Importance of advanced analytical techniques and methods for food quality control and pollution analysis for more sustainable future in the least developed countries

Chemistry education plays a central role in solving the world's pressing societal issues by equipping and inspiring chemists. However, chemistry education and research in the least developed countries (LDCs) is challenging due to a lack of physical infrastructure and human resources. Among a range of issues and challenges, food and herbal adulteration, microplastics pollution, and chemical hazards are more common in the LDCs, and these issues would impede the achievement of the United Nations sustainable development goals (SDGs). These societal issues are frequently highlighted in the academia and social media of the LDCs, and we believe that at least some aspects of these issues could be solved by advancement in chemistry education and research. However, the current chemistry education and research efforts are inadequate to address these societal issues in these countries. In this article, we have summarized the present scenario and offered examples where developments in chemistry education, particularly advancement in analytical techniques and methods, will provide technological solutions to these issues. Our analysis revealed that sophisticated analytical laboratories are unavailable or unaffordable in the LDCs. The governments of these countries are facing extreme challenges in their pursuit of sustainable development primarily due to a lack of financial resources and shortage of skilled personnel. Revised chemistry curricula and sophisticated analytical testing facilities are urgently required in higher education institutions (HEIs) in the LDCs in helping society achieve the SDGs. A concerted effort between policymakers, chemical societies, funding agencies, chemists, and industries is required to advance chemistry education.     

Recent advances in the study of progranulin and its role in sepsis

Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. The mortality rate of in-hospital patients whose conditions are complicated by sepsis remains high in spite of intensive-care treatment, therefore placing a significant financial burden on the health care system. In recent years, progranulin (PGRN), a cysteine-rich secretory protein (CRISP), has been found to play a crucial role in sepsis. PGRN participates in the pathogenesis of sepsis via diverse pathways, including bacterial clearance, cell growth and survival, tissue repair, and the regulation of inflammation. PGRN knockout mice suffer from serious infectious processes, whereas therapeutic administration of recombinant PGRN to such mice enhances bacterial clearance and reduces organ injury and mortality rate. Even though PGRN plays an important role in regulating sepsis, its potential mechanisms have not been completely clarified. In this review, we summarize the most recent research advances in the study of PGRN and its role in sepsis.     

Defining the role of CFTR channel blocker and ClC-2 activator in DNBS induced gastrointestinal inflammation

In the present study, we have investigated and/or compared the role of glibenclamide, G as cystic fibrosis transmembrane conductance regulator (CFTR) inhibitor, and lubiprostone, L as chloride channel-2 (ClC-2) activator in the 2,4-dinitrobenzene sulfonic acid (DNBS)-induced gastrointestinal inflammation. GI inflammation was induced by intrarectal administration of DNBS. Rats were randomly allocated in 5 groups as sham control, distilled water + DNBS, sulfasalazine (S) + DNBS, G + DNBS, and L + DNBS. All the groups were pre-treated successively for five days before the induction of colitis. One day before and the first four days after DNBS administration various parameters were studied. Later, blood chemistry, colon’s gross structure, histology, and the antioxidant load was examined. Pre-treatment with G significantly protected the change induced by DNBS concerning the change in body weight, food intake, diarrhea, occult blood in the feces, wet weight of the colon, and spleen. G because of its anti-inflammatory property down-regulated the neutrophil and WBC count and up-regulated the lymphocyte number. Moreover, G efficiently ameliorates the oxidative stress in the colon and declines the level of myeloperoxidase and malondialdehyde and up-regulated the level of superoxide dismutase and glutathione. Lubiprostone has not shown any promising effects, in fact, it causes an increase in diarrheal frequency. Our findings from this study represent that G has good potential to ameliorate GI inflammation induced by DNBS by its multiple actions including CFTR blockage and reducing the release of inflammatory markers from the MCs, anti-inflammatory and free radical scavenging property.     

The increased marginal zone B cells attenuates early inflammatory responses during sepsis in Gpr174 deficient mice

GPR174 plays a crucial role in immune responses, but the role of GPR174 in the pathological progress of sepsis remains incompletely understood. In this study, we generated a sepsis model by cecal ligation and puncture (CLP) to investigate the role of GPR174 in regulating functions and underlying mechanism of marginal zone B (MZ B) cells in sepsis. We found that in Gpr174 deficient mice, the number of splenic MZ B cells was increased. Moreover, Gpr174^−/− MZ B cells exhibited an enhanced response to LPS stimulation in vitro. By using the CLP-induced sepsis model, we demonstrated that the increased MZ B cells attenuated early inflammatory responses during sepsis. RNA sequencing results revealed that the expression of c-fos in splenic B lymphocytes was upregulated in Gpr174 deficient mice. However, the protective role of increased MZ B cells in Gpr174 deficient mice was weakened by a c-fos-specific inhibitor. Collectively, these findings suggested that GPR174 plays an immunomodulatory role in early immune responses during sepsis through the regulation of MZ B cells.     

In vitro and in vivo characterization of erythrosin B and derivatives against Zika virus

Zika virus (ZIKV) causes significant human diseases without specific therapy. Previously we found erythrosin B, an FDA-approved food additive, inhibited viral NS2B?NS3 interactions, leading to inhibition of ZIKV infection in cell culture. In this study, we performed pharmacokinetic and in vivo studies to demonstrate the efficacy of erythrosin B against ZIKV in 3D mini-brain organoid and mouse models. Our results showed that erythrosin B is very effective in abolishing ZIKV replication in the 3D organoid model. Although pharmacokinetics studies indicated that erythrosin B had a low absorption profile, mice challenged by a lethal dose of ZIKV showed a significantly improved survival rate upon oral administration of erythrosin B, compared to vehicle control. Limited structure?activity relationship studies indicated that most analogs of erythrosin B with modifications on the xanthene ring led to loss or reduction of inhibitory activities towards viral NS2B?NS3 interactions, protease activity and antiviral efficacy. In contrast, introducing chlorine substitutions on the isobenzofuran ring led to slightly increased activities, suggesting that the isobenzofuran ring is well tolerated for modifications. Cytotoxicity studies indicated that all derivatives are nontoxic to human cells. Overall, our studies demonstrated erythrosin B is an effective antiviral against ZIKV both in vitro and in vivo.     

A Detailed Protocol for Generation of Therapeutic Antibodies with Galactosylated Glycovariants at Laboratory Scale Using In-Vitro Glycoengineering Technology

N-linked glycosylation is an important post translational modification that occurs on Asparagine 297 residue or a homologous position on the Fc portion of monoclonal antibodies (mAbs). mAb Fc glycans play important roles in antibody structure, stability, and function including effector function and pharmacokinetics. The Fc glycans are made up of a wide variety of sugars including galactose, mannose, and sialic acid. The role of galactose in mediating antibody effector functions is not well understood. Hence, there is widespread interest in the antibody research community to understand the role of galactose in antibody effector functions as galactose is a major constituent of antibody glycans. This requires generation of highly enriched galactosylated variants that has been very challenging via cell culture process. To tackle this challenge, we developed a laboratory scale biochemical process to produce highly enriched galactosylated variants. In this article, we report optimized lab-scale workflows and detailed protocols for generation of deglycosylated, hypo-galactosylated and hyper-galactosylated variants of IgG therapeutic antibodies using the in-vitro glycoengineering technology. The optimized workflows offer short turnaround time and produce highly enriched deglycosylated/hypo-galactosylated/hyper-galactosylated IgG glycovariants, with high purity & molecular integrity as demonstrated by data from an example IgG.     

Effects of IL-22 on cardiovascular diseases

Interleukin-22 (IL-22), which belongs to the IL-10 family, is an alpha helix cytokine specifically produced by many lymphocytes, such as Th1, Th17, Th22, ILCs, CD4+ and CD8+ T cells. In recent years, more and more studies have demonstrated that IL-22 has an interesting relationship with various cardiovascular diseases, including myocarditis, myocardial infarction, atherosclerosis, and other cardiovascular diseases, and IL-22 signal may play a dual role in cardiovascular diseases. Here, we summarize the recent progress on the source, function, regulation of IL-22 and the effects of IL-22 signal in cardiovascular diseases. The study of IL-22 will suggest more specific strategies to maneuver these functions for the effective treatment of cardiovascular diseases and future clinical treatment.     

Effects of steric hindrance and electron density of ester prodrugs on controlling the metabolic activation by human carboxylesterase

Carboxylesterase (CES) plays an important role in the hydrolysis metabolism of ester–type drugs and prodrugs. In this study, we investigated the change in the hydrolysis rate of hCE1 by focusing on the steric hindrance of the ester structure and the electron density. For 26 kinds of synthesized indomethacin prodrugs, the hydrolytic rate was measured in the presence of human liver microsomes (HLM), human small intestine microsomes (HIM), hCE1 and hCE2. The synthesized prodrugs were classified into three types: an alkyl ester type that is specifically metabolized by hCE1, a phenyl ester type that is more easily metabolized by hCE1 than by hCE2, and a carbonate ester type that is easily metabolized by both hCE1 and hCE2. The hydrolytic rate of 1-methylpentyl (hexan–2–yl) ester was 10–times lower than that of 4–methylpentyl ester in hCE1 solution. hCE2 was susceptible to electron density of the substrate, and there was a difference in the hydrolysis rate of up to 3.5–times between p-bromophenyl ester and p-acetylphenyl ester. By changing the steric hindrance and electron density of the alkoxy group, the factors that change the hydrolysis rate by CES were elucidated.     

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.     

Physician-pharmacist collaboration on chronic non-cancer pain management during the opioid crisis: A qualitative interview study

BackgroundManagement of chronic non-cancer pain is complex, requiring clinicians to balance pain management with the risk of opioid abuse. The role of ambulatory care pharmacists in chronic pain management is well-established, but little research has explored the feasibility of building collaboration on chronic pain and opioid management between physicians and community pharmacists.ObjectiveTo explore physician and pharmacist perspectives on the opioid crisis and the possibility of physician and community pharmacist collaborations to manage chronic non-cancer pain in the context of the opioid crisis.MethodsSemi-structured interviews were performed with a snowball convenience sample 15 physicians and 25 pharmacists in North Carolina between November 2016 and April 2017. Transcribed data were analyzed using applied thematic analysis, and resulting codes were organized into themes and domains which emerged from analysis.ResultsBoth physicians and pharmacists described current care deficiencies and steps needed to mitigate opioid abuse and diversion. Physicians discussed the need for additional supports and resources for chronic pain management and regarded positively the role of the community pharmacist in chronic pain management and mitigating opioid abuse. Pharmacists identified cost as the major barrier to implementing new services, and expressed willingness to participate in new chronic pain and opioid interventions.ConclusionWithin the study sample, strong interest exists for collaboration between physicians and community pharmacists. This highlights a potential opportunity to expand care for patients with chronic non-cancer pain.     

Hydroxychloroquine is a novel therapeutic approach for rosacea

Rosacea is a chronic inflammatory disease in face. Hydroxychloroquine (HCQ), an anti-malaria drug, was reported to have anti-inflammation activities. However, the role of HCQ on rosacea remains unclear. In this study, we revealed the potential molecular mechanism by which HCQ improved rosacea in rosacea-like mice and mast cells (MCs). Moreover, the effects of HCQ treatment for rosacea patients were investigated. In this study, we found HCQ ameliorated the rosacea-like phenotype and MCs infiltration. The elevated pro-inflammatory factors and mast cell protease were significantly inhibited by HCQ treatment in rosacea-like mice. In vitro, HCQ suppresses LL37-induced MCs activation in vitro, including the release of inflammatory factors, chemotaxis, degranulation and calcium influx. Moreover, HCQ attenuated LL37-mediated MCs activation partly via inhibiting KCa3.1-mediated calcium signaling. Thus, these evidences suggest HCQ ameliorated rosacea-like dermatitis may be by regulating immune response of MCs. Finally, the 8-week HCQ treatment exerted satisfactory therapeutic effects on erythema and inflammatory lesions of rosacea patients, indicating that it is a promising drug for rosacea in clinical treatment.     

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.     

Discovery of the anti-angiogenesis effect of eltrombopag in breast cancer through targeting of HuR protein

HuR (human antigen R), an mRNA-binding protein responsible for poor prognosis in nearly all kinds of malignancies, is a potential anti-tumor target for drug development. While screening HuR inhibitors with a fluorescence polarization (FP) based high-throughput screening (HTS) system, the clinically used drug eltrombopag was identified. Activity of eltrombopag on molecular level was verified with FP, electrophoretic mobility shift assay (EMSA), simulation docking and surface plasmon resonance (SPR). Further, we showed that eltrombopag inhibited in vitro cell proliferation of multiple cancer cell lines and macrophages, and the in vivo anti-tumor activity was also demonstrated in a 4T1 tumor-bearing mouse model. The in vivo data showed that eltrombopag was efficient in reducing microvessels in tumor tissues. We then confirmed the HuR-dependent anti-angiogenesis effect of eltrombopag in 4T1 cells and RAW264.7 macrophages with qRT-PCR, HuR-overexpression and HuR-silencing assays, RNA stability assays, RNA immunoprecipitation and luciferase assays. Finally, we analyzed the in vitro anti-angiogenesis effect of eltrombopag on human umbilical vein endothelial cells (HUVECs) mediated by macrophages with cell scratch assay and in vitro Matrigel angiogenesis assay. With these data, we revealed the HuR-dependent anti-angiogenesis effect of eltrombopag in breast tumor, suggesting that the existing drug eltrombopag may be used as an anti-cancer drug.     

Protective role of berberine on ulcerative colitis through modulating enteric glial cells–intestinal epithelial cells–immune cells interactions

Ulcerative colitis (UC) manifests as an etiologically complicated and relapsing gastrointestinal disease. The enteric nervous system (ENS) plays a pivotal role in rectifying and orchestrating the inflammatory responses in gut tract. Berberine, an isoquinoline alkaloid, is known as its anti-inflammatory and therapeutic effects in experimental colitis. However, little research focused on its regulatory function on ENS. Therefore, we set out to explore the pathological role of neurogenic inflammation in UC and the modulating effects of berberine on neuro–immune interactions. Functional defects of enteric glial cells (EGCs), with decreased glial fibrillary acidic protein (GFAP) and increased substance P expression, were observed in DSS-induced murine UC. Administration of berberine can obviously ameliorate the disease severity and restore the mucosal barrier homeostasis of UC, closely accompanying by maintaining the residence of EGCs and attenuating inflammatory infiltrations and immune cells overactivation. In vitro, berberine showed direct protective effects on monoculture of EGCs, bone marrow-derived dendritic cells (BMDCs), T cells, and intestinal epithelial cells (IECs) in the simulated inflammatory conditions. Furthermore, berberine could modulate gut EGCs–IECs–immune cell interactions in the co-culture systems. In summary, our study indicated the EGCs–IECs–immune cell interactions might function as a crucial paradigm in mucosal inflammation and provided an infusive mechanism of berberine in regulating enteric neurogenic inflammation.     

Drug repurposing in skeletal muscle ion channelopathies

Skeletal muscle ion channelopathies are rare genetic diseases mainly characterized by myotonia (muscle stiffness) or periodic paralysis (muscle weakness). Here, we reviewed the available therapeutic options in non-dystrophic myotonias (NDM) and periodic paralyses (PP), which consists essentially in drug repositioning to address stiffness or weakness attacks. Empirical use followed by successful randomized clinical trials eventually led to the orphan drug designation and marketing authorization granting of mexiletine for NDM and dichlorphenamide for PP. Yet, these treatments neither consider the genetic cause of the diseases nor address the individual variability in drug response. Thus, ongoing research aims at the identification of repurposed drugs alternative to mexiletine and dichlorphenamide to allow personalization of treatment. This review highlights how drug repurposing may represent an efficient strategy in rare diseases, allowing reduction of drug development time and costs in a context in which the return on investment may be particularly challenging.     

Monoacylglycerol lipase inhibitors: modulators for lipid metabolism in cancer malignancy,neurological and metabolic disorders

Monoacylglycerol lipase (MAGL) is a serine hydrolase that plays a crucial role catalysing the hydrolysis of monoglycerides into glycerol and fatty acids. It links the endocannabinoid and eicosanoid systems together by degradation of the abundant endocannabinoid 2-arachidaoylglycerol into arachidonic acid, the precursor of prostaglandins and other inflammatory mediators. MAGL inhibitors have been considered as important agents in many therapeutic fields, including anti-nociceptive, anxiolytic, anti-inflammatory, and even anti-cancer. Currently, ABX-1431, a first-in-class inhibitor of MAGL, is entering clinical phase 2 studies for neurological disorders and other diseases. This review summarizes the diverse (patho)physiological roles of MAGL and will provide an overview on the development of MAGL inhibitors. Although a large number of MAGL inhibitors have been reported, novel inhibitors are still required, particularly reversible ones.     

Antioxidant and fibroblast-activating activities of the by-product of skate chondroitin extractive production

Owing to the increasing popularity of chondroitin sulfate (CS) for joint pain treatment, the CS-production industry has been producing an increasing amount of waste, which includes type II collagen, non-collagenous proteins, and residual CS. To effectively utilize these resources, we intended to develop new products from the by-product of skate chondroitin sulfate production (BP-sCS). In this study, we examined the antioxidant and fibroblast-activating properties of BP-sCS, intending to apply it for a wound-healing promoter. BP-sCS exhibited ABTS and DPPH radical scavenging activities, protected L929 fibroblasts from H₂O₂- or AAPH-induced oxidative stress, and scavenged intracellular reactive oxygen species. Moreover, BP-sCS promoted L929 fibroblast proliferation/metabolism and stimulated collagen deposition into the extracellular matrix. In addition, BP-sCS counteracted AAPH-induced oxidative stress damage that inhibited fibroblast migration. These effect were attributed to the cooperation among the molecules of BP-sCS, namely, type II collagen peptides, non-collagenous peptides, and CS polysaccharides. Our findings indicate that BP-sCS has the potential as a novel wound-healing promoter. This study is the first step toward the realization of a sustainable CS-production industry by waste utilization in healthcare products.     

Impact of molecular weight on the mechanism of cellular uptake of polyethylene glycols (PEGs) with particular reference to P-glycoprotein

Polyethylene glycols (PEGs) in general use are polydisperse molecules with molecular weight (MW) distributed around an average value applied in their designation e.g., PEG 4000. Previous research has shown that PEGs can act as P-glycoprotein (P-gp) inhibitors with the potential to affect the absorption and efflux of concomitantly administered drugs. However, questions related to the mechanism of cellular uptake of PEGs and the exact role played by P-gp has not been addressed. In this study, we examined the mechanism of uptake of PEGs by MDCK-mock cells, in particular, the effect of MW and interaction with P-gp by MDCK-hMDR1 and A549 cells. The results show that: (a) the uptake of PEGs by MDCK-hMDR1 cells is enhanced by P-gp inhibitors; (b) PEGs stimulate P-gp ATPase activity but to a much lesser extent than verapamil; and (c) uptake of PEGs of low MW (<2000 Da) occurs by passive diffusion whereas uptake of PEGs of high MW (>5000 Da) occurs by a combination of passive diffusion and caveolae-mediated endocytosis. These findings suggest that PEGs can engage in P-gp-based drug interactions which we believe should be taken into account when using PEGs as excipients and in PEGylated drugs and drug delivery systems.