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Zebrafish is a prominent vertebrate model, with many of its advantages related to its development, life cycle, and translational ability. While a great number of behavioral phenotypes and tasks to evaluate them are available, longitudinal studies across zebrafish life stages are scarce and made challenging because of the differences between protocols and endpoints assessed at each life stage. In this mini review, we highlight the relevance that longitudinal studies could have for neurobehavioral pharmacology using this model. We also present possible strategies to standardize behavior endpoints in domains related to human diseases throughout the life cycle, especially between larvae and adult fish. Furthermore, we discuss the remaining difficulties of these analyses and explore future advances needed to bridge this knowledge gap.

Epithelial-mesenchymal transition (EMT) is defined as a process in which differentiated epithelial cells undergo phenotypic transformation into myofibroblasts capable of producing extracellular matrix, and is generally regarded as an integral part of fibrogenesis after tissue injury. Although there is evidence that the complete EMT of tubular epithelial cells (TECs) is not a major contributor to interstitial myofibroblasts in kidney fibrosis, the partial EMT, a status that damaged TECs remain inside tubules, and co-express both epithelial and mesenchymal markers, has been demonstrated to be a crucial stage for intensifying fibrogenesis in the interstitium. The process of tubular EMT is governed by multiple intracellular pathways, among which Wnt/β-catenin signaling is considered to be essential mainly because it controls the transcriptome associated with EMT, making it a potential therapeutic target against kidney fibrosis. A growing body of data suggest that reducing the hyperactivity of Wnt/β-catenin by natural compounds, specific inhibitors, or manipulation of genes expression attenuates tubular EMT, and interstitial fibrogenesis in the TECs cultured under profibrotic environments and in animal models of kidney fibrosis. These emerging therapeutic strategies in basic researches may provide beneficial ideas for clinical prevention and treatment of chronic kidney disease.

Obesity is an epidemic worldwide and the obese people suffer from a range of respiratory complications including fibrotic changes in the lung. The influence of obesity on the lung is multi-factorial, which is related to both mechanical injury and various inflammatory mediators produced by excessive adipose tissues, and infiltrated immune cells. Adiposity causes increased production of inflammatory mediators, for example, cytokines, chemokines, and adipokines, both locally and in the systemic circulation, thereby rendering susceptibility to respiratory diseases, and altered responses. Lung fibrosis is closely related to chronic inflammation in the lung. Current data suggest a link between lung fibrosis and diet-induced obesity, although the mechanism remains incomplete understood. This review summarizes findings on the association of lung fibrosis with obesity, highlights the role of several critical inflammatory mediators (e.g., TNF-α, TGF-β, and MCP-1) in obesity related lung fibrosis and the implication of obesity in the outcomes of idiopathic pulmonary fibrosis patients.

Urodele amphibians (∼768 spp.), salamanders and newts, are a rich source of molecules with bioactive properties, especially those isolated from their skin secretions. These include pharmacological attributes, such as antimicrobial, antioxidant, vasoactive, immune system modulation, and dermal wound healing activities. Considering the high demand for new compounds to guide the discovery of new drugs to treat conventional and novel diseases, this review summarizes the characteristics of molecules identified in the skin of urodele amphibians. We describe urodele-derived peptides and alkaloids, with emphasis on their biological activities, which can be considered new scaffolds for the pharmaceutical industry. Although much more attention has been given to anurans, bioactive molecules produced by urodeles have the potential to be used for biotechnological purposes and stand as viable alternatives for the development of therapeutic agents.

Lupus glomerulonephritis (LN) is a complex autoimmune disease characterized by circulating autoantibodies, immune-complex deposition, immune dysregulation and defects in regulatory T cell (Tregs). Treatment options rely on general immunosuppressants and steroids that have serious side effects. Approaches to target immune cells, such as B cells in particular, has had limited success and new approaches are being investigated. Defects in Tregs in the setting of autoimmunity is well known and Treg-replacement strategies are currently being explored. The aim of this minireview is to rekindle interest on Treg-targeting strategies. We discuss the existing evidences for Treg-enhancement strategies using key cytokines interleukin (IL)-2, IL-33 and IL-6 that have shown to provide remission in LN. We also discuss strategies for indirect Treg-modulation for protection from LN.

Post-stroke depression (PSD) is the most common non-cognitive neuropsychiatric complication after stroke, and about a third of patients with stroke have depression. Although a great deal of effort has been made to treat PSD, the efficacy thereof has not been satisfactory, due to the complex pathological mechanism underlying PSD. In Traditional Chinese Medicine (TCM) theory, PSD is considered to be a combination of “stroke” and “Yu Zheng.” The holistic, multi-drug, and multi-objective nature of TCM is consistent with the treatment concept of systems medicine for PSD. TCM has a very long history of being used to treat depression, and various TCM prescriptions have been clinically proven to be effective in improving depression. Among the numerous prescriptions for treating depression, Shugan Jieyu capsule (SG) is one of the classic prescriptions. Additionally, clinical studies have increasingly confirmed that using SG alone or in combination with Western medicine can significantly improve the psychiatric symptoms of PSD patients. Here, we reviewed the mechanism of antidepressant action of SG and its targets in PSD pathologic systems. This review provides further insights into the pharmacological mechanism, drug interaction, and clinical application of TCM prescriptions, as well as a basis for the development of new drugs to treat PSD.

Allergic diseases are a global health burden with increasing prevalence. Side effects of available medications (antihistamines and steroids), lack of patients’ perceived effectiveness and high cost of biologic therapies (omalizumab) are challenges to the clinical management of allergic diseases. As allergy symptoms persist for a long time, complementary and alternative medicine (CAM) such as propolis may be considered a potential prophylactic or therapeutic option to avoid long-term medication use. Propolis is a natural resinous substance produced by bees. Although propolis is well known to possess antioxidant, antimicrobial, and anticancer properties, its anti-allergic potential is not fully explored. Several preclinical studies demonstrated the therapeutic effects of propolis extracts against allergic inflammation, asthma, allergic rhinitis, atopic dermatitis, and food allergy, which may be partly attributed to their inhibitory effects on the activation of mast cells and basophils. Clinically, the consumption of propolis as a supplement or an adjunct therapy is safe and attenuates various pathological conditions in asthma. Such an approach may be adopted for atopic dermatitis and allergic rhinitis. Although flavonoids (chrysin, kaempferol, galangin, and pinocembrin) and cinnamic acid derivatives (artepillin C and caffeic acid phenethyl ester) can contribute to the anti-allergic activities, they may not be present in all propolis samples due to variations in the chemical composition. Future studies should relate the anti-allergic activity of propolis with its chemical contents. This mini-review summarizes and discusses existing preclinical and clinical studies reporting the anti-allergic activities of propolis to provide insights into its potential applications in allergic diseases.

Higenamine, a natural product with multiple targets in heart diseases, is originally derived from Aconitum, which has been traditionally used in China for the treatment of heart disease, including heart failure, arrhythmia, bradycardia, cardiac ischemia/reperfusion injury, cardiac fibrosis, etc. This study is aimed to clarify the role of higenamine in heart diseases. Higenamine has effects on improving energy metabolism of cardiomyocytes, anti-cardiac fibroblast activation, anti-oxidative stress and anti-apoptosis. Accumulating evidence from various studies has shown that higenamine exerts a wide range of cardiovascular pharmacological effects in vivo and in vitro, including alleviating heart failure, reducing cardiac ischemia/reperfusion injury, attenuating pathological cardiac fibrosis and dysfunction. In addition, several clinical studies have reported that higenamine could continuously increase the heart rate levels of healthy volunteers as well as patients with heart disease, but there are variable effects on systolic blood pressure and diastolic blood pressure. Moreover, the heart protection and therapeutic effects of higenamine on heart disease are related to regulating LKB1/AMPKα/Sirt1, mediating the β2-AR/PI3K/AKT cascade, induction of heme oxygenase-1, suppressing TGF-β1/Smad signaling, and targeting ASK1/MAPK (ERK, P38)/NF-kB signaling pathway. However, the interventional effects of higenamine on heart disease and its underlying mechanisms based on experimental studies have not yet been systematically reviewed. This paper reviewed the potential pharmacological mechanisms of higenamine on the prevention, treatment, and diagnosis of heart disease and clarified its clinical applications. The literature shows that higenamine may have a potent effect on complex heart diseases, and proves the profound medicinal value of higenamine in heart disease.

Background: The endocannabinoid system (ECS) is involved in multiple physiological processes, including appetite regulation, pain perception, motor function development, and immune response regulation. Cannabinoids have been approved for the clinical treatment of nausea and vomiting caused by cytostatic therapy or cancer chemotherapy, loss of appetite in HIV/AIDS-associated cachexia, refractory spasms induced by multiple sclerosis, chronic pain, and urinary incontinence.Methods: Check out the research on ECS and bone diseases in the past 20 years.Results: Many studies have demonstrated that endocannabinoids (eCBs) and cannabinoid receptors (CBRs) are expressed in bone and synovial tissues, playing important roles in bone metabolism. Preclinical studies using cannabis-based therapies in animal models have shown that cannabinoids (CBs) can alleviate the development of osteoarthritis (OA), prevent osteoporosis (OP), reduce cancer-induced osteolytic destruction, and improve fracture healing, highlighting the therapeutic potential of CBs for human bone diseases.Conclusions: The present review summarizes various components of the ECS in bone diseases and their potential as a therapeutic target.

Gastric cancer and colorectal cancer are malignant tumors found in the human gastrointestinal tract. Bidirectional communication between tumor cells and their microenvironment can be realized through the transmission of exosomes—small, cell-derived vesicles containing complex RNA and proteins. Exosomes play an important role in the proliferation, metastasis, immune response, and drug resistance of cancer cells. In this review, we focus on the role and application of exosomes in gastric and colorectal cancer. We also summarize the role of exosomes secreted by different types of cells in tumor development and as drug carriers in cancer treatment.

Age related macular degeneration (AMD) and diabetic retinopathy (DR) are multifactorial, neurodegenerative and inflammatory diseases of the eye primarily involving cellular and molecular components of the outer and inner blood-retina barriers (BRB), respectively. Largely contributed by genetic factors, particularly polymorphisms in complement genes, AMD is a paradigm of retinal immune dysregulation. DR, a major complication of diabetes mellitus, typically presents with increased vascular permeability and occlusion of the retinal vasculature that leads, in the proliferative form of the disease, to neovascularization, a pathogenic trait shared with advanced AMD. In spite of distinct etiology and clinical manifestations, both pathologies share common drivers, such as chronic inflammation, either of immune (in AMD) or metabolic (in DR) origin, which initiates and propagates degeneration of the neural retina, yet the underlying mechanisms are still unclear. As a soluble pattern recognition molecule with complement regulatory functions and a marker of vascular damage, long pentraxin 3 (PTX3) is emerging as a novel player in ocular homeostasis and a potential pharmacological target in neurodegenerative disorders of the retina. Physiologically present in the human eye and induced in inflammatory conditions, this protein is strategically positioned at the BRB interface, where it acts as a “molecular trap” for complement, and modulates inflammation both in homeostatic and pathological conditions. Here, we discuss current viewpoints on PTX3 and retinal diseases, with a focus on AMD and DR, the roles therein proposed for this pentraxin, and their implications for the development of new therapeutic strategies.

Coumarins are a family of benzopyrones largely distributed in the natural kingdom, being present in the seeds, fruits, flowers, or roots of various plant species. Natural coumarin compounds are found in significant concentrations in some herbs or spices used as nutraceuticals, but they are also present in cosmetics or household products, due to their pleasant odor. Therefore, an accidental exposure to high doses of coumarins, could lead to the development of harmful effects in some patients. This review summarizes the latest published data from preclinical and clinical studies with natural coumarins, focused on the investigation of general and specific toxicity, with the aim of a better understanding of the safety profile of these valuable compounds. Regulatory aspects concerning the use of natural coumarins in several world regions are also reviewed.

Drug-resistant species of tuberculosis (TB), which spread faster than traditiona TB, is a severely infectious disease. The conventional drug therapy used in the management of tuberculosis has several challenges linked with adverse effects. Hence, nanotherapeutics served as an emerging technique to overcome problems associated with current treatment. Nanotherapeutics helps to overcome toxicity and poor solubility issues of several drugs used in the management of tuberculosis. Due to their diameter and surface chemistry, nanocarriers encapsulated with antimicrobial drugs are readily taken up by macrophages. Macrophages play a crucial role as they serve as target sites for active and passive targeting for nanocarriers. The surface of the nanocarriers is coated with ligand-specific receptors, which further enhances drug concentration locally and indicates the therapeutic potential of nanocarriers. This review highlights tuberculosis’s current facts, figures, challenges associated with conventional treatment, different nanocarrier-based systems, and its application in vaccine development.

Pancreatic cancer is a devastating gastrointestinal cancer, characterized by late diagnosis, low treatment success rate, and poor survival prognosis. The most common pathological type of pancreatic cancer is pancreatic ductal adenocarcinoma (PDAC), which is mainly driven by the K-Ras oncogene. Ferroptosis was originally described as Ras-dependent cell death, but is now defined as lipid peroxidation-mediated regulated necrosis, accompanied by excessive activation of the autophagy degradation pathway and limited membrane repair capacity. The impaired ferroptotic pathway is involved in many types of cancer, including PDAC. On the one hand, the chronic inflammation caused by ferroptotic damage contributes to the formation of K-Ras-driven PDAC. On the other hand, drug-induced ferroptosis is an emerging strategy to suppress tumor growth in established PDAC. In this mini-review, we outline the core process of ferroptosis, discuss the regulatory mechanism of ferroptosis in PDAC, and highlight some of the challenges of targeting ferroptosis in PDAC therapy.

In the United States, the number of people suffering from opioid use disorder has skyrocketed in all populations. Nevertheless, observations of racial disparities amongst opioid overdose deaths have recently been described. Opioid use disorder is characterized by compulsive drug consumption followed by periods of withdrawal and recurrent relapses while patients are participating in treatment programs. Similar to other rewarding substances, exposure to opioid drugs is accompanied by epigenetic changes in the brain. In addition, genetic factors that are understudied in some racial groups may also impact the clinical manifestations of opioid use disorder. These studies are important because genetic factors and epigenetic alterations may also influence responses to pharmacological therapeutic approaches. Thus, this mini-review seeks to briefly summarize what is known about the genetic bases of opioid use disorder in African Americans.

In the context of kidney injury, the role of Bregs is gaining interest. In a number of autoimmune diseases, the number and/or the function of Bregs has been shown to be impaired or downregulated, therefore restoring their balance might be a potential therapeutic tool. Moreover, in the context of kidney transplantation their upregulation has been linked to tolerance. However, a specific marker or set of markers that define Bregs as a unique cell subset has not been found and otherwise multiple phenotypes of Bregs have been studied. A quest on the proper markers and induction mechanisms is now the goal of many researchers. Here we summarize the most recent evidence on the role of Bregs in kidney disease by describing the relevance ofin vitroandin vivoBregs induction as well as the potential use of Bregs as cell therapy agents in kidney transplantation.

Metabolic related diseases such as cancer, diabetes mellitus and atherosclerosis are major challenges for human health and safety worldwide due to their associations with high morbidity and mortality. It is of great significance to develop the effective active pharmaceutical ingredient (API) delivery systems for treatment of metabolic diseases. With their unique merits like easy preparation, high adjustability, low toxicity, low cost, satisfactory stability and biodegradation, deep eutectic solvents (DESs) are unarguably green and sustainable API delivery systems that have been developed to improve drug solubility and treat metabolic related diseases including cancer, diabetes mellitus and atherosclerosis. Many reports about DESs as API delivery systems in the therapy of cancer, diabetes mellitus and atherosclerosis exist but no systematic overview of these results is available, which motivated the current work.

Epilepsy, which is characterized by spontaneous recurrent seizures, is one of the most common and serious chronic neurological diseases in the world. 30% patients failed to control seizures with multiple anti-seizure epileptic drugs, leading to serious outcomes. The pathogenesis of epilepsy is very complex and remains unclear. Brain-derived neurotrophic factor (BDNF), as a member of the neurotrophic factor family, is considered to play an important role in the survival, growth and differentiation of neurons during the development of the central nervous system. Recent years, a series of studies have reported that BDNF can maintain the function of the nervous system and promotes the regeneration of neurons after injury, which is believed to be closely related to epileptogenesis. However, two controversial views (BDNF inhibits or promotes epileptogenesis) still exist. Thus, this mini-review focuses on updating the new evidence of the role of BDNF in epileptogenesis and discussing the possibility of BDNF as an underlying target for the treatment of epilepsy.

Inflammatory bowel diseases (IBD) are chronic conditions of unknown etiology and immunomediated pathogenesis. In the last years, the comprehension of the complex mechanisms involved in the intestinal mucosal homeostasis, and the analysis of the alterations potentially leading to inflammatory pathologic states, has consistently increased. Specifically, the extraordinary impulse in the field of research of the intestinal microbiome has opened the door to the investigation of possible novel approaches to the diagnosis, management and therapeutic applications in IBD. In line with that, administration of probiotic bacteria has been intensely evaluated, leading to much more exciting results in experimental models than in clinical practice. Considering the consistent heterogeneity of the available studies on probiotics, the increased knowledge of the properties of the single bacterial species would ideally lead to unravel potential mechanisms of action that may bring therapeutic applications in specific pathologic condition. Among the relevant molecular pathways for mucosal homeostasis maintenance, the vitamin D/vitamin D receptor (VDR) pathway has been intensely studied in the very last years. In fact, besides osteometabolic functions, the vitamin D exerts important homeostatic effects in the organism at multiple levels, such as immunomodulation, inflammation control, and microbiota regulation, which are likely to play a relevant role in intestinal mucosa protection. In the present review, recent findings about probiotic applications in IBD and mechanisms of action linking vitamin D/VDR pathway to IBD are reported. Available evidence for probiotic effect on vitamin D/VDR are reviewed and potential future application in IBD patients are discussed. At present, many aspects of IBD pathogenesis are still obscure, and current therapeutic options for IBD treatment are at best suboptimal. The increasing comprehension of the different pathways involved in IBD pathogenesis will lead to novel findings ideally leading to potential clinical applications. Microbiota manipulation and vitamin/VDR pathway appear a promising field for future research and therapeutic developments.

Cardiovascular disease is a kind of heart, brain, and blood vessel injury disease by the interaction of various pathological factors. The pathogenesis of cardiovascular disease is complex with various risk factors, including abnormally elevated blood pressure, glucose, and lipid metabolism disorders, atherosclerosis, thrombosis, etc. Plant polysaccharides are a special class of natural products derived from plant resources, which have the characteristics of wide sources, diverse biological activities, and low toxicity or side effects. Many studies have shown that plant polysaccharides improve cardiovascular diseases through various mechanisms such as anti-oxidative stress, restoring the metabolism of biological macromolecules, regulating the apoptosis cascade to reduce cell apoptosis, and inhibiting inflammatory signal pathways to alleviate inflammation. This article reviews the pharmacological effects and protective mechanisms of some plant polysaccharides in modulating the cardiovascular system, which is beneficial for developing more effective drugs with low side effects for management of cardiovascular diseases.

Autoimmune thyroid diseases (AITD) are T-cell-mediated organ specific autoimmune disorders, deriving from an altered response of the immune system that leads to the immune attack to the thyroid. Hashimoto’s thyroiditis (HT) and Graves’ disease (GD) are the two principal AITD clinical presentations. Hypothyroidism and thyrotoxicosis are, respectively, the clinical hallmarks of HT and GD. Patients with autoimmune thyroiditis are treated daily with synthetic L-thyroxine (L-T4) at the dose of 1.5–1.7 μg/kg. Various L-T4 formulations are commercially available (tablet, liquid solution, or soft gel capsule). L-T4 in tablets is generally prescribed to treat hypothyroidism, whereas the liquid formulation, or soft gel capsules, can be administered in hypothyroid patients in case of malabsorption or in patients in therapy with drugs interfering with L-T4 absorption. Furthermore, myoinositol has a crucial role in thyroid autoimmunity and function. Clinical studies reported a significant decline in TSH and antithyroid autoantibodies levels after treatment with myoinositol + selenium in patients with subclinical hypothyroidism and autoimmune thyroiditis. Moreover, thyroidectomy can be rarely recommended in patients with autoimmune thyroiditis, with cosmetic reasons for a goiter, or with important signs or symptoms of local compression, or nodular disease with a “suspicious” cytology for malignancy. Furthermore, a recent randomized trial suggested that total thyroidectomy can improve quality of life and fatigue, while medical therapy did not. In this review, we overview currently available evidence in personalized medicine in patients with autoimmune thyroiditis and hypothyroidism. Further research is needed in larger population to investigate the effect of these new treatments on quality of life.

Pyroptosis is a recently identified type of lytic programmed cell death, in which pores form in the plasma membrane, and cells swell, rupture, and then release their contents, including inflammatory cytokines. Molecular studies indicated that pyroptosis may occur via a gasdermin D (GSDMD) and caspase-1 (Casp1) -dependent classical pathway, a GSDMD and Casp11/4/5-dependent non-classical pathway, or a gasdermin E (GSDME) and Casp3-dependent pathway. Studies of animal models and humans indicated that pyroptosis can exacerbate several complications of diabetes, including diabetic nephropathy (DN), a serious microvascular complication of diabetes. Many studies investigated the mechanism mediating the renoprotective effect of GSDMD regulation in the kidneys of patients and animal models with diabetes. As a newly discovered regulatory mechanism, GSDME and Casp3-dependent pyroptotic pathway in the progression of DN has also attracted people’s attention. Z-DEVD-FMK, an inhibitor of Casp3, ameliorates albuminuria, improves renal function, and reduces tubulointerstitial fibrosis in diabetic mice, and these effects are associated with the inhibition of GSDME. Studies of HK-2 cells indicated that the molecular and histological features of secondary necrosis were present following glucose stimulation due to GSDME cleavage, such as cell swelling, and release of cellular contents. Therefore, therapies targeting Casp3/GSDME-dependent pyroptosis have potential for treatment of DN. A novel nephroprotective strategy that employs GSDME-derived peptides which are directed against Casp3-induced cell death may be a key breakthrough. This mini-review describes the discovery and history of research in this pyroptosis pathway and reviews the function of proteins in the gasdermin family, with a focus on the role of GSDME-mediated pyroptosis in DN. Many studies have investigated the impact of GSDME-mediated pyroptosis in kidney diseases, and these studies used multiple interventions, in vitro models, and in vivo models. We expect that further research on the function of GDSME in DN may provide valuable insights that may help to improve treatments for this disease.

Objective: Sodium glucose cotransporter 2 inhibitors (SGLT2-is) are antidiabetic drugs that improve glycemic control by limiting urinary glucose reuptake in the proximal tubule. SGLT2-is might suppress atherosclerotic processes and ameliorate the prognosis of patients with diabetes mellitus diagnosed with or at high risk of atherosclerotic cardiovascular disease (ASCVD). In this mini review, we examine the role of SGLT2-is in the development and progression of atherosclerosis throughout its spectrum, from subclinical atherosclerosis to ASCVD. Data Sources���PubMed and Google Scholar were searched for publications related to SGLT2-is and atherosclerosis. All types of articles were considered, including clinical trials, animal studies, in vitro observations, and reviews and meta-analyses. Data were examined according to their impact and clinical relevance. Synopsis of Content���We first review the underlying mechanisms of SGLT2-is on the development and progression of atherosclerosis, including favorable effects on lipid metabolism, reduction of systemic inflammation, and improvement of endothelial function. We then discuss the putative impact of SGLT2-is on the formation, composition, and stability of atherosclerotic plaque. Furthermore, we evaluate the effects of SGLT2-is in subclinical atherosclerosis assessed by carotid intima media thickness and pulse wave velocity. Subsequently, we summarize the effects of SGLT2-is in ASCVD events, including ischemic stroke, angina pectoris, myocardial infarction, revascularization, and peripheral artery disease, as well as major adverse cardiovascular events, cardiovascular mortality, heart failure, and chronic kidney disease. Moreover, we examine factors that could modify the role of SGLT2-is in atherosclerosis, including sex, age, diabetes, glycemic control, ASCVD, and SGLT2-i compounds. Additionally, we propose future directions that can improve our understanding of SGLT2-is and atherosclerosis.

Augmented renal clearance (ARC) is a phenomenon of increased renal function in patients with risk factors. Sub-therapeutic drug concentrations and antibacterial exposure in ARC patients are the main reasons for clinical treatment failure. Decades of increased research have focused on these phenomena, but there are still some existing disputes and unresolved issues. This article reviews information on some important aspects of what we have known and provides suggestion on what we will do regarding ARC. In this article, we review the current research progress and its limitations, including clinical identification, special patients, risk factors, metabolism, animal models and clinical treatments, and provide some promising directions for further research in this area.

Glioblastoma multiforme (GBM) is the most common malignant primary brain tumor with a poor prognosis. The current standard treatment regimen represented by temozolomide/radiotherapy has an average survival time of 14.6 months, while the 5-year survival rate is still less than 5%. New therapeutics are still needed to improve the therapeutic outcome of glioblastoma treatment. The blood-brain barrier (BBB) is the main barrier that prevents therapeutic drugs from reaching the brain. Nanotechnologies that enable drug delivery across the BBB hold great promise for the treatment of glioblastoma. This review will summarize the various drug delivery systems used to treat glioma and focus on their approaches for overcoming the blood-brain barrier to enhance the accumulation of small molecules, protein and gene drugs, etc. in the brain.

Introduction: Patient information leaflets (PILs) of medicinal products are informative documents that accompany medicines and explain their components, modes of use, interactions with other medicines, and other relevant issues. When patients do not adequately understand the information in the leaflets, they may engage in behaviors that affect their health (e.g., self-medication).Objective: To identify patient-related factors and characteristics of PILs that can promote cognitive, emotional, and behavioral changes that lead to appropriate drug use practices. Additionally, we aimed to determine strategies that could be implemented to design leaflets that convey adequate information and are easier to understand.Method and Results: We evaluated scientific articles published in databases and containing information on PILs suitability to be used in a patient population. A total of 51 articles were selected as the sample. Certain leaflet factors that favored or hindered understanding were identified (e.g., format in which the leaflets are presented, their structure, their adaptation to the sociodemographic and linguistic characteristics of the population, their wording…). Similarly, we also identified patient factors, such as previous experience taking the drugs referred to in the leaflet; the type of emotions experienced when reading the leaflets; the emphasis on the adverse effects of the medications; sociodemographic variables (i.e., age or educational level); and degree of interest in their own healthcare.Conclusion: Patient and leaflet factors influence the comprehension of information in the PIL; hence, emphasis should be placed on these factors to increase treatment and medication adherence and to reduce health-risk behaviors.

In recent years, and particularly associated with the increase of cancer patients’ life expectancy, the occurrence of cancer treatment sequelae, including cognitive impairments, has received considerable attention. Chemotherapy-induced cognitive impairments (CICI) can be observed not only during pharmacological treatment of the disease but also long after cessation of this therapy. The lack of effective tools for its diagnosis together with the limited treatments currently available for alleviation of the side-effects induced by chemotherapeutic agents, demonstrates the need of a better understanding of the mechanisms underlying the pathology. This review focuses on the comprehensive appraisal of two main processes associated with the development of CICI: neuroinflammation and oxidative stress, and proposes the endogenous cannabinoid system (ECS) as a new therapeutic target against CICI. The neuroprotective role of the ECS, well described in other cognitive-related neuropathologies, seems to be able to reduce the activation of pro-inflammatory cytokines involved in the neuroinflammatory supraspinal processes underlying CICI. This review also provides evidence supporting the role of cannabinoid-based drugs in the modulation of oxidative stress processes that underpin cognitive impairments, and warrant the investigation of endocannabinoid components, still unknown, that may mediate the molecular mechanism behind this neuroprotective activity. Finally, this review points forward the urgent need of research focused on the understanding of CICI and the investigation of new therapeutic targets., LB and AL-B are supported by the Irish Research Council (IRCL/ 2017/78). RA is supported by Ministerio de Ciencia, Innovación y Universidades (PID2019-111510RB-I00) and Universidad Rey Juan Carlos.

Heart failure (HF), the leading cause of death among men and women world-wide, causes great health and economic burdens. HF can be triggered by many factors, such as coronary artery disease, heart attack, cardiomyopathy, hypertension, obesity, etc., all of which have close relations with calcium signal and the level of reactive oxygen species (ROS). Calcium is an essential second messenger in signaling pathways, playing a pivotal role in regulating the life and death of cardiomyocytes via the calcium-apoptosis link mediated by the cellular level of calcium. Meanwhile, calcium can also control the rate of energy production in mitochondria that are the major resources of ROS whose overproduction can lead to cell death. More importantly, there are bidirectional interactions between calcium and ROS, and such interactions may have therapeutic implications in treating HF through finely tuning the balance between these two by certain drugs. Many naturally derived products, e.g., flavones and isoflavones, have been shown to possess activities in regulating calcium and ROS simultaneously, thereby leading to a balanced microenvironment in heart tissues to exert therapeutic efficacies in HF. In this mini review, we aimed to provide an updated knowledge of the interplay between calcium and ROS in the development of HF. In addition, we summarized the recent studies (in vitro, in vivo and in clinical trials) using natural isolated flavones and isoflavones in treating HF. Critical challenges are also discussed. The information collected may help to evoke multidisciplinary efforts in developing novel agents for the potential prevention and treatment of HF.

Epithelial membrane transporter kinetics portray an irrefutable role in solute transport in and out of cells. Mechanistic models are used to investigate the transport of solutes at the organ, tissue, cell or membrane scale. Here, we review the recent advancements in using computational models to investigate epithelial transport kinetics on the cell membrane. Various methods have been employed to develop transport phenomena models of solute flux across the epithelial cell membrane. Interestingly, we noted that many models used lumped parameters, such as the Michaelis-Menten kinetics, to simplify the transporter-mediated reaction term. Unfortunately, this assumption neglects transporter numbers or the fact that transport across the membrane may be affected by external cues. In contrast, more recent mechanistic transporter kinetics models account for the transporter number. By creating models closer to reality researchers can investigate the downstream effects of physical or chemical disturbances on the system. Evidently, there is a need to increase the complexity of mechanistic models investigating the solute flux across a membrane to gain more knowledge of transporter-solute interactions by assigning individual parameter values to the transporter kinetics and capturing their dependence on each other. This change results in better pharmacokinetic predictions in larger scale platforms. More reliable and efficient model predictions can be made by creating mechanistic computational models coupled with dedicated in vitro experiments. It is also vital to foster collaborative efforts among transporter kinetics researchers in the modeling, material science and biological fields.

Since the 1980s, the development of a pharmacology based on nerve growth factor (NGF) has been postulated for the therapy of Alzheimer’s disease (AD). This hypothesis was based on the rescuing effect of the neurotrophin on the cholinergic phenotype of the basal forebrain neurons, primarily compromised during the development of AD. Subsequently, the use of NGF was put forward to treat a broader spectrum of neurological conditions affecting the central nervous system, such as Parkinson’s disease, degenerative retinopathies, severe brain traumas and neurodevelopmental dysfunctions. While supported by solid rational assumptions, the progress of a pharmacology founded on these hypotheses has been hampered by the difficulty of conveying NGF towards the brain parenchyma without resorting to invasive and risky delivery methods. At the end of the last century, it was shown that NGF administered intranasally to the olfactory epithelium was able to spread into the brain parenchyma. Notably, after such delivery, pharmacologically relevant concentration of exogenous NGF was found in brain areas located at considerable distances from the injection site along the rostral-caudal axis. These observations paved the way for preclinical characterization and clinical trials on the efficacy of intranasal NGF for the treatment of neurodegenerative diseases and of the consequences of brain trauma. In this review, a summary of the preclinical and clinical studies published to date will be attempted, as well as a discussion about the mechanisms underlying the efficacy and the possible development of the pharmacology based on intranasal conveyance of NGF to the brain.

Curcuma longa is a perennial herb that belongs to the Zingiberaceae family. To date, literature includes more than 11.000 scientific articles describing all its beneficial properties. In the last 3 decades various surveys by the U.S. Food and Drug Administration (FDA) concluded that curcumin, the most active ingredient of the drug, is a “generally safe” compound with strong anti-oxidant effects. Curcuma longa was introduced in the daily diet by ayurvedic teachers due to its beneficial effects on health. Nonetheless, recently several reports, from the various global surveillance systems on the safety of plant products, pointed out cases of hepatotoxicity linked to consumption of food supplements containing powdered extract and preparations of Curcuma longa. The latest trend is the use of Curcuma longa as a weight-loss product in combination with piperine, which is used to increase its very low systemic bioavailability. Indeed, only 20 mg piperine, one of the alkaloids found in black pepper (Piper nigrum), assumed at the same time with 2 g curcumin increased 20-fold serum curcumin bioavailability. This combination of natural products is now present in several weight loss supplements containing Curcuma longa. The enhanced drug bioavailability caused by piperine is due to its potent inhibition of drug metabolism, being able to inhibit human P-glycoprotein and CYP3A4, while it interferes with UDP-glucose dehydrogenase and glucuronidation activities in liver. While only few cases of hepatotoxicity, assessed using Roussel Uclaf Causality Assessment Method (RUCAM) method, from prolonged intake of piperine and curcumin have been reported, it would be reasonable to speculate that the suspected toxicity of Curcuma longa could be due to the concomitant presence of piperine itself. Hence, not only there is the need of more basic research to understand the etiopathology of curcumin-related hepatotoxicity and of the combination curcumin-piperine, but human trials will be necessary to settle this dispute.

Increased risk of colorectal cancer (CRC) in inflammatory bowel disease (IBD) patients has been attributed to long-standing chronic inflammation, with the contribution of genetic alterations and environmental factors such as the microbiota. Moreover, accumulating data indicate that IBD-associated CRC (IBD-CRC) may initiate and develop through a pathway of tumorigenesis distinct from that of sporadic CRC. This mini-review summarizes the current knowledge of IBD-CRC, focusing on the main mechanisms underlying its pathogenesis, and on the important role of immunomodulators and biologics used to treat IBD patients in interfering with the inflammatory process involved in carcinogenesis.

Background: Standard of Care (SoC) has been used with different significance across Randomized Clinical Trials (RCTs) on the treatment of Covid-19. In the context of a living systematic review on pharmacological interventions for COVID-19, we assessed the characteristics of the SoC adopted in the published RCTs.Methods: We performed a systematic review searching Medline, Pubmed, Embase, Cochrane Covid-19 register, international trial registers, medRxiv, bioRxiv, and arXiv up to April 10, 2021. We included all RCTs comparing any pharmacological intervention for Covid-19 against any drugs, placebo, or SoC. All trials selected have been classified as studies with SoC including treatments under investigation for COVID-19 (SoC+); studies with SoC without specifications regarding the potential therapies allowed (SoC-); studies including as control groups Placebo (P) or active controls (A+).Results: We included in our analysis 144 RCTs, comprising 78,319 patients. Most of these trials included SoC (108; 75.0%); some in all arms of the study (69.7%) or just as independent comparators (30.3%). Treatments under investigation for COVID-19 in other trials were included in the SoC (SoC+) in 67 cases (62.0%), Thirty-one different therapeutic agents (alone or in combination) were counted within the studies with SoC+: mostly hydroxychloroquine or chloroquine (28), lopinavir/ritonavir (20) or azithromycin (16). No specification was given regarding treatment allowed in the control groups (SoC-) in 41 studies (38.0%).Conclusion: Our analysis shows that the findings emerging from several clinical trials regarding the efficacy and safety of pharmacological intervention for COVID-19 might be jeopardized by the quality of control arms.

Sepsis is a life-threatening syndrome induced by aberrant host response towards infection. The autophagy-lysosomal pathway (ALP) plays a fundamental role in maintaining cellular homeostasis and conferring organ protection. However, this pathway is often impaired in sepsis, resulting in dysregulated host response and organ dysfunction. Transcription factor EB (TFEB) is a master modulator of the ALP. TFEB promotes both autophagy and lysosomal biogenesis via transcriptional regulation of target genes bearing the coordinated lysosomal expression and regulation (CLEAR) motif. Recently, increasing evidences have linked TFEB and the TFEB dependent ALP with pathogenetic mechanisms and therapeutic implications in sepsis. Therefore, this review describes the existed knowledge about the mechanisms of TFEB activation in regulating the ALP and the evidences of their protection against sepsis, such as immune modulation and organ protection. In addition, TFEB activators with diversified pharmacological targets are summarized, along with recent advances of their potential therapeutic applications in treating sepsis.

Graves’ disease (GD) is a condition caused by an autoimmune process involving the thyroid gland, whose main outcome is hyperthyroidism. TSAb start the autoimmune process stimulating the overproduction of thyroid hormones. In addition, TSAb can stimulate TSH-R expressed in fibroblasts and orbital pre-adipocytes leading to the manifestation of Graves’ ophtalmopathy (GO). Also, autoantibodies directed against IGF-1R have an important role in immune-pathogenesis of GO. Fundamental is the role played by cytokines (IFN-γ, TNF-α, Il-6), and Th1 chemokines in the immune-pathogenesis of both disorders, particularly in the active phase. Novel discoveries in the field led to the investigation of promising therapies, such as immune-therapies towards specific antigens (for example against TSH-R), aiming in restoring the immune tolerance versus the immune dominant epitopes associated with autoimmunity in GD. Moreover, Etanercept (that blocks the TNF-mediated inflammatory responses), TCZ (that acts against the IL-6 receptor), and RTX (that acts against CD20) have proven to be useful and safe therapeutic options in refractory GO treatment. Furthermore, teprotumumab (a human monoclonal anti-IGF-1R blocking antibody), have been revealed effective in the treatment of patients with moderate-severe GO and it is now approved for GO therapy in United States. Molecules able to act as antagonists of CXCR3, or to block CXCL10, are also under study. More extensive researches are needed to deepen out these drugs as well as to identify new targeted and effective therapies, that will permit a more precise identification of GD, or GO, patients able to respond to specific targeted therapies.

β-thalassemia, a disease that results from defects in β-globin synthesis, leads to an imbalance of β- and α-globin chains and an excess of α chains. Defective erythroid maturation, ineffective erythropoiesis, and shortened red blood cell survival are commonly observed in most β-thalassemia patients. In severe cases, blood transfusion is considered as a mainstay therapy; however, regular blood transfusions result in chronic iron overload with life-threatening complications, e.g., endocrine dysfunction, cardiomyopathy, liver disease, and ultimately premature death. Therefore, transplantation of healthy hematopoietic stem cells (HSCs) is considered an alternative treatment. Patients with a compatible human leukocyte antigen (HLA) matched donor can be cured by allogeneic HSC transplantation. However, some recipients faced a high risk of morbidity/mortality due to graft versus host disease or graft failure, while a majority of patients do not have such HLA match-related donors. Currently, the infusion of autologous HSCs modified with a lentiviral vector expressing the β-globin gene into the erythroid progenitors of the patient is a promising approach to completely cure β-thalassemia. Here, we discuss a history of β-thalassemia treatments and limitations, in particular the development of β-globin lentiviral vectors, with emphasis on clinical applications and future perspectives in a new era of medicine.

Despite structural similarity, the five subtypes comprising the cholinergic muscarinic family of G protein-coupled receptors regulate remarkably diverse biological functions. This mini review focuses on the closely related and commonly co-expressed M1R and M3R muscarinic acetylcholine receptor subtypes encoded respectively by CHRM1 and CHRM3. Activated M1R and M3R signal via Gq and downstream initiate phospholipid turnover, changes in cell calcium levels, and activation of protein kinases that alter gene transcription and ultimately cell function. The unexpectedly divergent effects of M1R and M3R activation, despite similar receptor structure, distribution, and signaling, are puzzling. To explore this conundrum, we focus on the gastrointestinal (GI) tract and liver because abundant data identify opposing effects of M1R and M3R activation on the progression of gastric, pancreatic, and colon cancer, and liver injury and fibrosis. Whereas M3R activation promotes GI neoplasia, M1R activation appears protective. In contrast, in murine liver injury models, M3R activation promotes and M1R activation mitigates liver fibrosis. We analyze these findings critically, consider their therapeutic implications, and review the pharmacology and availability for research and therapeutics of M1R and M3R-selective agonists and antagonists. We conclude by considering gaps in knowledge and other factors that hinder the application of these drugs and the development of new agents to treat GI and liver diseases.

Fructose, especially industrial fructose (sucrose and high fructose corn syrup) is commonly used in all kinds of beverages and processed foods. Liver is the primary organ for fructose metabolism, recent studies suggest that excessive fructose intake is a driving force in non-alcoholic fatty liver disease (NAFLD). Dietary fructose metabolism begins at the intestine, along with its metabolites, may influence gut barrier and microbiota community, and contribute to increased nutrient absorption and lipogenic substrates overflow to the liver. Overwhelming fructose and the gut microbiota-derived fructose metabolites (e.g., acetate, butyric acid, butyrate and propionate) trigger thede novolipogenesis in the liver, and result in lipid accumulation and hepatic steatosis. Fructose also reprograms the metabolic phenotype of liver cells (hepatocytes, macrophages, NK cells, etc.), and induces the occurrence of inflammation in the liver. Besides, there is endogenous fructose production that expands the fructose pool. Considering the close association of fructose metabolism and NAFLD, the drug development that focuses on blocking the absorption and metabolism of fructose might be promising strategies for NAFLD. Here we provide a systematic discussion of the underlying mechanisms of dietary fructose in contributing to the development and progression of NAFLD, and suggest the possible targets to prevent the pathogenetic process.

The epithelial-to-mesenchymal transition (EMT), an embryonic program relaunched during wound healing and in pathological conditions such as fibrosis and cancer, continues to gain the attention of the research community, as testified by the exponential trend of publications since its discovery in the seventies. From the first description as a mesenchymal transformation, the concept of EMT has been substantially refined as an in-depth comprehension of its functional role has recently emerged thanks to the implementation of novel mouse models as well as the use of sophisticated mathematical modeling and bioinformatic analysis. Nevertheless, attempts to targeting EMT in fibrotic diseases are at their infancy and continue to pose several challenges. The aim of this mini review is to recapitulate the most recent concepts in the EMT field and to summarize the different strategies which have been exploited to target EMT in fibrotic disorders.

Programmed death protein 1 (PD1) is a common immunosuppressive member on the surface of T cells and plays an imperative part in downregulating the immune system and advancing self-tolerance. Its ligand programmed cell death ligand 1 (PDL1) is overexpressed on the surface of malignant tumor cells, where it binds to PD1, inhibits the proliferation of PD1-positive cells, and participates in the immune evasion of tumors leading to treatment failure. The PD1/PDL1-based pathway is of great value in immunotherapy of cancer and has become an important immune checkpoint in recent years, so understanding the mechanism of PD1/PDL1 action is of great significance for combined immunotherapy and patient prognosis. The inhibitors of PD1/PDL1 have shown clinical efficacy in many tumors, for example, blockade of PD1 or PDL1 with specific antibodies enhances T cell responses and mediates antitumor activity. However, some patients are prone to develop drug resistance, resulting in poor treatment outcomes, which is rooted in the insensitivity of patients to targeted inhibitors. In this paper, we reviewed the mechanism and application of PD1/PDL1 checkpoint inhibitors in tumor immunotherapy. We hope that in the future, promising combination therapy regimens can be developed to allow immunotherapeutic tools to play an important role in tumor treatment. We also discuss the safety issues of immunotherapy and further reflect on the effectiveness of the treatment and the side effects it brings.

COVID-19 pneumonia caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has ravaged the world, resulting in an alarming number of infections and deaths, and the number continues to increase. The pathogenesis caused by the novel coronavirus was found to be a disruption of the pro-inflammatory/anti-inflammatory response. Due to the lack of effective treatments, different strategies and treatment methods are still being researched, with the use of vaccines to make the body immune becoming the most effective means of prevention. Antiviral drugs and respiratory support are often used clinically as needed, but are not yet sufficient to alleviate the cytokine storm (CS) and systemic inflammatory response syndrome. How to neutralize the cytokine storm and inhibit excessive immune cell activation becomes the key to treating neocoronavirus pneumonia. Immunotherapy through the application of hormones and monoclonal antibodies can alleviate the immune imbalance, but the clinical effectiveness and side effects remain controversial. This article reviews the pathogenesis of neocoronavirus pneumonia and discusses the immunomodulatory therapies currently applied to COVID-19. We aim to give some conceptual thought to the prevention and immunotherapy of neocoronavirus pneumonia.

Regulatory agencies installed orphan drug regulations to stimulate research and development of new innovative treatments for life-threatening diseases with a low prevalence (rare diseases). We established a list of well-known food-related ingredients with clinical evidence for rare diseases in the open medical literature that obtained marketing authorization as an expensive "orphan drug", protected by intellectual property (IP) rights. We show that these ingredients are part of an established practice of medicinal compounding-a form of point of care manufacturing. We argue that these ingredients should be considered as "pharmaceutical commons", and that regulatory incentives for private companies and market protection mechanisms such as IP rights are not justified in this case. ispartof: FRONTIERS IN PHARMACOLOGY vol:12 ispartof: location:Switzerland status: published

Natural products are well-characterized to have pharmacological or biological activities that can be of therapeutic benefits for cancer therapy, which also provide an important source of inspiration for discovery of potential novel small-molecule drugs. In the past three decades, accumulating evidence has revealed that natural products can modulate a series of key autophagic signaling pathways and display therapeutic effects in different types of human cancers. In this review, we focus on summarizing some representative natural active compounds, mainly including curcumin, resveratrol, paclitaxel, Bufalin, and Ursolic acid that may ultimately trigger cancer cell death through the regulation of some key autophagic signaling pathways, such as RAS-RAF-MEK-ERK, PI3K-AKT-mTOR, AMPK, ULK1, Beclin-1, Atg5 and p53. Taken together, these inspiring findings would shed light on exploiting more natural compounds as candidate small-molecule drugs, by targeting the crucial pathways of autophagy for the future cancer therapy.

Kidney transplant recipients are at high risk of developing severe COVID-19 due to the coexistence of several transplant-related comorbidities (e.g., cardiovascular disease, diabetes) and chronic immunosuppression. As a consequence, a large part of SARS-CoV-2 infected patients have been managed with a reduction of immunosuppression. The mTOR-I, together with antimetabolites, have been often discontinued in order to minimize the risk of pulmonary toxicity and to antagonize pharmacological interaction with antiviral/anti-inflammatory drugs. However, at our opinion, this therapeutic strategy, although justified in kidney transplant recipients with severe COVID-19, should be carefully evaluated in asymptomatic/paucisymptomatic patients in order to avoid the onset of acute allograft rejections, to potentially exploit the mTOR-I antiviral properties, to reduce proliferation of conventional T lymphocytes (which could mitigate the cytokine storm) and to preserve Treg growth/activity which could reduce the risk of progression to severe disease. In this review, we discuss the current literature regarding the therapeutic potential of mTOR-Is in kidney transplant recipients with COVID-19 with a focus on pulmonary fibrosis.

Advancements in treatment for the rare genetic disorder known as Alagille Syndrome (ALGS) have been regrettably slow. The large variety of mutations to the JAG1 and NOTCH2 genes which lead to ALGS pose a unique challenge for developing targeted treatments. Due to the central role of the Notch signaling pathway in several cancers, traditional treatment modalities which compensate for the loss in activity caused by mutation are rightly excluded. Unfortunately, current treatment plans for ALGS focus on relieving symptoms of the disorder and do not address the underlying causes of disease. Here we review several of the current and potential key technologies and strategies which may yield a significant leap in developing targeted therapies for this disorder.

Atherosclerosis poses serious health problems and increases the risk of various cardiovascular diseases, including myocardial infarction, heart failure, ischemic stroke, and peripheral arterial disease. Atherosclerosis patients require long-term medications to prevent complications, some of which are costly and may result in unwanted adverse reactions. Natural products have emerged as potential sources of bioactive compounds that provide health benefits in cardiovascular diseases. Increased inflammation and vascular remodeling have been associated with atherosclerosis pathogenesis. The molecules involved in signaling pathways are considered valuable targets for new treatment approaches. Therefore, this review aimed to summarize the available evidence of the anti-inflammatory effects of thymoquinone, the major active compound isolated from Nigella sativa L., via inflammatory signaling pathways in atherosclerosis. Specifically, nuclear factor-κB and mitogen-activated protein kinase signaling pathways were considered. Furthermore, the potential toxic effects elicited by thymoquinone were addressed. These findings suggest a potential role of thymoquinone in managing atherosclerosis, and further studies are required to ascertain its effectiveness and safety profile.

Altered tumor metabolism is a hallmark of cancer and targeting tumor metabolism has been considered as an attractive strategy for cancer therapy. Prostaglandin Reductase 1 (PTGR1) is a rate-limiting enzyme involved in the arachidonic acid metabolism pathway and mainly responsible for the deactivation of some eicosanoids, including prostaglandins and leukotriene B4. A growing evidence suggested that PTGR1 plays a significant role in cancer and has emerged as a novel target for cancer therapeutics. In this review, we summarize the progress made in recent years toward the understanding of PTGR1 function and structure, highlight the roles of PTGR1 in cancer, and describe potential inhibitors of PTGR1. Finally, we provide some thoughts on future directions that might facilitate the PTGR1 research and therapeutics development.

Pancreatic islet transplantation is a minimally invasive procedure to replace β-cells in a subset of patients with autoimmune type 1 diabetic mellitus, who are extremely sensitive to insulin and lack counter-regulatory measures, and thereby increasing their risk of neuroglycopenia and hypoglycemia unawareness. Thus, pancreatic islet transplantation restores normoglycemia and insulin independence, and prevents long-term surgical complications associated with whole-organ pancreas transplantation. Nonetheless, relative inefficiency of islet isolation and storage process as well as progressive loss of islet function after transplantation due to unvoidable islet inflammation and apoptosis, hinder a successful islet transplantation. Carbon monoxide (CO), a gas which was once feared for its toxicity and death at high concentrations, has recently emerged as a medical gas that seems to overcome the challenges in islet transplantation. This minireview discusses recent findings about CO in preclinical pancreatic islet transplantation and the underlying molecular mechanisms that ensure islet protection during isolation, islet culture, transplantation and post-transplant periods in type 1 diabetic transplant recipients. In addition, the review also discusses clinical translation of these promising experimental findings that serve to lay the foundation for CO in islet transplantation to replace the role of insulin therapy, and thus acting as a cure for type 1 diabetes mellitus and preventing long-term diabetic complications.

The association between sodium-glucose cotransporter 2 inhibitors (SGLT2is) and various cardiovascular and respiratory diseases is unestablished. This meta-analysis aimed to explore whether use of SGLT2is is significantly associated with the occurrences of 80 types of cardiovascular diseases and 55 types of respiratory diseases. Large randomized trials of SGLT2is were included in analysis. Meta-analysis was conducted to synthesize risk ratio (RR) and 95% confidence interval (CI). Nine large trials were included in analysis. Compared to placebo, SGLT2is were associated with the reduced risks of 9 types of cardiovascular diseases (e.g., atrial fibrillation [RR 0.78, 95% CI 0.67-0.91], bradycardia [RR 0.60, 95% CI 0.40-0.89], and hypertensive emergency [RR 0.29, 95% CI 0.12-0.72]) and 11 types of respiratory diseases (e.g., chronic obstructive pulmonary disease [RR 0.77, 95% CI 0.61-0.97], asthma [RR 0.57, 95% CI 0.35-0.95], and sleep apnoea syndrome [RR 0.36, 95% CI 0.15-0.87]). The results of random-effects meta-analysis were similar with those of fixed-effects meta-analysis. No heterogeneity or only little heterogeneity was found in most meta-analyses. No publication bias was observed in most of the meta-analyses conducted in this study. SGLT2is were not significantly associated with the other 115 cardiovascular and respiratory diseases. SGLT2is are associated with the reduced risks of 9 types of cardiovascular diseases (e.g., atrial fibrillation, bradycardia, and hypertensive emergency) and 11 types of respiratory diseases (e.g., chronic obstructive pulmonary disease, asthma, and sleep apnoea syndrome). This proposes the potential of SGLT2is to be used for prevention of these cardiovascular and respiratory diseases.

Kidneys are critical for the elimination of many drugs and metabolites via the urine, filtering waste and maintaining proper fluid and electrolyte balance. Emerging technologies incorporating engineered three-dimensional (3D) in vitro cell culture models, such as organoids and microphysiological systems (MPS) culture platforms, have been developed to replicate nephron function, leading to enhanced efficacy, safety, and toxicity evaluation of new drugs and environmental exposures. Organoids are tiny, self-organized three-dimensional tissue cultures derived from stem cells that can include dozens of cell types to replicate the complexity of an organ. In contrast, MPS are highly controlled fluidic culture systems consisting of isolated cell type(s) that can be used to deconvolute mechanism and pathophysiology. Both systems, having their own unique benefits and disadvantages, have exciting applications in the field of kidney disease modeling and therapeutic discovery and toxicology. In this review, we discuss current uses of both hPSC-derived organoids and MPS as pre-clinical models for studying kidney diseases and drug induced nephrotoxicity. Examples such as the use of organoids to model autosomal dominant polycystic kidney disease, and the use of MPS to predict renal clearance and nephrotoxic concentrations of novel drugs are briefly discussed. Taken together, these novel platforms allow investigators to elaborate critical scientific questions. While much work needs to be done, utility of these 3D cell culture technologies has an optimistic outlook and the potential to accelerate drug development while reducing the use of animal testing.