Acetylshikonin Sensitizes Hepatocellular Carcinoma Cells to Apoptosis through ROS-Mediated Caspase Activation

This work is licensed under a Creative Commons Attribution 4.0 International License.The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has shown strong and explicit cancer cell-selectivity, which results in little toxicity toward normal tissues, and has been recognized as a potential, relatively safe anticancer agent. However, several cancers are resistant to the apoptosis induced by TRAIL. A recent study found that shikonin b (alkannin, 5,8-dihydroxy-2-[(1S)-1-hydroxy-4-methylpent-3-en-1-yl]naphthalene-1,4-dione) might induce apoptosis in TRAIL-resistant cholangiocarcinoma cells through reactive oxygen species (ROS)-mediated caspases activation. However, the strong cytotoxic activity has limited its potential as an anticancer drug. Thus, the current study intends to discover novel shikonin derivatives which can sensitize the liver cancer cell to TRAIL-induced apoptosis while exhibiting little toxicity toward the normal hepatic cell. The trypan blue exclusion assay, western blot assay, 4′,6-diamidino-2-phenylindole (DAPI) staining and the terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay as well as the ‘comet’ assay, were used to study the underlying mechanisms of cell death and to search for any mechanisms of an enhancement of TRAIL-mediated apoptosis in the presence of ASH. Herein, we demonstrated that non-cytotoxic doses of acetylshikonin (ASH), one of the shikonin derivatives, in combination with TRAIL, could promote apoptosis in HepG2 cells. Further studies showed that application of ASH in a non-cytotoxic dose (2.5 μM) could increase intracellular ROS production and induce DNA damage, which might trigger a cell intrinsic apoptosis pathway in the TRAIL-resistant HepG2 cell. Combination treatment with a non-cytotoxic dose of ASH and TRAIL activated caspase and increased the cleavage of PARP-1 in the HepG2 cell. However, when intracellular ROS production was suppressed by N-acetyl-l-cysteine (NAC), the synergistic effects of ASH and TRAIL on hepatocellular carcinoma (HCC) cell apoptosis was abolished. Furthermore, NAC could alleviate p53 and the p53 upregulated modulator of apoptosis (PUMA) expression induced by TRAIL and ASH. Small (or short) interfering RNA (siRNA) targeting PUMA or p53 significantly reversed ASH-mediated sensitization to TRAIL-induced apoptosis. In addition, Bax gene deficiency also abolished ASH-induced TRAIL sensitization. An orthotopical HCC implantation mice model further confirmed that co-treated ASH overcomes TRAIL resistance in HCC cells without exhibiting potent toxicity in vivo. In conclusion, the above data suggested that ROS could induce DNA damage and activating p53/PUMA/Bax signaling, and thus, this resulted in the permeabilization of mitochondrial outer membrane and activating caspases as well as sensitizing the HCC cell to apoptosis induced by TRAIL and ASH treatment

Prioritized solutions for overcoming barriers when implementing lean in the healthcare supply chain: a Saudi perspective

The main purpose of this paper is to propose solutions for overcoming the obstacles that healthcare organizations might face when implementing lean. An in-depth review of existing barriers for lean implementation in healthcare supply chain is presented and validated by experts. Although there is a widespread use of lean concepts in developed countries, little attention has been paid to implementing a lean approach by healthcare providers in developing countries. The present study’s key novelty and contribution is related to this research gap. The study is thus focused in proposing solutions for healthcare organisations in developing countries, especially in Saudi Arabia. The efficacy of these solutions is assessed through experts’ opinion. The paper enhances the body of knowledge for the successful implementation of lean in a hospital settin

Exploring the active mechanism of berberine against HCC by systematic pharmacology and experimental validation

This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.Berberine (BBR) is the main component of Coptidis rhizoma, the dried rhizome of Coptis chinensis and is a potential plant alkaloid used for the treatment of cancer due to its high antitumor activity. The present study examined the therapeutic potential and molecular mechanism of action of BBR against HCC, using systematic pharmacology combined with a molecular docking approach and experimental validation in vitro. Through systematic pharmacological analysis, it was found that BBR serves a significant role in inhibiting HCC by affecting multiple pathways, especially the PI3K/AKT signaling pathway. Furthermore, the docking approach indicated that the binding of BBR to AKT could lead to the suppression of AKT activity. The present study examined the inhibitory effect of BBR on the PI3K/AKT pathway in HCC and identified that BBR downregulated the expressions of phosphorylated AKT and PI3K in MHCC97‑H and HepG2 cells, inhibiting their growth, cell migration and invasion in a dose‑dependent manner. In addition, inhibition of the AKT pathway by BBR also contributed to cell apoptosis in MHCC97‑H and HepG2 cells. Taken together, the results of the present study suggested that BBR may be a promising antitumor drug for HCC that acts by inhibiting the PI3K/AKT pathway

Completeness and Legibility of Handwritten Prescriptions in Sana’a, Yemen

Objective: The aim of this study was to investigate the completeness and legibility of prescriptions dispensed in community pharmacies located in Sana’a, Yemen. Materials and Methods: A cross-sectional study was conducted at 23 randomly selected community pharmacies throughout the capital city of Sana’a, Yemen, from May 2015 to January 2016. A total of 2,178 prescriptions were analyzed for the essential elements of a complete prescription using a validated checklist. Results: Of the 2,178 prescriptions, 19 (0.87%) were considered to be of good quality. The remaining 2,159 (99.12%) were considered as being of very poor quality. Writing errors relating to patients and prescribed medications were the most common errors. Conclusion: In this study, the quality of prescription writing was found to be very poor. Hence, continuous professional development programs are recommended to improve the quality of prescription writing among physicians. Future studies in other cities and investigation of the impact of continuous educational programs on the quality of prescription writing are strongly recommended

Host immune responses to salivary components : a critical facet of tick-host interactions

Tick sialome is comprised of a rich cocktail of bioactive molecules that function as a tool to disarm host immunity, assist blood-feeding, and play a vibrant role in pathogen transmission. The adaptation of the tick’s blood-feeding behavior has lead to the evolution of bioactive molecules in its saliva to assist them to overwhelm hosts’ defense mechanisms. During a blood meal, a tick secretes different salivary molecules including vasodilators, platelet aggregation inhibitors, anticoagulants, anti-inflammatory proteins, and inhibitors of complement activation; the salivary repertoire changes to meet various needs such as tick attachment, feeding, and modulation or impairment of the local dynamic and vigorous host responses. For instance, the tick’s salivary immunomodulatory and cement proteins facilitate the tick’s attachment to the host to enhance prolonged bloodfeeding and to modulate the host’s innate and adaptive immune responses. Recent advances implemented in the field of “omics” have substantially assisted our understanding of host immune modulation and immune inhibition against the molecular dynamics of tick salivary molecules in a crosstalk between the tick–host interface. A deep understanding of the tick salivary molecules, their substantial roles in multifactorial immunological cascades, variations in secretion, and host immune responses against these molecules is necessary to control these parasites. In this article, we reviewed updated knowledge about the molecular mechanisms underlying host responses to diverse elements in tick saliva throughout tick invasion, as well as host defense strategies. In conclusion, understanding the mechanisms involved in the complex interactions between the tick salivary components and host responses is essential to decipher the host defense mechanisms against the tick evasion strategies at tick-host interface which is promising in the development of effective anti-tick vaccines and drug therapeutics

Head and Neck Surgery: A Differential Diagnosis in Otolaryngology

Introduction: In otolaryngology of the head and neck surgery; differential diagnosis is a practical and comprehensive guide that is organized uniquely by signs and symptoms instead of by diseases. Aim: This study will describe the keys to diagnostic evaluation and differential diagnosis of presenting symptoms for problems affecting each otolaryngology organ system.Methods: Each symptom opens with the patient’s presentation followed by an easily accessible list of potential diagnoses and supplementary data on the features of the different diseases to help correctly identify the problem. And identify features labeled by signs and symptoms, not by disease, and then enable quick clinical reference In-depth coverage of the diagnostic and treatment evaluation of all ENT disorders.

A network pharmacology-based study on the anti-hepatoma effect of Radix Salviae Miltiorrhizae

This work is licensed under a Creative Commons Attribution 4.0 International License.Background Radix Salviae Miltiorrhizae (RSM), a well-known traditional Chinese medicine, has been shown to inhibit tumorigenesis in various human cancers. However, the anticancer effects of RSM on human hepatocellular carcinoma (HCC) and the underlying mechanisms of action remain to be fully elucidated. Methods In this study, we aimed to elucidate the underlying molecular mechanisms of RSM in the treatment of HCC using a network pharmacology approach. In vivo and in vitro experiments were also performed to validate the therapeutic effects of RSM on HCC. Results In total, 62 active compounds from RSM and 72 HCC-related targets were identified through network pharmacological analysis. RSM was found to play a critical role in HCC via multiple targets and pathways, especially the EGFR and PI3K/AKT signaling pathways. In addition, RSM was found to suppress HCC cell proliferation, and impair cancer cell migration and invasion in vitro. Flow cytometry analysis revealed that RSM induced cell cycle G2/M arrest and apoptosis, and western blot analysis showed that RSM up-regulated the expression of BAX and down-regulated the expression of Bcl-2 in MHCC97-H and HepG2 cells. Furthermore, RSM administration down-regulated the expression of EGFR, PI3K, and p-AKT proteins, whereas the total AKT level was not altered. Finally, the results of our in vivo experiments confirmed the therapeutic effects of RSM on HCC in nude mice. Conclusions We provide an integrative network pharmacology approach, in combination with in vitro and in vivo experiments, to illustrate the underlying therapeutic mechanisms of RSM action on HCC

Perceived Risk of falls among Acute Care Patients

Purpose: In an effort to lower the number of falls that occur among hospitalized patients, several facilities have begun introducing various fall prevention programs. However, the efficacy of fall prevention programs is diminished if patients do not consider themselves to be at risk for falls and do not follow recommended procedures. The goal of this study was to characterize how patients in four different acute care specialist services felt about their risk of falling while in the hospital. Methods: One hundred patients admitted to the study hospital with a Morse Fall Scale score of 45 or higher were given the Patient Perception Questionnaire, a tool designed to assess a patient's perception of their own fall risk, fear of falling, and motivation to take part in fall prevention efforts. Scores on the Morse Fall Scale were gathered through a historical assessment of medical records. Descriptive statistics, Pearson's correlation coefficients, and independent sample t tests were used to examine the data. Results: The average age was 65, and around half (52%) were men and half (48%) were women. Based on their ratings on the Morse Fall Scale, all 100 participants were classified as being at high risk for falls. However, only 55.5% of the individuals agreed with this assessment. The likelihood that a patient would seek assistance and the degree to which they feared falling both declined as their faith in their mobility improved. Patients hospitalized after a fall exhibited considerably lower confidence scores and greater fear scores than patients who had not been injured in a fall. Conclusions: Patients who have a high fall risk assessment score may not believe they are at risk for falls and may not take any steps to reduce their risk. The prevalence of falls in hospitals might be mitigated by the creation of a fall risk assessment technique that takes into account both objective and subjective factors

Freshwater microalgae-based wastewater treatment under abiotic stress

Wastewater treatment by microalgae is an eco-friendly and sustainable method for pollutant removal and biomass generation. Microalgae production under abiotic stress (such as salinity/salt stress) has an impact on nutrient removal and fatty acid accumulation. In this study, a freshwater microalgal strain (Desmodesmus communis GEEL-12) was cultured in municipal wastewater with various NaCl concentrations (ranging from 25–150 mM). The growth kinetics and morphological changes of the microalgae were observed. The nutrient removal, salinity change, fatty acid composition, and biodiesel quality under various groups were also investigated. The maximum growth of D. communis GEEL-12 was observed in the control group at 0.48 OD680nm. The growth inhibition was observed under high salt conditions (150 mM), which showed poor tolerance with 0.15 OD680nm. The nitrogen (N) and phosphorus (P) removal significantly decreased from 99–81% and 5.0–5.9% upon the addition of 100–150 mM salt, respectively. Palmitic acid (C16:0) and stearic acid (C18:0) were the most common fatty acid profiles. The abundance of C18:0 enhanced from 49.37%–56.87% in D. communis GEEL-12 upon high NaCl concentrations (100–150 mM). The biodiesel quality index of D. communis GEEL-12 under 50–75 mM salt concentrations reached the levels advised by international standards