Corrigendum: Sesquiterpene lactones attenuate paclitaxel resistance via inhibiting MALAT1/STAT3/ FUT4 axis and P-Glycoprotein transporters in lung cancer cells.

[This corrects the article DOI: 10.3389/fphar.2022.795613.].

Cleaved SPP1-rich extracellular vesicles from osteoclasts promote bone regeneration via TGFß1/SMAD3 signaling.

Bone remodeling is a tightly coupled process between bone forming osteoblasts (OBs) and bone resorbing osteoclasts (OCs) to maintain bone architecture and systemic mineral homeostasis throughout life. However, the mechanisms responsible for the coupling between OCs and OBs have not been fully elucidated. Herein, we first validate that secreted extracellular vesicles by osteoclasts (OC-EVs) promote osteogenic differentiation of mesenchymal stem cells (MSCs) and further demonstrate the efficacy of osteoclasts and their secreted EVs in treating tibial bone defects. Furthermore, we show that OC-EVs contain several osteogenesis-promoting proteins as cargo. By employing proteomic and functional analysis, we reveal that mature osteoclasts secrete thrombin cleaved phosphoprotein 1 (SPP1) through extracellular vesicles which triggers MSCs osteogenic differentiation into OBs by activating Transforming Growth Factor ß1 (TGFß1) and Smad family member 3 (SMAD3) signaling. In conclusion, our findings prove an important role of SPP1, present as cargo in OC-derived EVs, in signaling to MSCs and driving their differentiation into OBs. This biological mechanism implies a paradigm shift regarding the role of osteoclasts and their signaling toward the treatment of skeletal disorders which require bone formation.

Cybersecurity Awareness and Training (CAT) Framework for Remote Working Employees.

Currently, cybersecurity plays an essential role in computing and information technology due to its direct effect on organizations' critical assets and information. Cybersecurity is applied using integrity, availability, and confidentiality to protect organizational assets and information from various malicious attacks and vulnerabilities. The COVID-19 pandemic has generated different cybersecurity issues and challenges for businesses as employees have become accustomed to working from home. Firms are speeding up their digital transformation, making cybersecurity the current main concern. For software and hardware systems protection, organizations tend to spend an excessive amount of money procuring intrusion detection systems, antivirus software, antispyware software, and encryption mechanisms. However, these solutions are not enough, and organizations continue to suffer security risks due to the escalating list of security vulnerabilities during the COVID-19 pandemic. There is a thriving need to provide a cybersecurity awareness and training framework for remote working employees. The main objective of this research is to propose a CAT framework for cybersecurity awareness and training that will help organizations to evaluate and measure their employees' capability in the cybersecurity domain. The proposed CAT framework will assist different organizations in effectively and efficiently managing security-related issues and challenges to protect their assets and critical information. The developed CAT framework consists of three key levels and twenty-five core practices. Case studies are conducted to evaluate the usefulness of the CAT framework in cybersecurity-based organizational settings in a real-world environment. The case studies' results showed that the proposed CAT framework can identify employees' capability levels and help train them to effectively overcome the cybersecurity issues and challenges faced by the organizations.

Cloud Servers: Resource Optimization Using Different Energy Saving Techniques.

Currently, researchers are working to contribute to the emerging fields of cloud computing, edge computing, and distributed systems. The major area of interest is to examine and understand their performance. The major globally leading companies, such as Google, Amazon, ONLIVE, Giaki, and eBay, are truly concerned about the impact of energy consumption. These cloud computing companies use huge data centers, consisting of virtual computers that are positioned worldwide and necessitate exceptionally high-power costs to preserve. The increased requirement for energy consumption in IT firms has posed many challenges for cloud computing companies pertinent to power expenses. Energy utilization is reliant upon numerous aspects, for example, the service level agreement, techniques for choosing the virtual machine, the applied optimization strategies and policies, and kinds of workload. The present paper tries to provide an answer to challenges related to energy-saving through the assistance of both dynamic voltage and frequency scaling techniques for gaming data centers. Also, to evaluate both the dynamic voltage and frequency scaling techniques compared to non-power-aware and static threshold detection techniques. The findings will facilitate service suppliers in how to encounter the quality of service and experience limitations by fulfilling the service level agreements. For this purpose, the CloudSim platform is applied for the application of a situation in which game traces are employed as a workload for analyzing the procedure. The findings evidenced that an assortment of good quality techniques can benefit gaming servers to conserve energy expenditures and sustain the best quality of service for consumers located universally. The originality of this research presents a prospect to examine which procedure performs good (for example, dynamic, static, or non-power aware). The findings validate that less energy is utilized by applying a dynamic voltage and frequency method along with fewer service level agreement violations, and better quality of service and experience, in contrast with static threshold consolidation or non-power aware technique.

Morchella esculenta mushroom polysaccharide attenuates diabetes and modulates intestinal permeability and gut microbiota in a type 2 diabetic mice model.

Type 2 diabetes mellitus (T2DM) is a health issue that causes serious worldwide economic problems. It has previously been reported that natural polysaccharides have been studied with regard to regulating the gut microbiota, which plays an important role in T2DM. Here, we investigate the effects of Morchella esculenta polysaccharide (MEP) on a high-fat diet (HFD) and streptozotocin (STZ)-induced T2DM in BALB/c mice. The administration of MEP effectively regulated hyperglycemia and hyperlipidemia and improved insulin sensitivity. We also determined an improvement in gut microbiota composition by 16sRNA pyrosequencing. Treatment with MEP showed an increase in beneficial bacteria, i.e., Lactobacillus and Firmicutes, while the proportion of the opportunistic bacteria Actinobacteria, Corynebacterium, and Facklamia decreased. Furthermore, the treatment of T2DM mice with MEP resulted in reduced endotoxemia and insulin resistance-related pro-inflammatory cytokines interleukin 1ß (IL-1ß), tumor necrosis factor-alpha (TNF-α), and interleukin 6 (IL-6). Moreover, MEP treatment improved intestinal permeability by modulating the expression of the colon tight-junction proteins zonula occludens-1 (ZO-1), occludin, claudin-1, and mucin-2 protein (MUC2). Additionally, MEP administration affects the metagenome of microbial communities in T2DM mice by altering the functional metabolic pathways. All these findings suggested that MEP is a beneficial prebiotic associated with ameliorating the gut microbiota and its metabolites in T2DM.

Recent advances in applications of artificial intelligence in solid waste management: A review.

Efficient management of solid waste is essential to lessen its potential health and environmental impacts. However, the current solid waste management practices encounter several challenges. The development of effective waste management systems using advanced technologies is vital to overcome the challenges faced by the current approaches. Artificial Intelligence (AI) has emerged as a powerful tool for applications in various fields. Several studies also reported the applications of AI techniques in the management of solid waste. This article critically reviews the recent advancements in the applications of AI techniques for the management of solid waste. Various AI and hybrid techniques have been successfully employed to predict the performance of various methods used for the generation, segregation, storage, and treatment of solid waste. The key challenges that limit the applications of AI in solid waste are highlighted. These include the availability and selection of applicable data, poor reproducibility, and less evidence of applications in real solid waste. Based on identified gaps and challenges, recommendations for future work are provided. This review is beneficial for all stakeholders in the field of solid waste management, including policy-makers, governments, waste management organizations, municipalities, and researchers.

Sesquiterpene Lactones Attenuate Paclitaxel Resistance Via Inhibiting MALAT1/STAT3/ FUT4 Axis and P-Glycoprotein Transporters in Lung Cancer Cells.

Paclitaxel resistance is a challenging factor in chemotherapy resulting in poor prognosis and cancer recurrence. Signal transducer and activator of transcription factor 3 (STAT3), a key transcription factor, performs a critical role in cancer development, cell survival and chemoresistance, while its inactivation overwhelms drug resistance in numerous cancer types including lung cancer. Additionally, the fucosyltransferase 4 (FUT4) is a crucial enzyme in post-translational modification of cell-surface proteins involved in various pathological conditions such as tumor multidrug resistance (MDR). The P-glycoprotein (P-GP) is the well-known ABC transporter member that imparts drug resistance in different cancer types, most notably paclitaxel resistance in lung cancer cells. LncRNA-MALAT1 exerts a functional role in the cancer development as well as the drug resistance and is linked with STAT3 activation and activity of FUT4. Moreover, STAT3-mediated induction of P-GP is well-documented. Natural compounds of Sesquiterpene Lactone (SL) family are well-known for their anticancer properties with particular emphasis over STAT3 inhibitory capabilities. In this study, we explored the positive correlation of MALAT1 with STAT3 and FUT4 activity in paclitaxel resistant A549 (A549/T) lung cancer cells. Additionally, we investigated the anticancer activity of two well-known members of SLs, alantolactone (ALT) and Brevilin A (Brv-A), in A549/T lung cancer cells. ALT and Brv-A induced apoptosis in A549/T cells. Furthermore, these two natural SLs suppressed MALAT1 expression, STAT3 activation, and FUT4 and P-GP expression which are the hallmarks for paclitaxel resistance in A549 lung cancer cells. The inhibition of MALAT1 enhanced the competence of these SLs members significantly, which accounted for the growth inhibition as well as anti-migratory and anti-invasive effects of ALT and Brv-A. These findings suggest SLs to be the promising agents for overcoming paclitaxel resistance in A549 lung cancer cells.

A Multivocal Literature Review on Growing Social Engineering Based Cyber-Attacks/Threats During the COVID-19 Pandemic: Challenges and Prospective Solutions.

The novel coronavirus (COVID-19) pandemic has caused a considerable and long-lasting social and economic impact on the world. Along with other potential challenges across different domains, it has brought numerous cybersecurity challenges that must be tackled timely to protect victims and critical infrastructure. Social engineering-based cyber-attacks/threats are one of the major methods for creating turmoil, especially by targeting critical infrastructure, such as hospitals and healthcare services. Social engineering-based cyber-attacks are based on the use of psychological and systematic techniques to manipulate the target. The objective of this research study is to explore the state-of-the-art and state-of-the-practice social engineering-based techniques, attack methods, and platforms used for conducting such cybersecurity attacks and threats. We undertake a systematically directed Multivocal Literature Review (MLR) related to the recent upsurge in social engineering-based cyber-attacks/threats since the emergence of the COVID-19 pandemic. A total of 52 primary studies were selected from both formal and grey literature based on the established quality assessment criteria. As an outcome of this research study; we discovered that the major social engineering-based techniques used during the COVID-19 pandemic are phishing, scamming, spamming, smishing, and vishing, in combination with the most used socio-technical method: fake emails, websites, and mobile apps used as weapon platforms for conducting successful cyber-attacks. Three types of malicious software were frequently used for system and resource exploitation are; ransomware, trojans, and bots. We also emphasized the economic impact of cyber-attacks performed on different organizations and critical infrastructure in which hospitals and healthcare were on the top targeted infrastructures during the COVID-19 pandemic. Lastly, we identified the open challenges, general recommendations, and prospective solutions for future work from the researcher and practitioner communities by using the latest technology, such as artificial intelligence, blockchain, and big data analytics.

Inhibition of JNK-Mediated Autophagy Promotes Proscillaridin A- Induced Apoptosis via ROS Generation, Intracellular Ca+2 Oscillation and Inhibiting STAT3 Signaling in Breast Cancer Cells.

Breast cancer is the most heterogenous cancer type among women across the world. Despite concerted efforts, breast cancer management is still unsatisfactory. Interplay between apoptosis and autophagy is an imperative factor in categorizing therapeutics for cancer treatment. Proscillaridin A (PSD-A), a well-known cardiac glycoside used for cardiac arrest and arrythmias, has been unveiled in many cancer types but the underlying mechanism for apoptosis and autophagy in breast cancer is not fully understood. In our study, PSD-A restricted cell growth, inhibited STAT3 activation and induced apoptosis and autophagy in breast cancer cells via ROS generation and Ca+2 oscillation. Pretreatment of NAC and BAPTA-AM restored PSD-A induced cellular events in breast cancer cells. PSD-A induced apoptosis via DNA fragmentation, caspase-cascade activation, PARP cleavage, mitochondrial dysfunction, Bax/Bcl-2 proteins modulation and ER chaperone GRP78 inhibition along with decreased phosphorylation of ERK1/2. Inhibition of STAT3 activation was found to be associated with decreased phosphorylation of SRC. Moreover, PSD-A induced events of autophagy i.e. conversion of LC3-I to LC3-II, and Atg3 expression via JNK activation and decreased mTOR and AKT phosphorylation. In this study, pretreatment of SP600125, a JNK inhibitor, reduced autophagy and enhanced STAT3 inhibition and apoptosis. Additionally, SB203580, a commercial p38 inhibitor, stimulated STAT3 activation and improved autophagic events rate in breast cancer cells, displaying the role of the MAPK signaling pathway in interplay between apoptosis and autophagy. Our data suggest that the rate of apoptotic cell death is improved by blocking JNK-induced autophagy in PSD-A treated MCF-7 and MDA-MB-231 breast cancer cells.

Activation of farnesoid X receptor (FXR) induces crystallin zeta expression in mouse medullary collecting duct cells.

Crystallin zeta (CRYZ) is a phylogenetically restricted water-soluble protein and provides cytoprotection against oxidative stress via multiple mechanisms. Increasing evidence suggests that CRYZ is high abundantly expressed in the kidney where it acts as a transacting factor in increasing glutaminolysis and the Na+/K+/2Cl- cotransporter (BSC1/NKCC2) expression to help maintain acid-base balance and medullary hyperosmotic gradient. However, the mechanism by which CRYZ is regulated in the kidney remains largely uncharacterized. Here, we show that CRYZ is a direct target of farnesoid X receptor (FXR), a nuclear receptor important for renal physiology. We found that CRYZ was ubiquitously expressed in mouse kidney and constitutively expressed in the cytoplasm of medullary collecting duct cells (MCDs). In primary cultured mouse MCDs, CRYZ expression was significantly upregulated by the activation and overexpression of FXR. FXR-induced CRYZ expression was almost completely abolished in the MCD cells with siRNA-mediated FXR knockdown. Consistently, treatment with FXR agonists failed to induce CRYZ expression in the MCDs isolated from mice with global and collecting duct-specific FXR deficiency. We identified a putative FXR response element (FXRE) on the CRYZ gene promoter. The luciferase reporter and ChIP assays revealed that FXR can bind directly to the FXRE site, which was further markedly enhanced by FXR activation. Furthermore, we found CRYZ overexpression in MCDs significantly attenuated hypertonicity-induced cell death possibly via increasing Bcl-2 expression. Collectively, our findings demonstrate that CRYZ is constitutively expressed in renal medullary collecting duct cells, where it is transcriptionally controlled by FXR. Given a critical role of FXR in MCDs, CRYZ may be responsible for protective effect of FXR on the survival of MCDs under hypertonic condition during dehydration.

Hypoxic Preconditioning Improves the Therapeutic Potential of Aging Bone Marrow Mesenchymal Stem Cells in Streptozotocin-Induced Type-1 Diabetic Mice.

Insulin replacement is the current therapeutic option for type-1 diabetes. However, exogenous insulin cannot precisely represent the normal pattern of insulin secretion. Another therapeutic strategy is transplantation of pancreatic islets, but this is limited by immune rejection, intrinsic complications, and lack of donor availability. Stem cell therapy that results in the regeneration of insulin-producing cells represents an attractive choice. However, with advancing age, stem cells also undergo senescence, which leads to changes in the function of various cellular processes that result in a decrease in the regeneration potential of these aging stem cells. In this study, the effect of young and aging mesenchymal stem cells (MSCs) on the regeneration of pancreatic beta cells in streptozotocin (STZ)-induced type-1 diabetic mice was observed after hypoxic preconditioning. Hypoxia was chemically induced by 2, 4-dinitrophenol (DNP). Plasma insulin and glucose levels were measured at various time intervals, and pancreatic sections were analyzed histochemically. The effect of DNP was also analyzed on apoptosis of MSCs by flow cytometry and on gene expression of certain growth factors by quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR). We observed that hypoxic preconditioning caused changes in the gene expression levels of growth factors in both young and aging MSCs. Young MSCs showed significant regeneration potential compared with the aging cells in vivo. However, hypoxic preconditioning was able to improve the regeneration potential of aging MSCs. It is concluded from the present study that the regeneration potential of aging MSCs into pancreatic ß-cells can be enhanced by hypoxic preconditioning, which causes changes in the gene expression of certain growth factors.

Transcription profile of genes affected in response to pathological changes in drug-induced rat model of acute kidney injury.

OBJECTIVE: The objective of the present study was to examine the changes in the expression profile of certain genes in rat model of gentamicin-induced acute kidney injury (AKI) and to see whether time period and routes of administration affect their expression levels. METHODS: Rat AKI model was established with gentamicin injection using two different routes of administration and two different time periods. The models were evaluated through histopathological observations. Renal specific genes were selected on the basis of their role during kidney injury. These genes were analyzed through reverse transcriptase (RT) PCR. RESULTS: Marked disorganization of normal structure of proximal and distal tubules was observed in all the gentamicin-treated groups. Many tubules showed loss of brush border and presence of intratubular protein casts. Changes in gene expression levels were observed for kidney injury molecule (KIM-1), osteopontin, bone morphogenic protein-7 (BMP-7), extracellular signal-regulated kinases (ERK), stem cell factor (SCF) and IL-7 receptor with different levels of significance in the renal injury groups studied depending on the time period and route of administration. CONCLUSION: Gene expression seems to be dependent partly on the type of injury, route of administration and time period after induction of injury. An improved mechanistic understanding of gene regulation pathways in AKI may provide basis for potential therapeutic development.