A promising therapeutic target for psoriasis: Neuropeptides in human skin

Psoriasis is a chronic inflammatory skin disease featured by excessive proliferation of keratinocytes, clearly defined round erythema and dry, scaly plaques, long-term inflammatory cells infiltration in skin lesions. However, the physiopathological mechanism of psoriasis is still not clearly understood. Neuropeptides, a class of peptides secreted by the nervous system, may play important roles in promoting excessive proliferation of keratinocyte, enhancing angiogenesis, vasodilation, plasma extravasation and chemotaxis of inflammatory cells during the development of psoriasis. To understand the pathogenesis of neuropeptides in psoriasis, we summarized the function of several common neuropeptides in psoriasis and hypothesize neuropeptides may serve as therapeutic potential novel targets in psoriasis.     

Synthesis and evaluation of tofacitinib analogs designed to mitigate metabolic activation

Tofacitinib (TFT), a JAK inhibitor used for the treatment of rheumatoid arthritis and other diseases, is associated with severe liver injury that is believed to be caused by its reactive aldehyde or epoxide metabolites. In this study, we synthesized six tofacitinib analogs designed to avoid the formation of reactive metabolites and evaluated their JAK3 inhibitory activity, metabolic stability, CYP3A time-dependent inhibition, and cytotoxicity. Our data indicated that purine analog 3, which showed little inhibition of CYP3A and cytotoxicity and inhibited JAK3 in the nanomolar range, could be a safer drug candidate than TFT. In addition, the results of the bioactivation study using TFT and its analogs suggest that the epoxide metabolite might contribute to TFT-induced CYP3A4 mechanism-based inhibition and hepatic toxicity.     

Mesoporous silica nanoparticles: Their potential as drug delivery carriers and nanoscavengers in Alzheimer's and Parkinson's diseases

Worldwide, populations face significant burdens from neurodegenerative disorders (NDDs), especially Alzheimer's and Parkinson's diseases. Although there are many proposed etiologies for neurodegenerative disorders, including genetic and environmental factors, the exact pathogenesis for these disorders is not fully understood. Most patients with NDDs are given lifelong treatment to improve their quality of life. There are myriad treatments for NDDs; however, these agents are limited by their side effects and difficulty in passing the blood–brain barrier (BBB). Furthermore, the central nervous system (CNS) active pharmaceuticals could offer symptomatic relief for the patient's condition without providing a complete cure or prevention by targeting the disease's cause. Recently, Mesoporous silica nanoparticles (MSNs) have gained interest in treating NDDs since their physicochemical properties and inherent ability to pass BBB make them possible drug carriers for several drugs for NDDs treatment. This paper provides insight into the pathogenesis and treatment of NDDs, along with the recent advances in applying MSNs as fibril scavengers. Moreover, the application of MSNs-based formulations in enhancing or sustaining drug release rate, and brain targeting via their responsive release properties, besides the neurotoxicity of MSNs, have been reviewed.     

Curcumin ameliorates hepatic chronic inflammation induced by bile duct obstruction in mice through the activation of heme oxygenase-1

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Store-operated calcium entry: From physiology to tubular aggregate myopathy

Store-Operated Ca²⁺ entry (SOCE) is recognized as a key mechanism in muscle physiology necessary to refill intracellular Ca²⁺ stores during sustained muscle activity. For many years the cell structures expected to mediate SOCE in skeletal muscle fibres remained unknown. Recently, the identification of Ca²⁺ Entry Units (CEUs) in exercised muscle fibres opened new insights into the role of extracellular Ca²⁺ in muscle contraction and, more generally, in intracellular Ca²⁺ homeostasis. Accordingly, intracellular Ca²⁺ unbalance due to alterations in SOCE strictly correlates with muscle disfunction and disease. Mutations in proteins involved in SOCE (STIM1, ORAI1, and CASQ1) have been linked to tubular aggregate myopathy (TAM), a disease that causes muscle weakness and myalgia and is characterized by a typical accumulation of highly ordered and packed membrane tubules originated from the sarcoplasmic reticulum (SR). Achieving a full understanding of the molecular pathways activated by alterations in Ca²⁺ entry mechanisms is a necessary step to design effective therapies for human SOCE-related disorders.     

Mitochondrial-targeted nanoparticles: Delivery and therapeutic agents in cancer

Antitumor agents are delivered via nanoparticles (NPs) to the mitochondria. The drugs attack the mitochondria resulting in mitochondrial damage and the release of cytochrome C (Cyto-C). Cyto-C binds with Apaf1 and Caspase-9 to form an apoptosome. The apoptosome activates Caspase 3, which ultimately results in the death of cancer cells.

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Targeting regulated cell death (RCD) with small-molecule compounds in cancer therapy: A revisited review of apoptosis,autophagy-dependent cell death and necroptosis

Evasion of regulated cell death (RCD), mainly referring to apoptosis, autophagy-dependent cell death, necroptosis, and other subroutines, is one of the well-established hallmarks of cancer cells. Accumulating evidence has revealed several small-molecule compounds that target different subroutines of RCD in cancer therapy. In this review, we summarize key pathways of apoptosis, autophagy-dependent cell death and necroptosis in cancer, and describe small-molecule compounds that target these pathways and have potential as therapeutics. These inspiring findings light the way towards the discovery of more ‘magic bullets’ that could work individually or cooperatively to target precisely the three RCD subroutines and so improve cancer treatment.     

Targeting autophagy in colorectal cancer: An update on pharmacological small-molecule compounds

Autophagy, an evolutionarily highly conserved cellular degradation process, plays the Janus role (either cytoprotective or death-promoting) in colorectal cancer, so the targeting of several key autophagic pathways with small-molecule compounds may be a new therapeutic strategy. In this review, we discuss autophagy-associated cell death pathways and key cytoprotective autophagy pathways in colorectal cancer. Moreover, we summarize a series of small-molecule compounds that have the potential to modulate autophagy-associated cell death or cytoprotective autophagy for therapeutic purposes. Taken together, these findings demonstrate the Janus role of autophagy in colorectal cancer, and shed new light on the exploitation of a growing number of small-molecule compounds to target autophagy in future cancer drug discovery.     

Nanoparticles of cisplatin augment drug accumulations and inhibit multidrug resistance transporters in human glioblastoma cells

BackgroundCisplatin (CSP) is a potent anticancer drug widely used in treating glioblastoma multiforme (GBM). However, CSP's clinical efficacy in GBM contrasted with low therapeutic ratio, toxicity, and multidrug resistance (MDR). Therefore, we have developed a system for the active targeting of cisplatin in GBM via cisplatin loaded polymeric nanoplatforms (CSP-NPs).MethodsCSP-NPs were prepared by modified double emulsion and nanoprecipitation techniques. The physiochemical characterizations of CSP-NPs were performed using zeta sizer, scanning electron microscopy (SEM), drug release kinetics, and drug content analysis. Cytotoxicity, induction of apoptosis, and cell cycle-specific activity of CSP-NPs in human GBM cell lines were evaluated by MTT assay, fluorescent microscopy, and flow cytometry. Intracellular drug uptake was gauged by fluorescent imaging and flow cytometry. The potential of CSP-NPs to inhibit MDR transporters were assessed by flow cytometry-based drug efflux assays.ResultsCSP-NPs have smooth surface properties with discrete particle size with required zeta potential, polydispersity index, drug entrapment efficiency, and drug content. CSP-NPs has demonstrated an ‘initial burst effect’ followed by sustained drug release properties. CSP-NPs imparted dose and time-dependent cytotoxicity and triggered apoptosis in human GBM cells. Interestingly, CSP-NPs significantly increased uptake, internalization, and accumulations of anticancer drugs. Moreover, CSP-NPs significantly reversed the MDR transporters (ABCB1 and ABCG2) in human GBM cells.ConclusionThe nanoparticulate system of cisplatin seems to has a promising potential for active targeting of cisplatin as an effective and specific therapeutic for human GBM, thus eliminating current chemotherapy's limitations.     

A guide to oral vaccination: Highlighting electrospraying as a promising manufacturing technique toward a successful oral vaccine development

Most vaccines approved by regulatory bodies are administered via intramuscular or subcutaneous injections and have shortcomings, such as the risk of needle-associated blood infections, pain and swelling at the injection site. Orally administered vaccines are of interest, as they elicit both systemic and mucosal immunities, in which mucosal immunity would neutralize the mucosa invading pathogen before the onset of an infection. Hence, oral vaccination can eliminate the injection associated adverse effects and enhance the person's compliance. Conventional approaches to manufacturing oral vaccines, such as coacervation, spray drying, and membrane emulsification, tend to alter the structural proteins in vaccines that result from high temperature, organic and toxic solvents during production. Electrohydrodynamic processes, specifically electrospraying, could solve these challenges, as it also modulates antigen release and has a high loading efficiency. This review will highlight the mucosal immunity and biological basis of the gastrointestinal immune system, different oral vaccine delivery approaches, and the application of electrospraying in vaccines development.     

Phyllanthus emblica (Amla) methanolic extract regulates multiple checkpoints in 15-lipoxygenase mediated inflammopathies: Computational simulation and in vitro evidence

Amla (Phyllanthus emblica) has long been used in traditional folk medicine to prevent and cure a variety of inflammatory diseases. In this study, the antioxidant activity (DPPH scavenging and reducing power), anti-inflammatory activity (RBC Membrane Stabilization and 15-LOX inhibition), and anticoagulation activity (Serin protease inhibition and Prothrombin Time assays) of the methanolic extract of amla were conducted. Amla exhibited a substantial amount of phenolic content (TPC: 663.53 mg GAE/g) and flavonoid content (TFC: 418.89 mg GAE/g). A strong DPPH scavenging effect was observed with an IC₅₀ of 311.31 µg/ml as compared to standard ascorbic acid with an IC₅₀ of 130.53 µg/ml. In reducing power assay, the EC₅₀ value of the extract was found to be 196.20 µg/ml compared to standard ascorbic acid (EC₅₀ = 33.83 µg/ml). The IC₅₀ value of the RBC membrane stabilization and 15-LOX assays was observed as 101.08 µg/ml (IC₅₀ of 58.62 µg/ml for standard aspirin) and 195.98 µg/ml (IC₅₀ of 19.62 µg/ml for standard quercetin), respectively. The extract also strongly inhibited serine protease (trypsin) activity with an IC₅₀ of 505.81 µg/ml (IC₅₀ of 295.44 µg/ml for standard quercetin). The blood coagulation time (PTT) was found to be 11.91 min for amla extract and 24.11 min for standard Warfarin. Thus, the findings of an in vitro study revealed that the methanolic extract of amla contains significant antioxidant, anti-inflammatory, and anticoagulation activity. Furthermore, in silico docking and simulation of reported phytochemicals of amla with human 15-LOXA and 15-LOXB were carried out to validate the anti-inflammatory activity of amla. In this analysis, epicatechin and catechin showed greater molecular interaction and were considerably stable throughout the 100 ns simulation with 15-lipoxygenase A (15-LOXA) and 15-lipoxygenase B (15-LOXB) respectively.     

Opportunities for overcoming tuberculosis: Emerging targets and their inhibitors

Tuberculosis (TB), an airborne infectious disease mainly caused by Mycobacterium tuberculosis (Mtb), remains a leading cause of human morbidity and mortality worldwide. Given the alarming rise of resistance to anti-TB drugs and latent TB infection (LTBI), new targets and novel bioactive compounds are urgently needed for the treatment of this disease. We provide an overview of the recent advances in anti-TB drug discovery, emphasizing several newly validated targets for which an inhibitor has been reported in the past five years. Our review presents several attractive directions that have potential for the development of next-generation therapies.     

The epigenetic face of lupus: Focus on antigen-presenting cells

In recent years, epigenetic mechanisms became widely known due to their ability to regulate and maintain physiological processes such as cell growth, development, differentiation and genomic stability. When dysregulated, epigenetic mechanisms, may introduce gene expression changes and disturbance in immune homeostasis leading to autoimmune diseases. Systemic lupus erythematosus (SLE), the most extensively studied autoimmune disorder, has already been correlated with epigenetic modifications, especially in T cells. Since these cell rely on antigen presentation, it may be assumed that erroneous activity of antigen-presenting cells (APCs), culminates in T cell abnormalities. In this review we summarize and discuss the epigenetic modifications in SLE affected APCs, with the focus on dendritic cells (DCs), B cells and monocytes. Unravelling this aspect of SLE pathogenesis, might result in identification of new disease biomarkers and putative therapeutic approaches.     

Influence of anti-thymocyte globulin plasma levels on outcome parameters in stem cell transplanted children

IntroductionAllogenic hematopoietic stem cell transplantation is a curative option for malignant and non-malignant pediatric diseases. Serotherapy is often employed to avoid graft-versus-host disease (GvHD) on one hand and graft rejection on the other hand. Therapeutic drug monitoring is increasingly used to allow for more precise dosing especially in pediatric patients due to their specific pharmacological characteristics. Application of T-cell directed antibodies is not routinely monitored, but may benefit from more precise dosing regimens.MethodsTwo different preparations of rabbit anti-thymocyte globulin (rATG), Thymoglobuline® and ATG-F (Grafalon®), are frequently used to prevent GvHD in pediatric patients by in vivo T-cell depletion. Total rATG levels and active rATG levels were analyzed prospectively in pediatric patients undergoing HSCT. Clinical and laboratory outcome parameters were recorded.ResultsrATG levels were measured in 32 patients, 22 received thymoglobuline and 10 received ATG-F. The median total peak plasma level was 419.0 µg/ml for ATG-F and 60.4 µg/ml for thymoglobuline. For ATG-F, exposure could be predicted from the calculated dose more precisely than for thymoglobuline. Active peak plasma levels neither of ATG-F, nor of thymoglobuline correlated significantly with the number of lymphocytes prior to serotherapy. There was no significant difference in incidence of aGvHD, cGvHD, rejection, mixed chimerism or viral infections in the two cohorts. However, in our cohort, patients with high thymoglobuline exposure showed a compromised reconstitution of T cells.ConclusionsATG-F and thymoglobuline show different pharmacological and immunological impact in children, whose clinical significance needs to be investigated in larger cohorts.     

Pharmacological approaches to mitigate neuroinflammation in Alzheimer’s disease

Alzheimer's disease (AD) is one of the most prevalent neurodegenerative diseases characterized by the formation of extracellular amyloid beta (Aβ) plaques and intracellular neurofibrillary tangles (NFTs). Growing evidence suggested that there is an association between neuronal dysfunction and neuroinflammation (NI) in AD, coordinated by the chronic activation of astrocytes and microglial cells along with the subsequent excessive generation of the proinflammatory molecule. Therefore, a better understanding of the relationship between the nervous and immune systems is important in order to delay or avert the neurodegenerative events of AD. The inflammatory/immune pathways and the mechanisms to control these pathways may provide a novel arena to develop new drugs in order to target NI in AD. In this review, we represent the influence of cellular mediators which are involved in the NI process, with regards to the progression of AD. We also discuss the processes and the current status of multiple anti-inflammatory agents which are used in AD and have gone through or going through clinical trials. Moreover, new prospects for targeting NI in the development of AD drugs have also been highlighted.     

Bioactive natural compounds against human coronaviruses: a review and perspective

Coronaviruses (CoVs), a family of enveloped positive-sense RNA viruses, are characterized by club-like spikes that project from their surface, unusually large RNA genome, and unique replication capability. CoVs are known to cause various potentially lethal human respiratory infectious diseases, such as severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), and the very recent coronavirus disease 2019 (COVID-19) outbreak. Unfortunately, neither drug nor vaccine has yet been approved to date to prevent and treat these diseases caused by CoVs. Therefore, effective prevention and treatment medications against human coronavirus are in urgent need. In the past decades, many natural compounds have been reported to possess multiple biological activities, including antiviral properties. In this article, we provided a comprehensive review on the natural compounds that interfere with the life cycles of SARS and MERS, and discussed their potential use for the treatment of COVID-19.     

CRISPR-Cas9 in Alzheimer’s disease: Therapeutic trends,modalities, and challenges

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Safety and tolerability of Empagliflozin use during the holy month of Ramadan by fasting patients with type 2 diabetes: A prospective cohort study

BackgroundType 2 Diabetes Mellitus (T2DM) patients are exposed to a 7.5 times higher risk of hypoglycemia while fasting during Ramadan. Relevant diabetes guidelines prioritize the use of SGLT2 inhibitors over other classes. There is a great need to enrich data on their safe and effective use by fasting patients at greater risk of hypoglycemia. Therefore, this study aims to assess the safety and tolerability of Empagliflozin in T2DM Muslim patients during Ramadan.MethodologyA prospective cohort study was conducted for adult Muslim T2DM patients. Patients who met the inclusion criteria were categorized into two sub-cohorts based on Empagliflozin use during Ramadan (Control versus Empagliflozin). The primary outcomes were the incidence of hypoglycemia symptoms and confirmed hypoglycemia. Other outcomes were secondary. All patients were followed up to eight weeks post-Ramadan. A propensity score (PS) matching and Risk Ratio (RR) were used to report the outcomes.ResultsAmong 1104 patients with T2DM who were screened, 220 patients were included, and Empagliflozin was given to 89 patients as an add-on to OHDs. After matching with PS (1:1 ratio), the two groups were comparable. The use of other OHDs, such as sulfonylurea, DPP4 inhibitors, and Biguanides, was not statistically different between the two groups. The risk of hypoglycemia symptoms during Ramadan was lower in patients who received Empagliflozin than in the control group (RR 0.48 CI 0.26, 0.89; p-value = 0.02). Additionally, the risk of confirmed hypoglycemia was not statistically significant between the two groups (RR 1.09 CI 0.37, 3.22; p-value = 0.89).ConclusionEmpagliflozin use during Ramadan fasting was associated with a lower risk of hypoglycemia symptoms and higher tolerability. Further randomized control trials are required to confirm these findings.