Non-coding RNAs in leukemia drug resistance: new perspectives on molecular mechanisms and signaling pathways.

Like almost all cancer types, timely diagnosis is needed for leukemias to be effectively cured. Drug efflux, attenuated drug uptake, altered drug metabolism, and epigenetic alterations are just several of the key mechanisms by which drug resistance develops. All of these mechanisms are orchestrated by up- and downregulators, in which non-coding RNAs (ncRNAs) do not encode specific proteins in most cases; albeit, some of them have been found to exhibit the potential for protein-coding. Notwithstanding, ncRNAs are chiefly known for their contribution to the regulation of physiological processes, as well as the pathological ones, such as cell proliferation, apoptosis, and immune responses. Specifically, in the case of leukemia chemo-resistance, ncRNAs have been recognized to be responsible for modulating the initiation and progression of drug resistance. Herein, we comprehensively reviewed the role of ncRNAs, specifically its effect on molecular mechanisms and signaling pathways, in the development of leukemia drug resistance.

Patent ductus arteriosus stenting as therapeutic bridge in a patient with type A3 truncus arteriosus variant with multiple comorbidities.

Type A3 truncus arteriosus describes pulmonary atresia with non-confluent mediastinal pulmonary arteries in which one pulmonary artery arises from a patent ductus arteriosus and the contralateral pulmonary artery from the aorta resulting in ductal dependent pulmonary blood flow. We describe a premature neonate with caudal regression syndrome and type A3 truncus arteriosus who was palliated with a ductal stent allowing completion of a prolonged neonatal ICU hospitalisation for multiple comorbidities.

Nanoparticle-based drug delivery systems in cancer: A focus on inflammatory pathways.

It has become necessary to accept the clinical reality of therapeutic agents targeting the cancer-associated immune system. In recent decades, several investigations have highlighted the role of inflammation in cancer development. It has now been recognized that inflammatory cells secrete mediators, including enzymes, chemokines, and cytokines. These secreted substances produce an inflammatory microenvironment that is critically involved in cancer growth. Inflammation may enhance genomic instability leading to DNA damage, activation of oncogenes, or compromised tumor suppressor activity, all of which may promote various phases of carcinogenesis. Conventional cancer treatment includes surgery, radiation, and chemotherapy. However, treatment failure occurs because current strategies are unable to achieve complete local control due to metastasis. Nanoparticles (NPs) are a broad spectrum of drug carriers typically below the size of 100 nm, targeting tumor sites while reducing off-target consequences. More importantly, NPs can stimulate innate and adaptive immune systems in the tumor microenvironment (TME); hence, they induce a cancer-fighting immune response. Strikingly, targeting cancer cells with NPs helps eliminate drug resistance and tumor recurrence, as well as prevents inflammation. Throughout this review, we provide recent data on the role of inflammation in cancer and explore nano-therapeutic initiatives to target significant mediators, for example, nuclear factor-kappa B (NF-κB), tumor necrosis factor-α (TNF-α), and interleukins (ILs) associated with cancer-related inflammation, to escort the immunomodulators to cancer cells and associated systemic compartments. We also highlight the necessity of better identifying inflammatory pathways in cancer pathophysiology to develop effective treatment plans.

The interaction of Helicobacter pylori with cancer immunomodulatory stromal cells: New insight into gastric cancer pathogenesis.

Gastric cancer is the fourth most common cause of cancer-linked deaths in the world. Gastric tumor cells have biological characteristics such as rapid proliferation, high invasiveness, and drug resistance, which result in recurrence and poor survival. Helicobacter pylori (H. pylori) has been proposed as a first-class carcinogen for gastric cancer according to the 1994 world health organization (WHO) classification. One of the important mechanisms by which H. pylori affects the gastric environment and promotes carcinogenesis is triggering inflammation. H. pylori induces an inflammatory response and a plethora of different signal transduction processes, leading to gastric mucosal disturbance, chronic gastritis, and a multi-step complex pathway that initiates carcinogenesis. It seems undeniable that the interaction between various cell types, including immune cells, gastric epithelium, glands, and stem cells, is vital for the progression and development of carcinogenesis concerning H. pylori. The interactions of H. pylori with surrounding cells play a key role in cancer progression. In this review, we discuss the interplay between H. pylori and tumor-supportive cells, including mesenchymal stem cells (MSCs), cancer-associated fibroblasts (CAFs), tumor-associated macrophages (TAMs), and myeloid derived-suppressor cells (MDSCs) in gastric cancer. It is hoped that clarifying the specific mechanisms for 'cross-talk' between H. pylori and these cells will provide promising strategies for developing new treatments.

Curcumin and chemokines: mechanism of action and therapeutic potential in inflammatory diseases.

Chemokines belong to the family of cytokines with chemoattractant properties that regulate chemotaxis and leukocyte migration, as well as the induction of angiogenesis and maintenance of hemostasis. Curcumin, the major component of the Curcuma longa rhizome, has various pharmacological actions, including anti-inflammatory, immune-regulatory, anti-oxidative, and lipid-modifying properties. Chemokines and chemokine receptors are influenced/modulated by curcumin. Thus, the current review focuses on the molecular mechanisms associated with curcumin's effects on chemoattractant cytokines, as well as putting into context the many studies that have reported curcumin-mediated regulatory effects on inflammatory conditions in the organs/systems of the body (e.g., the central nervous system, liver, and cardiovascular system). Curcumin's effects on viral and bacterial infections, cancer, and adverse pregnancy outcomes are also reviewed.

Curcumin: A therapeutic strategy for targeting the Helicobacter pylori-related diseases.

Helicobacter pylori is a significant human pathogen of the stomach's epithelial lining. This type of carcinogen is associated with gastric cancer, indigestion, peptic ulcers, and upper digestive diseases. Therefore, successful treatment and eradication of this bacterium are required to reduce the prevalence of these diseases, especially in high-risk individuals. Moreover, some concerns exist regarding the extensive use of elimination therapy, such as anti-microbial resistance and rising H. pylori-associated diseases. Since there is still no effective vaccine, finding alternative therapies would appear to be a worthwhile pursuit. In this regard, curcumin exhibits anti-inflammatory, anti-carcinogenic, anti-oxidant properties and is widely used as a natural product-derived medicine or nutraceutical. Furthermore, curcumin has been reported to have anti-bacterial activity. Therefore, curcumin might be an effective herbal-based medicine for preventing, managing, or treating H. pylori infection. This review discusses the anti-inflammatory, anti-cancer, and anti-bacterial properties of curcumin as it pertains to gastric cancer and H. pylori-associated diseases.

Immunomodulatory effects of curcumin in systemic autoimmune diseases.

Systemic autoimmune diseases like rheumatoid arthritis, multiple sclerosis, and systemic lupus erythematosus represent various autoimmune conditions identified by immune system dysregulation. The activation of immune cells, auto-antigen outbreak, inflammation, and multi-organ impairment is observed in these disorders. The immune system is an essential complex network of cells and chemical mediators which defends the organism's integrity against foreign microorganisms, and its precise operation and stability are compulsory to avoid a wide range of medical complications. Curcumin is a phenolic ingredient extracted from turmeric and belongs to the Zingiberaceae, or ginger family. Curcumin has multiple functions, such as inhibiting inflammation, oxidative stress, tumor cell proliferation, cell death, and infection. Nevertheless, the immunomodulatory influence of curcumin on immunological reactions/processes remains mostly unknown. In the present narrative review, we sought to provide current information concerning the preclinical and clinical uses of curcumin in systemic autoimmune diseases.

Antidiabetic drugs and oxidized low-density lipoprotein: A review of anti-atherosclerotic mechanisms.

Cardiovascular disease is one of the leading causes of mortality globally. Atherosclerosis is an important step towards different types of cardiovascular disease. The role of oxidized low-density lipoprotein (oxLDL) in the initiation and progression of atherosclerosis has been thoroughly investigated in recent years. Moreover, clinical trials have established that diabetic patients are at a greater risk of developing atherosclerotic plaques. Hence, we aimed to review the clinical and experimental impacts of various classes of antidiabetic drugs on the circulating levels of oxLDL. Metformin, pioglitazone, and dipeptidyl peptidase-4 inhibitors were clinically associated with a suppressive effect on oxLDL in patients with impaired glucose tolerance. However, there is an insufficient number of studies that have clinically evaluated the relationship between oxLDL and newer agents such as agonists of glucagon-like peptide 1 receptor or inhibitors of sodium-glucose transport protein 2. Next, we attempted to explore the multitude of mechanisms that antidiabetic agents exert to counter the undesirable effects of oxLDL in macrophages, endothelial cells, and vascular smooth muscle cells. In general, antidiabetic drugs decrease the uptake of oxLDL by vascular cells and reduce subsequent inflammatory signaling, which prevents macrophage adhesion and infiltration. Moreover, these agents suppress the oxLDL-induced transformation of macrophages into foam cells by either inhibiting oxLDL entrance, or by facilitating its efflux. Thus, the anti-inflammatory, anti-oxidant, and anti-apoptotic properties of antidiabetic agents abrogate changes induced by oxLDL, which can be extremely beneficial in controlling atherosclerosis in diabetic patients.

Protective Effects of Curcumin on Pulmonary Arterial Hypertension.

Pulmonary hypertension is one of the most common diseases among older people. This disease is usually associated with complications such as vascular changes, vascular remodeling, vasoconstriction, endothelial dysfunction, right ventricular failure, and reduction in nitric oxide availability. Many chemical drugs have been used to treat pulmonary hypertension, but result in limited efficacy and several side effects, and these medications are not always available worldwide. Various studies in traditional medicine have shown that changes in lifestyle and nutritional habits can be extremely effective in both the prevention and treatment of various diseases. One treatment method related to changing nutritional habits is the use of curcumin as a nutritional supplement. Curcumin plays an important role in treating pulmonary hypertension and positively alters the aforementioned complications.

A Review on the Phytochemistry, Pharmacology, and Therapeutic Effects of Rheum ribes.

Herbal medications are typically used for the treatment of diverse diseases without significant adverse effects. The Rheum ribes (R. ribes), commonly called rhubarb, is a hardy perennial herb and is consumed all over the world. There is growing evidence of the therapeutic benefits of R. ribes. Extensive in vitro and in vivo investigations have shown that R. ribes reveals beneficial properties via different mechanisms. In the current article, various pharmacological and therapeutic effects of R. ribes have been reviewed. For this purpose, different online databases using keywords such as R. ribes, therapeutic effects, and pharmacological effects were searched until the end of December 2020. R. ribes has been suggested to be effective in the treatment of a wide range of disorders including stomachache, nausea and vomiting, hemorrhoids, and measles. Additionally, different studies have demonstrated that R. ribes possesses numerous pharmacological properties including anti-inflammatory, anticancer, antibacterial, and antiviral, and may also function as an expectorant. The present narrative review provides a detailed survey of scientific investigations regarding the pharmacological properties and therapeutic effects of R. ribes.

Paving the Road Toward Exploiting the Therapeutic Effects of Ginsenosides: An Emphasis on Autophagy and Endoplasmic Reticulum Stress.

Programmed cell death processes such as apoptosis and autophagy strongly contribute to the onset and progression of cancer. Along with these lines, modulation of cell death mechanisms to combat cancer cells and elimination of resistance to apoptosis is of great interest. It appears that modulation of autophagy and endoplasmic reticulum (ER) stress with specific agents would be beneficial in the treatment of several disorders. Interestingly, it has been suggested that herbal natural products may be suitable candidates for the modulation of these processes due to few side effects and significant therapeutic potential. Ginsenosides are derivatives of ginseng and exert modulatory effects on the molecular mechanisms associated with autophagy and ER stress. Ginsenosides act as smart phytochemicals that confer their effects by up-regulating ATG proteins and converting LC3-I to -II, which results in maturation of autophagosomes. Not only do ginsenosides promote autophagy but they also possess protective and therapeutic properties due to their capacity to modulate ER stress and up- and down-regulate and/or dephosphorylate UPR transducers such as IRE1, PERK, and ATF6. Thus, it would appear that ginsenosides are promising agents to potentially restore tissue malfunction and possibly eliminate cancer.

Age-Specific Differences in the Severity of COVID-19 Between Children and Adults: Reality and Reasons.

In severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections, children experience mild symptoms compared to adults. However, the precise explanations for this disparity are not clear. Thus, we attempted to identify rational explanations about age-related differences as reported in different studies. Given the incomplete data on SARS-CoV-2, some information has been gathered from other studies of earlier coronavirus or influenza outbreaks. Age-related differences in disease severity are important with regard to diagnosis, prognosis, and treatment of SARS-CoV-2 infections. In addition, these differences impact social distancing needs, since pediatric patients with mild or asymptomatic are likely to play a significant role in disease transmission.

The Level of Procalcitonin in Severe COVID-19 Patients: A Systematic Review and Meta-Analysis.

There is data from individual clinical trials suggesting that procalcitonin (PCT) may be a prognostic factor in the severity of COVID-19 disease. Therefore, this systematic review and meta-analysis was performed to investigate PCT levels in severe COVID-19 patients. We searched Embase, ProQuest, MEDLINE/PubMed, Scopus, and ISI/Web of Science for studies that reported the level of PCT of patient with severe COVID-19. We included all studies regardless of design that reported the level of PCT in patients with severe COVID-19. We excluded articles not regarding COVID-19 or not reporting PCT level, studies not in severe patients, review articles, editorials or letters, expert opinions, comments, and animal studies. Nine studies were included in the analysis. The odds of having more severe COVID-19 disease was higher in subjects with elevated PCT (≥0.05 ng/mL) compared with those having low procalcitonin (<0.05 ng/mL) [n = 6, OR(95% CI) = 2.91(1.14, 7.42), p = 0.025). After estimating the mean and standard deviation values from the sample size, median, and interquartile range, a pooled effect analysis indicated higher serum PCT concentrations in patients with severe versus less severe disease [n = 6, SMD(95% CI) = 0.64(0.02, 1.26), p = 0.042]. The results of this study showed that PCT is increased in patients with severe COVID-19 infection.

Medicinal plants and bioactive natural products as inhibitors of NLRP3 inflammasome.

The NLR family, pyrin domain-containing 3 (NLRP3) inflammasome is a multiprotein complex that induces caspase-1 activation and the downstream substrates involved with the processing and secretion of the pro-inflammatory cytokines interleukin-1ß (IL-1ß) and IL-18 and tumor necrosis factor-α (TNF- α). The NLRP3 inflammasome is activated by a wide range of danger signals that derive from metabolic dysregulation. Activation of this complex often involves the adaptor ASC and upstream sensors including NLRP1, NLRP3, NLRC4, AIM2, and pyrin, which are activated by different stimuli including infectious agents and changes in cell homeostasis. It has been shown that nutraceuticals and medicinal plants have antiinflammatory properties and could be used as complementary therapy in the treatment of several chronic diseases that are related to inflammation, for example, cardiovascular diseases and diabetes mellitus. Herb-based medicine has demonstrated protective effects against NLRP3 inflammasome activation. Therefore, this review focuses on the effects of nutraceuticals and bioactive compounds derived from medicinal plants on NLRP3 inflammasome activation and the possible mechanisms of action of these natural products. Thus, herb-based, natural products/compounds can be considered novel, practical, and accessible agents in chronic inflammatory diseases by inhibiting NLRP3 inflammasome activation.

The clinical use of curcumin on neurological disorders: An updated systematic review of clinical trials.

Neuroprotective effects of curcumin have been shown in previous studies. This updated systematic review of clinical trials aimed to investigate the effect of curcumin on neurological disorders. Databases including PubMed, Scopus, Web of Science, and Google Scholar were systematically searched to identify clinical trials investigating the effects of curcumin/turmeric supplements alone, or in combination with other ingredients, on neurological diseases. Nineteen studies comprising 1,130 patients met the inclusion criteria. Generally, intervention and study outcomes were heterogeneous. In most of the studies, curcumin had a favorable effect on oxidative stress and inflammation. However, with the exception of AD, curcumin supplementation either alone, or in combination with other ingredients, had beneficial effects on clinical outcomes for the other aforementioned neurodegenerative diseases. For example, the frequency, severity, and duration of migraine attacks, scores on the revised ALS functional rating scale, and the occurrence of motor complications in PD were all significantly improved with curcumin supplementation either alone or in combination with other ingredients. However, in three studies, several adverse side effects (mostly gastrointestinal in nature) were reported. Curcumin supplementation may have favorable effects on inflammatory status and clinical outcomes of patients with neurological disease, although the results were not consistent.

Foam Cells as Therapeutic Targets in Atherosclerosis with a Focus on the Regulatory Roles of Non-Coding RNAs.

Atherosclerosis is a major cause of human cardiovascular disease, which is the leading cause of mortality around the world. Various physiological and pathological processes are involved, including chronic inflammation, dysregulation of lipid metabolism, development of an environment characterized by oxidative stress and improper immune responses. Accordingly, the expansion of novel targets for the treatment of atherosclerosis is necessary. In this study, we focus on the role of foam cells in the development of atherosclerosis. The specific therapeutic goals associated with each stage in the formation of foam cells and the development of atherosclerosis will be considered. Processing and metabolism of cholesterol in the macrophage is one of the main steps in foam cell formation. Cholesterol processing involves lipid uptake, cholesterol esterification and cholesterol efflux, which ultimately leads to cholesterol equilibrium in the macrophage. Recently, many preclinical studies have appeared concerning the role of non-encoding RNAs in the formation of atherosclerotic lesions. Non-encoding RNAs, especially microRNAs, are considered regulators of lipid metabolism by affecting the expression of genes involved in the uptake (e.g., CD36 and LOX1) esterification (ACAT1) and efflux (ABCA1, ABCG1) of cholesterol. They are also able to regulate inflammatory pathways, produce cytokines and mediate foam cell apoptosis. We have reviewed important preclinical evidence of their therapeutic targeting in atherosclerosis, with a special focus on foam cell formation.

Bortezomib: a proteasome inhibitor for the treatment of autoimmune diseases.

Autoimmune diseases (ADs) are conditions in which the immune system cannot distinguish self from non-self and, as a result, tissue injury occurs primarily due to the action of various inflammatory mediators. Different immunosuppressive agents are used for the treatment of patients with ADs, but some clinical cases develop resistance to currently available therapies. The proteasome inhibitor bortezomib (BTZ) is an approved agent for first-line therapy of people with multiple myeloma. BTZ has been shown to improve the symptoms of different ADs in animal models and ameliorated symptoms in patients with systemic lupus erythematous, rheumatoid arthritis, myasthenia gravis, neuromyelitis optica spectrum disorder, Chronic inflammatory demyelinating polyneuropathy, and autoimmune hematologic diseases that were nonresponsive to conventional therapies. Proteasome inhibition provides a potent strategy for treating ADs. BTZ represents a proteasome inhibitor that can potentially be used to treat AD patients resistant to conventional therapies.

CD47 in the Brain and Neurodegeneration: An Update on the Role in Neuroinflammatory Pathways.

CD47 is a receptor belonging to the immunoglobulin (Ig) superfamily and broadly expressed on cell membranes. Through interactions with ligands such as SIRPα, TSP-1, integrins, and SH2-domain bearing protein tyrosine phosphatase substrate-1 (SHPS-1), CD47 regulates numerous functions like cell adhesion, proliferation, apoptosis, migration, homeostasis, and the immune system. In this aspect, previous research has shown that CD47 modulates phagocytosis via macrophages, the transmigration of neutrophils, and the activation of T-cells, dendritic cells, and B-cells. Moreover, several studies have reported the increased expression of the CD47 receptor in a variety of diseases, including acute lymphoblastic leukemia (ALL), chronic myeloid leukemia, non-Hodgkin's lymphoma (NHL), multiple myeloma (MM), bladder cancer, acute myeloid leukemia (AML), Gaucher disease, Multiple Sclerosis and stroke among others. The ubiquitous expression of the CD47 cell receptor on most resident cells of the CNS has previously been established through different methodologies. However, there is little information concerning its precise functions in the development of different neurodegenerative pathologies in the CNS. Consequently, further research pertaining to the specific functions and roles of CD47 and SIRP is required prior to its exploitation as a druggable approach for the targeting of various neurodegenerative diseases that affect the human population. The present review attempts to summarize the role of both CD47 and SIRP and their therapeutic potential in neurodegenerative disorders.

Wnt Network: A Brief Review of Pathways and Multifunctional Components.

The Wnt signaling pathway appears to activate intracellular signaling transduction in embryonic development, cell migration, hematopoiesis, and several diseases. Wnt signaling is basically recognized as a canonical ß-catenin-dependent signaling pathway. However, in recent years, generally three Wnt-mediated pathways have been investigated, which operate independently of ß-catenin and include calcium/calmodulin-dependent kinase II and protein kinase C, planar cell polarity, and a third one recruits hetrotrimeric GTP-binding proteins to stimulate phospholipase C and phosphodiesterase. We provide an overview of the noncanonical Wnt signaling pathway and then will focus on canonical Wnt signaling components, Wnt ligands, agonists, and antagonist. This review will also discuss ß-catenin, both cytoplasmic and nuclear mechanisms, through signaling transduction, and, as a consequence, we have briefly highlighted potential implications of Wnt/ß-catenin in some cancers.

Potential of Cationic Liposomes as Adjuvants/Delivery Systems for Tuberculosis Subunit Vaccines.

The weakness of the BCG vaccine and its highly variable protective efficacy in controlling tuberculosis (TB) in different age groups as well as in different geographic areas has led to intense efforts towards the development and design of novel vaccines. Currently, there are several strategies to develop novel TB vaccines. Each strategy has its advantages and disadvantages. However, the most important of these strategies is the development of subunit vaccines. In recent years, the use of cationic liposome-based vaccines has been considered due to their capacity to elicit strong humoral and cellular immune responses against TB infections. In this review, we aim to evaluate the potential for cationic liposomes to be used as adjuvants/delivery systems for eliciting immune responses against TB subunit vaccines. The present review shows that cationic liposomes have extensive applications either as adjuvants or delivery systems, to promote immune responses against Mycobacterium tuberculosis (Mtb) subunit vaccines. To overcome several limitations of these particles, they were used in combination with other immunostimulatory factors such as TDB, MPL, TDM, and Poly I:C. Cationic liposomes can provide long-term storage of subunit TB vaccines at the injection site, confer strong electrostatic interactions with APCs, potentiate both humoral and cellular (CD4 and CD8) immune responses, and induce a strong memory response by the immune system. Therefore, cationic liposomes can increase the potential of different TB subunit vaccines by serving as adjuvants/delivery systems. These properties suggest the use of cationic liposomes to produce an efficient vaccine against TB infections.