrease in cell viability. Toceranib showed decreased cell viability only at higher concentrations. When zoledronate was used in combination with chemotherapy drugs, while it showed potential synergistic effects with toceranib, potential antagonistic effects with vinorelbine and isophosphoramide mustard were observed. However, the results differed by cell line and thus, further evaluation is warranted to understand the exact mechanism of action.

Augmentation of Docetaxel-Induced Cytotoxicity in Human PC-3 Androgen-Independent Prostate Cancer Cells by Combination With Four Natural Apoptosis-Inducing Anticancer Compounds.

Docetaxel (DTX) is the treatment of choice for metastatic castration-resistant prostate cancer. However, developing drug resistance is a significant challenge for achieving effective therapy. This study evaluated the anticancer and synergistic effects on DTX of four natural compounds (calebin A, 3'-hydroxypterostilbene, hispolon, and tetrahydrocurcumin) using PC-3 androgen-resistant human prostate cancer cells. We utilized the CellTiter-Glo® luminescent cell viability assay and human PC-3 androgen-independent prostate cancer cells to determine the antiproliferative effects of the four compounds alone and combined with DTX. Cytotoxicity to normal human prostate epithelial cells was tested in parallel using normal immortalized human prostate epithelial cells (RWPE-1). We used cell imaging and quantitative caspase-3 activity to determine whether these compounds induce apoptosis. We also measured the capacity of each drug to inhibit TNF-α-induced NF-kB using a colorimetric assay. Our results showed that all four natural compounds significantly augmented the toxicity of DTX to androgen-resistant PC-3 prostate cancer cells at IC50. Interestingly, when used alone, each of the four compounds had a higher cytotoxic activity to PC-3 than DTX. Mechanistically, these compounds induced apoptosis, which we confirmed by cell imaging and caspase-3 colorimetric assays. Further, when used either alone or combined with DTX, the four test compounds inhibited TNF-α-induced NF-kB production. More significantly, the cytotoxic effects on normal immortalized human prostate epithelial cells were minimal and non-significant, suggesting prostate cancer-specific effects. In conclusion, the combination of DTX with the four test compounds could effectively enhance the anti-prostate cancer activity of DTX. This combination has the added value of reducing the DTX effective concentration. We surmise that calebin A, 3'-hydroxypterostilbene, hispolon, and tetrahydrocurcumin were all excellent drug candidates that produced significant antiproliferative activity when used alone and synergistically enhanced the anticancer effect of DTX. Further in vivo studies using animal models of prostate cancer are needed to confirm our in vitro findings.

Prevalence and Risk Factors for Iatrogenic Opioid Withdrawal in Medical Critical Care Patients.

Opioids are the mainstay of pain management and sedation in critically ill patients, which can lead to the development of physiologic tolerance and dependency. The prevalence of iatrogenic opioid withdrawal syndrome (IWS) is reported as 17-32% in the ICU; however, limited evidence exists for the medical ICU patient population. OBJECTIVES: To identify the and risk factors for IWS in adult patients admitted to critical care medicine services who received greater than or equal to 24 hours of continuous opioid infusion therapy. DESIGN SETTING AND PARTICIPANTS: A prospective, observational study was conducted in a tertiary care hospital in adult medical ICU patients. Ninety-two patients who received greater than or equal to 24 hours of continuous opioid infusions were included in the study. MAIN OUTCOMES AND MEASUREMENTS: Patients were assessed daily after opioid infusion discontinuation using the Clinical Opiate Withdrawal Scale (COWS) and the Diagnostic and Statistical Manual of Mental Disorders (DSM-V) opioid withdrawal criteria for a maximum of 5 days. The primary outcome was the prevalence of IWS of moderate severity or greater using COWS. Secondary outcomes included the prevalence of IWS diagnosis of any severity based on COWS, the prevalence of IWS diagnosis based on a positive DSM-V score, and the identification of potential risk factors for developing IWS of any severity. RESULTS: Four hundred forty-seven patients received greater than or equal to 24 hours of continuous opioid therapy. Of these, 385 were excluded, leaving 92 patients included in the final analysis. Except for a higher prevalence of psychiatric history in the IWS-positive group, baseline characteristics were similar. Overall, 11 patients (12%) developed IWS of moderate severity or greater, based on COWS. The IWS-positive group also had longer durations of opioid infusions, higher cumulative opioid infusion doses, higher mean daily doses, and higher infusion rates at any given time. The concomitant use of dexmedetomidine (38.3 vs 15.6%, p = 0.014) and benzodiazepines (63.8 vs 37.8%, p = 0.021) during or after the opioid infusion were significantly higher in the IWS-positive group compared with the IWS-negative group. No significant differences were found between the two groups for scheduled or as needed opioids after cessation of the opioid infusion. Continuous opioid infusions greater than or equal to 72 hours and total daily dose greater than or equal to 1,200 µg were found to be independent predictors for the development of iatrogenic opioid withdrawal via logistic regression. CONCLUSIONS AND RELEVANCE: Approximately one in every eight patients receiving continuous infusion opioid for greater than 24 hours while mechanically ventilated in the medical ICU will develop IWS of moderate severity or greater; this increases to one in three patients diagnosed with DSM-V criteria or any level of IWS severity. Patients receiving opioid infusions greater than or equal to 72 hours, or a total daily fentanyl dose of greater than or equal to 1,200 µg (~ 50 µg/hr) are at a higher risk for developing IWS and should be monitored as part of clinical practice when opioid infusions are discontinued.

Effects of developmental exposures to Bisphenol-A and Bisphenol-S on hepatocellular function in male Long-Evans rats.

Bisphenol-S (BPS) is a current substitute for Bisphenol-A (BPA) in various commercial products (paper, plastics, protective can-coatings, etc.) used by all age groups globally. The current literature indicates that a drastic surge in pro-oxidants, pro-apoptotic, and pro-inflammatory biomarkers in combination with diminished mitochondrial activity can potentially decrease hepatic function leading to morbidity and mortality. Consequently, there are increasing public health concerns that substantial Bisphenol-mediated effects may impact hepatocellular functions, particularly in newborns exposed to BPA and BPS postnatally. However, the acute postnatal impact of BPA and BPS and the molecular mechanisms affecting hepatocellular functions are unknown. Therefore, the current study investigated the acute postnatal effect of BPA and BPS on the biomarkers of hepatocellular functions, including oxidative stress, inflammation, apoptosis, and mitochondrial activity in male Long-Evans rats. BPA and BPS (5 and 20 microgram/Liter (µg/L) of drinking water) were administered to 21-day-old male rats for 14 days. BPS had no significant effect on apoptosis, inflammation, and mitochondrial function but significantly reduced the reactive oxygen species (51-60 %, **p < 0.01) and nitrite content (36 %, *p < 0.05), exhibiting hepatoprotective effects. As expected, based on the current scientific literature, BPA induced significant hepatoxicity, as seen by significant glutathione depletion (50 %, *p < 0.05). The in-silico analysis indicated that BPS is effectively absorbed in the gastrointestinal tract without crossing the blood-brain barrier (whereas BPA crosses the blood-brain barrier) and is not a substrate of p-Glycoprotein and Cytochrome P450 enzymes. Thus, the current in-silico and in vivo findings revealed that acute postnatal exposure to BPS had no significant hepatotoxicity.

Major Publications in the Critical Care Pharmacotherapy Literature: 2021.

To summarize the most impactful articles relevant to the pharmacotherapy of critically ill adult patients published in 2021. DATA SOURCE: PubMed/MEDLINE. STUDY SELECTION: Randomized controlled trials, prospective studies, or systematic review/meta-analyses of adult critical care patients assessing a pharmacotherapeutic intervention and reporting clinical endpoints published between January 1, 2021, and December 31, 2021. DATA EXTRACTION: Candidate articles were organized by clinical domain based on the emerging themes from all studies. A modified Delphi process was applied to obtain consensus on the most impactful publication within each clinical domain based on overall contribution to scientific knowledge and novelty to the literature. DATA SYNTHESIS: The search revealed 830 articles, of which 766 were excluded leaving 64 candidate articles for the Delphi process. These 64 articles were organized by clinical domain including: emergency/neurology, cardiopulmonary, nephrology/fluids, infectious diseases, metabolic, immunomodulation, and nutrition/gastroenterology. Each domain required the a priori defined three Delphi rounds. The resultant most impactful articles from each domain included five randomized controlled trials and two systematic review/meta-analyses. Topics studied included sedation during mechanical ventilation, anticoagulation in COVID-19, extended infusion beta-lactams, interleukin-6 antagonists in COVID-19, balanced crystalloid resuscitation, vitamin C/thiamine/hydrocortisone in sepsis, and promotility agents during enteral feeding. CONCLUSIONS: This synoptic review provides a summary and perspective of the most impactful articles relevant to the pharmacotherapy of critically ill adults published in 2021.

Gefitinib Inhibits Rifampicin-Induced CYP3A4 Gene Expression in Human Hepatocytes.

During multidrug combination chemotherapy, activation of the nuclear receptor and the transcription factor human pregnane xenobiotic receptor (hPXR) has been shown to play a role in the development of chemoresistance. Mechanistically, this could occur due to the cancer drug activation of hPXR and the subsequent upregulation of hPXR target genes such as the drug metabolism enzyme, cytochrome P450 3A4 (CYP3A4). In the context of hPXR-mediated drug resistance, hPXR antagonists would be useful adjuncts to PXR-activating chemotherapy. However, there are currently no clinically approved hPXR antagonists in the market. Gefitinib (GEF), a tyrosine kinase inhibitor used for the treatment of advanced non-small-cell lung cancer and effectively used in combinational chemotherapy treatments, is a promising candidate owing to its hPXR ligand-like features. We, therefore, investigated whether GEF would act as an hPXR antagonist when combined with a known hPXR agonist, rifampicin (RIF). At therapeutically relevant concentrations, GEF successfully inhibited the RIF-induced upregulation of endogenous CYP3A4 gene expression in human primary hepatocytes and human hepatocells. Additionally, GEF inhibited the RIF induction of hPXR-mediated CYP3A4 promoter activity in HepG2 human liver carcinoma cells. The computational modeling of molecular docking predicted that GEF could bind to multiple sites on hPXR including the ligand-binding pocket, allowing for potential as a direct antagonist as well as an allosteric inhibitor. Indeed, GEF bound to the ligand-binding domain of the hPXR in cell-free assays, suggesting that GEF directly interacts with the hPXR. Taken together, our results suggest that GEF, at its clinically relevant therapeutic concentration, can antagonize the hPXR agonist-induced CYP3A4 gene expression in human hepatocytes. Thus, GEF could be a potential candidate for use in combinational chemotherapies to combat hPXR agonist-induced chemoresistance. Further studies are warranted to determine whether GEF has sufficient hPXR inhibitor abilities to overcome the hPXR agonist-induced chemoresistance.

Early transcriptomic response of mouse adrenal gland and Y-1 cells to dexamethasone.

Glucocorticoids have short- and long-term effects on adrenal gland function and development. RNA sequencing (RNA-seq) was performed to identify early transcriptomic responses to the synthetic glucocorticoid, dexamethasone (Dex), in vitro and in vivo. In total, 1711 genes were differentially expressed in the adrenal glands of the 1-h Dex-treated mice. Among them, only 113 were also considered differentially expressed genes (DEGs) in murine adrenocortical Y-1 cells treated with Dex for 1 h. Gene ontology analysis showed that the upregulated DEGs in the adrenal gland of the 1-h Dex-treated mice were highly associated with the development of neuronal cells, suggesting the adrenal medulla had a rapid response to Dex. Interestingly, only 4.3% of Dex-responsive genes in the Y-1 cell line under Dex treatment for 1 h were differentially expressed under Dex treatment for 24 h. The heatmaps revealed that most early responsive DEGs in Y-1 cells during 1 h of treatment exhibited a transient response. The expression of these genes under treatment for 24 h returned to basal levels similar to that during control treatment. In summary, this research compared the rapid transcriptomic effects of Dex stimulation in vivo and in vitro. Notably, adrenocortical Y-1 cells had a transient early response to Dex treatment. Furthermore, the DEGs had a minimal overlap in the 1-h Dex-treated group in vivo and in vitro.

Interplay between the Cannabinoid System and microRNAs in Cancer.

Cancer patients often use cannabinoids for alleviating symptoms induced by cancer pathogenesis and cancer treatment. This use of cannabinoids can have unexpected effects in cancer patients depending on the cancer type, resulting in either beneficial (e.g., anticancer) or adverse (e.g., oncogenic) effects. While cannabinoids can enhance the growth and progression of some cancers, they can also suppress the growth and progression of other cancers. However, the underlying mechanisms of such differential effects are poorly understood. miRNAs have been shown to be involved in driving the hallmarks of cancer, affecting cancer growth and progression as well as cancer therapy response. Although the understanding of the effects of cannabinoids and miRNAs as they relate to cancer continues to improve, the interplay between cannabinoid system and miRNAs in cancer pathogenesis and cancer treatment response is poorly understood. Investigation of such interactions between the cannabinoid system and miRNAs could provide novel insights into the underlying mechanisms of the differential effects of cannabinoids in cancer and can help predict and improve the prognosis of cancer patients.

Cardioprotective Effects of Oroxylum indicum Extract Against Doxorubicin and Cyclophosphamide-Induced Cardiotoxicity.

Administration of Chemotherapeutics, especially doxorubicin (DOX) and cyclophosphamide (CPS), is commonly associated with adverse effects such as myelosuppression and cardiotoxicity. At this time, few approved therapeutic options are currently available for the management of chemotherapy-associated cardiotoxicity. Thus, identification of novel therapeutics with potent cardioprotective properties and minimal adverse effects are pertinent in treating Doxorubicin and Cyclophosphamide-induced cardiotoxicity. Oroxylum indicum extract (OIE, Sabroxy®) is a natural product known to possess several beneficial biological functions including antioxidant, anti-inflammatory and cytoprotective effects. We therefore set to investigate the cardioprotective effects of OIE against Doxorubicin and Cyclophosphamide-induced cardiotoxicity and explore the potential cardioprotective mechanisms involved. Adult male mice were treated with DOX and CPS in combination, OIE alone, or a combination of OIE and DOX & CPS. Swimming test was performed to assess cardiac function. Markers of oxidative stress were assessed by levels of reactive oxygen species (ROS), nitrite, hydrogen peroxide, catalase, and glutathione content. The activity of interleukin converting enzyme and cyclooxygenase was determined as markers of inflammation. Mitochondrial function was assessed by measuring Complex-I activity. Apoptosis was assessed by Caspase-3 and protease activity. Mice treated with DOX and CPS exhibited reduced swim rate, increased oxidative stress, increased inflammation, and apoptosis in the heart tissue. These cardiotoxic effects were significantly reduced by co-administration of OIE. Furthermore, computational molecular docking studies revealed potential binding of DOX and CPS to tyrosine hydroxylase which validated our in vivo findings regarding the inhibition of tyrosine hydroxylase activity. Our current findings indicated that OIE counteracts Doxorubicin and Cyclophosphamide-induced cardiotoxicity-through inhibition of ROS-mediated apoptosis and by blocking the effect on tyrosine hydroxylase. Taken together, our findings suggested that OIE possesses cardioprotective effects to counteract potentially fatal cardiac complications associated with chemotherapy treatment.

A clinically relevant combination treatment with doxorubicin and cyclophosphamide does not induce hepatotoxicity in C57BL/6J mice.

BACKGROUND AND AIM: Chronic exposure to chemotherapeutics can lead to severe adverse events including hepatotoxicity. A combination chemotherapy regimen of doxorubicin (DOX) and cyclophosphamide (CPS) is employed in treatment of several cancers such as leukemia, lymphoma, and breast cancer. It is not well understood whether a combination therapy of DOX and CPS can induce hepatotoxicity. We therefore sought to determine whether co-administration of DOX and CPS at their clinically relevant doses and frequency results in hepatotoxicity. METHODS: Male C57BL/6J mice received one intraperitoneal injection of saline or DOX-2mg /kg and CPS-50mg/kg once a week for 4 weeks. After the treatment period, liver histology and various serum biomarkers of hepatotoxicity were assessed. RESULTS: Co-treatment of DOX and CPS did not alter the serum levels of alanine aminotransferase (ALT), alkaline phosphatase (ALP), bilirubin, albumin, globulin, or total protein. Similarly, co-administration of DOX and CPS did not result in a noticeable change in liver histology. However, it was notable that the concomitant treatment with DOX and CPS resulted in a significant increase in serum levels of aspartate aminotransferase (AST). Elevated serum AST levels were also associated with increased serum creatinine kinase (CK) levels, suggesting that the elevated serum AST levels are likely due to muscle injury following the co-administration of DOX and CPS. CONCLUSION: Taken together, our results, for the first time, suggest that co-administration of DOX and CPS, at their clinically relevant doses and frequency does not induce a significant hepatotoxicity in the mice.

Oroxylum indicum extract, at a physiologically relevant dosage, does not induce hepatotoxicity in C57BL/6J mice.

BACKGROUND: Botanical supplements have been proven to provide beneficial health effects. However, they can induce unintended adverse events such as hepatotoxicity. Oroxylum indicum extract (OIE, Sabroxy®) has several health benefits including anti-inflammatory, anti-arthritic, antifungal, antibacterial, and neuroprotective effects. It is currently unknown whether OIE has the potential to induce hepatotoxicity. PURPOSE: In the current study, we sought to determine whether OIE can induce hepatotoxicity in C57BL/6J mouse model. METHODS: The male mice were fed powdered rodent food (control group) or powdered rodent food mixed with OIE (Sabroxy®, 500mg/kg) daily for 4 weeks. Following the treatment, we assessed liver histology and serum levels of biomarkers commonly associated with liver damage, including alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP). RESULTS: No significant alterations were observed in liver histology, and serum levels of ALT, AST, ALP, bilirubin, albumin, globulin and total protein in the OIE fed mice compared to the control mice. CONCLUSION: Taken together, our results suggest that OIE, when fed at its physiologically relevant dosage, does not induce hepatotoxicity in C57BL/6J mice.

Oroxylum Indicum ameliorates chemotherapy induced cognitive impairment.

While chemotherapy is the most effective therapeutic approach for treating a variety of cancer patients, commonly used chemotherapeutic agents, often induce several adverse effects. Escalating evidence indicates that chemotherapeutics, particularly doxorubicin (DOX) and cyclophosphamide (CPS), induce cognitive impairment associated with central nervous system toxicity. This study was performed to determine neuroprotective effects of Oroxylum indicum extract (OIE) in regard to preventing chemotherapy induced cognitive impairment (CICI) occurring after 4 cycles of DOX (2mg/kg) and CPS (50mg/kg) combination chemotherapy in male C57BL/6J mice. OIE significantly prevented the chemotherapy impaired short-term cognitive performance, exploratory behavior associated with cognitive performance, cognitive performance, and spatial learning and memory in the Y-maze, Open-Field, Novel Object Recognition, and Morris Water Maze tests, respectively. These data suggest that OIE protects from the CICI. OIE decreased the reactive oxygen species and lipid peroxide generated by the chemotherapy treatment in the brain, while also blocking the chemotherapy-induced glutathione depletion. These results establish that OIE exhibits potent antioxidant activity in chemotherapy treated mice. Notably, OIE significantly increased the Complex-I and Complex-IV activities in the brain, indicating that OIE enhances mitochondrial function in the brain. In silico analysis of the major active chemical constituents (Oroxylin A, Baicalein and Chrysin) of OIE indicated that OIE has a favorable absorption, distribution, metabolism and excretion (ADME) profile. Taken together, our results are consistent with the conclusion that OIE prevents CICI by counteracting oxidative stress and perhaps by improving mitochondrial function.

Characteristics, Comorbidities, Complications, and Outcomes Among 802 Patients With Severe Acute Respiratory Syndrome Coronavirus 2 in a Community Hospital in Florida.

OBJECTIVES: Coronavirus disease 2019 continues to increase throughout the United States. Despite the rapid progression of the disease, there is limited information of the factors associated with mortality in Florida. This study aims to review the demographics, characteristics, comorbidities, complications, and outcomes of hospitalized patients, and their association with mortality. DESIGN: Cohort study. SETTING: A community-based tertiary-care hospital of Orlando Health, Orlando Regional Medical Center. PATIENTS/SUBJECTS: Data of hospitalized patients who tested positive for severe acute respiratory syndrome coronavirus 2 between March 1, 2020, and August 31, 2020, at the Orlando Regional Medical Center. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Main data assessed included patient demographics, clinical characteristics, comorbidities, complications, outcomes, and inhospital mortality. The median age for hospitalized patients was 61 years; among them, 56% were males. Most were of African American (n = 288, 35.9%), Hispanic (n = 237, 29.6%), and Caucasian (n = 217, 27.1%) descent. More patients presented with symptoms developing at home (n = 589, 75.9%) than from skilled nursing and long-term acute care facilities. The most common comorbidities were diabetes mellitus (42.8%), obesity (39.2%), lung disease (23.3%), coronary artery disease (20.2%), and congestive heart failure (18.3%). Complications with higher odds of mortality were mechanical ventilation (odds ratio, 148.00, p < 0.001), coinfections (odds ratio, 56.42, p < 0.001), acute kidney injury (odds ratio, 84.01, p < 0.001), atrial fibrillation (odds ratio, 28.30, p < 0.001), acute myocardial infarction (odds ratio, 23.29, p < 0.001), and acute venous thromboembolism (odds ratio, 26.43, p < 0.001). CONCLUSIONS: We identified an increase of severity of coronavirus disease 2019 within older patients of African American and Hispanic descent with comorbidities such as diabetes, coronary artery disease, congestive heart failure, chronic kidney disease, cancer, liver disease, or cerebrovascular disease. Noninvasive positive-pressure ventilation and high-flow nasal cannula oxygen may have helped avert mechanical ventilation, and this may have improved patient outcomes over the course of the study period.

Functional outcomes of pediatric laparoscopic pyeloplasty: post-operative functional recovery is superior in infants compared to older children.

AIM: Laparoscopic pyeloplasty (LP) is less popular and considered less successful in infants compared to older children. There are few reports analyzing the functional results of LP in relation to age of surgery. The aim of this paper is to compare the functional results of LP in infants (group 1) with children over 1 year of age (group 2). MATERIAL AND METHODS: The data of all children undergoing LP between August 2016 and July 2019 were retrospectively analyzed for patient details and follow-up. Only children (n = 135) with at least 1-year follow-up and completed post-operative ultrasound and diuretic renogram were included. All children underwent pre-operative and post-operative ultrasound and diuretic renogram; pre-operative, operative and post-operative parameters were compared between both groups. Statistical analysis was done using software; Mann-Whitney U test, Student t test, and Fisher's exact test were applied. RESULTS: There were 71 infants (group 1) and 64 children > 1 year (group 2). Pre-operatively, all kidneys had SFU grade 3 or 4 HDN and 131/135 kidneys had a renal pelvic APD > 20 mm; all kidneys had unequivocal obstruction on DR. At surgery, the preferred drainage method was intra-operative antegrade placement of a JJ stent in 68 (96%) group 1 and 63 (98%) group 2 children. The remaining 4 cases (3 group 1, 1 group 2) had a nephrostomy with trans-anastomotic external stent placement, because the JJ stent could not be negotiated into the bladder. The demographic data and comparison of pre- and post-operative parameters between both groups are summarized in Tables 1 and 2, respectively. Group 1 had significantly more children with antenatal diagnosis of HDN (87% vs 56%, p = 0.0005). The 36 children with antenatal diagnosis in group 2 were initially followed expectantly; the indication for pyeloplasty was deterioration of SRF on serial DR, urinary infection, and pain, in 13, 14, and 9 children, respectively. The operating time was significantly longer in group 2 (p = 0.0001). There was no difference in the success of LP or complication rate in both groups. Group 2 had significantly more children with extrinsic obstruction (1.4% vs 17%, p = 0.001). All children underwent post-operative US and DR; a significant reduction in hydronephrosis (APD) on follow-up was noted in both groups (p = 0.0001). The mean pre-operative SRF in both groups was comparable (p = 0.088). The mean SRF in both groups improved significantly after LP; however, the mean post-operative SRF was significantly higher in group 1 when compared to group 2 (p = 0.0001). Furthermore, group 1 had significantly more kidneys demonstrating > 10% increase in SRF after LP (53% vs 26%, p = 0.0003). CONCLUSIONS: The safety profile and success of LP in infants was comparable to older children. Infant LP took shorter time to perform, while older children had increased incidence of extrinsic obstruction. Infant kidneys demonstrated better functional improvement than older children after LP. These findings should encourage more surgeons to utilize LP for pyeloplasty even in infants.

Dysregulation of Endobiotic Homeostasis Mechanisms: Novel Insights into Adverse Pharmacokinetic Interactions between Illicit Substances and Clinical Drugs.

Many patients with a variety of medical conditions take illicit substances concomitantly with clinical drugs. This concomitant usage can lead to life-threatening adverse events. Despite the evidence that these adverse events can be caused by pharmacokinetic interactions, the underlying mechanisms are poorly understood. Investigation of mechanisms involved in dysregulation of endobiotic homeostasis during the concomitant usage of illicit substances with clinical drugs could provide novel insights into pharmacokinetic mechanisms of adverse interactions between illicit substances and clinical drugs.

Effects of Autologous Conditioned Serum, Autologous Protein Solution, and Triamcinolone on Inflammatory and Catabolic Gene Expression in Equine Cartilage and Synovial Explants Treated With IL-1ß in Co-culture.

Autologous conditioned serum (ACS) and autologous protein solution (APS) are newer therapeutic options for osteoarthritis (OA). Co-culture of cartilage and synovium stimulated with IL-1ß produces a similar physiologic response to tissues from naturally-ocurring OA. The study objective was to investigate the effects of ACS, APS, and triamcinolone (TA) on inflammatory and catabolic gene expression of inflamed joint tissues in co-culture. Blood was collected and processed for ACS and APS from six horses. Cartilage and synovial explants were harvested from the stifle, placed in co-culture, and treated as: (1) unstimulated control (2) stimulated control (3) ACS at 25% v/v (4) ACS at 50% v/v (5) APS at 25% v/v (6) APS at 50% v/v, (7) TA (10-6 M). Treatment groups 2-7 were stimulated with IL-1ß (10 ng/ml). Cultures were maintained for 96 hours, and then both media and explants were harvested for measurement of gene expression and protein. IL-1ß stimulation significantly increased IL-1ß (p = 0.029), IL-8 (p = 0.011) and MMP-3 (p = 0.043) expression in synovium and IL-1ß (p = 0.003) and TNF-α (p = 0.001) expression in cartilage. Treatment with 50% ACS and APS v/v downregulated IL-1ß expression in cartilage more than TA treatment (p = 0.001 and p = 0.0004) and APS downregulated MMP-1 expression in synovial membrane (p = 0.025). Treatment with ACS and APS caused a trend in upregulation of IL-10 expression in synovium and type II collagen and aggrecan expression in cartilage. PGE2 media concentrations were significantly reduced following treatment with APS (13.7-fold decrease, p = 0.0001) and ACS (4.13-fold decrease, p = 0.024); while TA did not reduce PGE2 significantly (2.3-fold decreased p = 0.406). As disease-modifying therapies, ACS and APS modified the cellular response from synovial membrane and articular cartilage. ACS and APS may offer an improved strategy to improve clinical signs of horses with naturally occurring OA, compared to TA treatment.