Due to their neurodevelopmental toxicity, flame retardants (FRs) like polybrominated diphenyl ethers are banned from the market and replaced by alternative FRs, like organophosphorus FRs, that have mostly unknown toxicological profiles. To study their neurodevelopmental toxicity, we evaluated the hazard of several FRs including phased-out polybrominated FRs and organophosphorus FRs: 2,2′,4,4′-tetrabromodiphenylether (BDE-47), 2,2′,4,4′,5-pentabromodiphenylether (BDE-99), tetrabromobisphenol A, triphenyl phosphate, tris(2-butoxyethyl) phosphate and its metabolite bis-(2-butoxyethyl) phosphate, isodecyl diphenyl phosphate, triphenyl isopropylated phosphate, tricresyl phosphate, tris(1,3-dichloro-2-propyl) phosphate, tert-butylphenyl diphenyl phosphate, 2-ethylhexyl diphenyl phosphate, tris(1-chloroisopropyl) phosphate, and tris(2-chloroethyl) phosphate. Therefore, we used a human cell–based developmental neurotoxicity (DNT) in vitro battery covering a large variety of neurodevelopmental endpoints. Potency according to the respective most sensitive benchmark concentration (BMC) across the battery ranked from <1 μM (5 FRs), 1<10 μM (7 FRs) to the >10 μM range (3 FRs). Evaluation of the data with the ToxPi tool revealed a distinct ranking (a) than with the BMC and (b) compared to the ToxCast data, suggesting that DNT hazard of these FRs is not well predicted by ToxCast assays. Extrapolating the DNT in vitro battery BMCs to human FR exposure via breast milk suggests low risk for individual compounds. However, it raises a potential concern for real-life mixture exposure, especially when different compounds converge through diverse modes-of-action on common endpoints, like oligodendrocyte differentiation in this study. This case study using FRs suggests that human cell–based DNT in vitro battery is a promising approach for neurodevelopmental hazard assessment and compound prioritization in risk assessment.
Graphical abstractMitochondrial-associated endoplasmic reticulum (ER) membranes (MAMs) play a key role in several physiological functions, including calcium ion (Ca2+) transfer and autophagy; however, the molecular mechanism controlling this interaction in cadmium (Cd)-induced neurotoxicity is unknown. This study shows that Cd induces alterations in MAMs and mitochondrial Ca2+ levels in PC12 cells and primary neurons. Ablation or silencing of mitofusin 2 (Mfn2) in PC12 cells or primary neurons blocks the colocalization of ER and mitochondria while reducing the efficiency of mitochondrial Ca2+ uptake. Moreover, Mfn2 defects reduce interactions or colocalization between GRP75 and VDAC1. Interestingly, the enhancement of autophagic protein levels, colocalization of LC3 and Lamp2, and GFP-LC3 puncta induced by Cd decreased in Mfn2?/? or Grp75?/? PC12 cells and Mfn2- or Grp75-silenced primary neurons. Notably, the specific Ca2+ uniporter inhibitor RuR blocked both mitochondrial Ca2+ uptake and autophagy induced by Cd. Finally, this study proves that the mechanism by which IP3R-Grp75-VDAC1 tethers in MAMs is associated with the regulation of autophagy by Mfn2 and involves their role in mediating mitochondrial Ca2+ uptake from ER stores. These results give new evidence into the organelle metabolic process by demonstrating that Ca2+ transport between ER-mitochondria is important in autophagosome formation in Cd-induced neurodegeneration.
Graphical abstractCancer is the second major threat to human society and one of the main challenges facing healthcare systems. One of the main problems of cancer care is the metastases of cancer cells that cause 90% of deaths due to cancer. Multiple molecular mechanisms are involved in cancer cell metastasis. Therefore, a better understanding of these molecular mechanisms is necessary for designing restrictive strategies against cancer cell metastasis. Accumulating data suggests that MicroRNAs (miRNAs) are involved in metastasis and invasion of human tumors through regulating multiple genes expression levels that are involved in molecular mechanisms of metastasis. The goal of this review is to present the molecular pathways by which the miR 200 family manifests its effects on EMT, cancer stem cells, angiogenesis, anoikis, and the effects of tumor cell metastases.
MethodsA detailed literature search was conducted to find information about the role of the miR-200 family in the processes involved in metastasis in various databases.
ResultsNumerous lines of evidence revealed an association between the mir-200 family and metastasis of human tumors by impressing processes such as cancer stem cells, EMT, angiogenesis, and anoikis.
ConclusionsUnderstanding the molecular mechanisms associated with metastasis in which the miR-200 family is involved can be effective in treating metastatic cancers.
Graphic abstractNeuroblastoma is the most common extracranial solid tumour in childhood, originated from cells of the neural crest during the development of the Sympathetic Nervous System. Retinoids are vitamin-A derived differentiating agents utilised to avoid disease resurgence in high-risk neuroblastoma treatment. Several studies indicate that hypoxia—a common feature of the tumoural environment—is a key player in cell differentiation and proliferation. Hypoxia leads to the accumulation of the hypoxia-inducible factor-1α (HIF-1α). This work aims to investigate the effects of the selective inhibition of HIF-1α on the differentiation induced by retinoic acid in human neuroblastoma cells from the SH-SY5Y lineage to clarify its role in cell differentiation. Our results indicate that HIF-1α inhibition impairs RA-induced differentiation by reducing neuron-like phenotype and diminished immunolabeling and expression of differentiation markers.
Graphic AbstractHIF1A is involved in Retinoic Acid (RA) induced differentiation in SH-SY5Y neuroblastoma cells. siRNA HIF1A gene silencing leads to a weaker response to RA, demonstrated by changes in the neuro-like phenotype and diminished expression of differentiation markers.
Circular RNA of vimentin (circ-VIM) is a predictor for poor prognosis of acute myeloid leukemia, but we had little information on its function in esophageal cancer (EC). Here we examined the effects of circ-VIM together with sevoflurane on immune escape and multiple oncogenic activities of EC.
MethodsBioinformatic tools, luciferase assay, and RNA immunoprecipitation were used to examine regulations between circ-VIM, miR-124-3p (miR-124), and PD-L1. CCK-8, wound healing, and Transwell assays were used to measure cell proliferation, migration, and invasion, respectively. The impacts of EC cells on cytotoxicity, proliferation, and apoptosis of CD8+ T cells were examined using LDH assay, CFSE staining, and Annexin V/PI staining, respectively. The in vivo tumorigenesis and lung metastases were assessed using xenograft model and tail vein injection of EC cells.
ResultsSignificant upregulation of circ-VIM and PD-L1 and downregulation of miR-124 were detected in EC tissues or cells. Circ-VIM sponged miR-124 and released its suppression on the downstream target PD-L1. Sevoflurane, independent of circ-VIM, also upregulated miR-124 to lower PD-L1 expression. By modulating miR-124/PD-L1 axis, silencing circ-VIM and applying sevoflurane both inhibited immune escape and multiple oncogenic activities of EC in vitro, and suppressed xenograft growth and lung metastases in vivo. The inactivation of Ras/ERK signaling pathway was involved in suppression of malignant phenotypes by silencing circ-VIM and sevoflurane treatment.
ConclusionsSilencing circ-VIM and applying sevoflurane, by separately regulating miR-124/PD-L1 axis, presented synergistic effects in inhibiting immune escape and multiple malignant phenotypes of EC cells.
Graphical abstractResveratrol (RES) is a polyphenol with increasing interest for its inhibitory effects on a wide variety of viruses. Zika virus (ZIKV) is an arbovirus which causes a broad spectrum of ophthalmological manifestations in humans. Currently there is no certified therapy or vaccine to treat it, thus it has become a major global health threat. Retinal pigment epithelium (RPE) is highly permissive and susceptible to ZIKV. This work explored the protective effects of RES on ZIKV-infected human RPE cells. RES treatment resulted in a significant reduction of infectious viral particles in infected male ARPE-19 and female hTERT-RPE1 cells. This protection was positively influenced by the action of RES on mitochondrial dynamics. Also, docking studies predicted that RES has a high affinity for two enzymes of the rate-limiting steps of pyrimidine and purine biosynthesis and viral polymerase. This evidence suggests that RES might be a potential antiviral agent to treat ZIKV-induced ocular abnormalities.
Graphic abstractThe present work aimed to investigate the antioxidant, anti-inflammatory and wound healing potential of ethyl acetate fraction from Bauhinia ungulata L. (FABU) on in vitro and in vivo models. Wound healing assay using human lung adenocarcinoma A549 cell line was employed to evaluate the ability of FABU in modulating cell migration. In addition, a surgical wound model in C57BL/6 mice was used to study the healing potential of FABU incorporated into gel carbomer 940 (Carbopol®). Evaluation of lipid peroxidation, inflammatory and anti-inflammatory mediator gene expression, rate of wound closure, and histological analysis were done. FABU significantly reduced the gap area in in vitro wound healing assay, 24 h after treatment. In the animal model, FABU at 0.5% topically applied once-daily for 5 days to the surgical wounds significantly reduced the lesion area. Moreover, it significantly decreased the levels of lipid peroxidation in the lesions and decreased the relative gene expression levels of IL-1β and TNF-α in the injured region. In conclusion, our study suggests that Bauhinia ungulata can effectively promote the wound healing, probably by regulating the inflammatory environment during the early stages of the process.
Graphic abstractThe mushrooms have contributed to the development of active ingredients of fundamental importance in the field of pharmaceutical chemistry as well as of important tools in human and animal health, nutrition, and functional food. This review considers studies on the beneficial effects of medicinal mushrooms on the nutrition and health of humans and farm animals. An overview of the chemical structure and composition of mycochemicals is presented in this review with particular reference to phenolic compounds, triterpenoids and sterols, fatty acids and lipids, polysaccharides, proteins, peptides, and lectins. The nutritional value and chemical composition of wild and cultivated mushrooms in Italy is also the subject of this review which also deals with mushrooms as nutraceuticals and the use of mushrooms in functional foods. The nutraceutical benefits of UV irradiation of cultivated species of basidiomycetes to generate high amounts of vitamin D2 is also highlighted and the ability of the muhsrooms to inhibit glycation is analyzed. Finally, attention is paid to studies on bioactivities of some Italian wild and cultivated mushrooms with particular reference to species belonging to the genus Pleurotus. The review highlights the potential of medicinal mushrooms in the production of mycochemicals that represent a source of drugs, nutraceutical, and functional food.
Graphic abstractThe increased phenomenon of antimicrobial resistance and the slow pace of development of new antibiotics are at the base of a global health concern regarding microbial infections. Antibiotic resistance kills an estimated 700,000 people each year worldwide, and this number is expected to increase dramatically if efforts are not made to develop new drugs or alternative containment strategies. Increased vaccination coverage, improved sanitation or sustained implementation of infection control measures are among the possible areas of action. Indeed, vaccination is one of the most effective tools of preventing infections. Starting from 1970s polysaccharide-based vaccines against Meningococcus, Pneumococcus and Haemophilus influenzae type b have been licensed, and provided effective protection for population. However, the development of safe and effective vaccines for infectious diseases with broad coverage remains a major challenge in global public health. In this scenario, nanosystems are receiving attention as alternative delivery systems to improve vaccine efficacy and immunogenicity. In this report, we provide an overview of current applications of glyconanomaterials as alternative platforms in the development of new vaccine candidates. In particular, we will focus on nanoparticle platforms, used to induce the activation of the immune system through the multivalent-displacement of saccharide antigens.
Graphical abstractIt has been widely reported that long non-coding RNAs (lncRNAs) could affect the varieties of tumor response to radiotherapy. LncRNA HNF1A-AS1 is transcribed from HNF1A gene cluster’s antisense strand. This work focused on the mechanism of how HNF1A-AS1 participated in the radiosensitivity of non-small cell lung cancer (NSCLC).
MethodsThe mRNA or protein expression of HNF1A-AS1, miR-92a-3p MAP2K4, and JNK in NSCLC cells and tissues was detected by qRT-PCR or western blotting. RNA immunoprecipitation (RIP) detection and luciferase reporting system were used to evaluate the relationship between HNFA-AS1 and miR-92a-3p or between miR-92a-3p and MAP2K4. Flow cytometry assays, colony formation, and MTT were performed to analyze the function changes in A549 and Calu-1 cells. The rescue experiment was also conducted to explore the underlying mechanisms.
ResultsHNF1A-AS1 was investigated in NSCLC cells and tissues and highly related to the advanced pathological stage. HNF1A-AS1 bound with miR-92a-3p, which was downregulated in NSCLC. It showed that miR-92a-3p was negatively related to HNF1A-AS1. Knockdown of HNF1A-AS1 impacted most cell biological behaviors in NSCLC cells, including restricting the proliferation and aggravating apoptosis. Furthermore, knockdown of HNF1A-AS1 dramatically enhanced radiotherapy sensitivity of NSCLC. Moreover, miR-92a-3p was found to target MAP2K4 and could reduce MAP2K4 expression. Inhibition of HNF1A-AS1 elevated radiotherapy sensitivity and retarded the progression of NSCLC cells, followed by decreasing expression levels of MAP2K4. Besides, MAP2K4 mimic rescued the si-HNF1A-AS1 effects on the biological behavior of NSCLC cells.
ConclusionHNF1A-AS1 is highly expressed in NSCLC. MiR-92a-3p is the target gene of HNF1A-AS1 and involved in tumor progression by regulating the MAP2K4/JNK pathway. HNF1AS1/miR-92a-3p/MAP2K4 axis plays important roles in radiotherapy resistance of NSCLC.
Graphical abstractPoor quality and quantity of sleep are very common in elderly people throughout the world. Growing evidence has suggested that sleep disturbances could accelerate the process of neurodegeneration. Recent reports have shown a positive correlation between sleep deprivation and amyloid-β (Aβ)/tau aggregation in the brain of Alzheimer’s patients. Glial cells have long been implicated in the progression of Alzheimer’s disease (AD) and recent findings have also suggested their role in regulating sleep homeostasis. However, how glial cells control the sleep–wake balance and exactly how disturbed sleep may act as a trigger for Alzheimer’s or other neurological disorders have recently gotten attention. In an attempt to connect the dots, the present review has highlighted the role of glia-derived sleep regulatory molecules in AD pathogenesis.
Graphical AbstractRole of glia in sleep disturbance and Alzheimer’s progression.
It is considered a significant challenge to understand the neuronal cell death mechanisms with a suitable cure for neurodegenerative disorders in the coming years. Calpains are one of the best-considered “cysteine proteases activated” in brain disorders. Calpain is an important marker and mediator in the pathophysiology of neurodegeneration. Calpain activation being the essential neurodegenerative factor causing apoptotic machinery activation, it is crucial to develop reliable and effective approaches to prevent calpain-mediated apoptosis in degenerating neurons. It has been recently seen that the “inhibition of calpain activation” has appeared as a possible therapeutic target for managing neurodegenerative diseases. A systematic literature review of PubMed, Medline, Bentham, Scopus, and EMBASE (Elsevier) databases was conducted. The present article reviews the basic pathobiology and role of selective calpain inhibitors used in various neurodegenerative diseases as a therapeutic target.
Graphical AbstractDrusen deposition on sub-retinal pigment epithelium is the causal factor for age-related macular degeneration for the old-aged individuals. These deposits contain hydroxyapatite–cholesterol spherules on which several proteins and lipids accumulate to cover the retina and choroid, causing blurred vision and blindness. Amyloid-β, the known culprit in Alzheimer’s disease, is one among the few major proteins known to occur in these deposits. In the present article, we report preliminary analyses of interactions between amyloid-β and hydroxyapatite–cholesterol composites using Thioflavin-T binding kinetics, solid-state NMR and transmission electron microscopy (TEM). Thioflavin-T fluorescence kinetics shows that amyloid-β (1–42) aggregates only under certain conditions of concentration of cholesterol in the hydroxyapatite–cholesterol composites prepared by two different methods. These results were confirmed by 1D 13C CPMAS solid-state NMR. TEM imaging revealed that there is an exposure of the cholesterol surface in the composites prepared by sonication method. These imaging experiments explain the dependence of aggregation kinetics on the exposure and availability of cholesterol surface in the composites to a certain extent.
Graphic AbstractIn this paper, we study the postcranial morphology (humerus, ulna, innominate, femur, tibia, astragalus, navicular, and metatarsal III) of Neoepiblema, a giant Late Miocene South American rodent, searching for evidence about its paleobiology based on unpublished specimens from Solimões Formation (Upper Miocene, Brazil). The study includes a morphofunctional analysis of the postcranial bones and a comparison with extant and extinct rodents, especially Phoberomys. The morphofunctional analysis of the postcranial bones suggests that Neoepiblema (as well as Phoberomys) would have a crouched forelimb that was not fully extended, with powerful pectoral and triceps musculature, and able to produce movements of pronation/supination and possibly with a hand able to grasp. The combination of characters of the innominate bone, femur, and tibia indicates a predominance of parasagittal movements and a thigh with powerful musculature used during propulsion. In sum, the analyzed postcranial features are consistent with the limb morphology of ambulatory rodents, but with faculty to dig or swim. The sedimentary evidence of the localities in which fossils of neoepiblemids have been found suggests that these rodents lived in wet and water-related environments (near swamps, lakes, and/or rivers).
Graphical abstractThe concentration of human population along coastlines has far-reaching effects on ocean and societal health. The oceans provide benefits to humans such as food, coastal protection and improved mental well-being, but can also impact negatively via natural disasters. At the same time, humans influence ocean health, for example, via coastal development or through environmental stewardship. Given the strong feedbacks between ocean and human health there is a need to promote desirable interactions, while minimising undesirable interactions. To this end, we articulate two scenarios for 2030. First, Business-as-Usual, named ‘Command and (out of) Control’, focuses on the anticipated future based on our current trajectory. Second, a more sustainable scenario called ‘Living and Connecting’, emphasises the development of interactions between oceans and society consistent with achieving the Sustainable Development Goals. We describe a potential pathway to achieving the ‘Living and Connecting’ scenario, centred on improving marine citizenship, achieving a more equitable distribution of power among stakeholders, and more equitable access to resources and opportunities. The constituent actions of this pathway can be categorised into four groups: (i) improved approaches to science and health communication that account for society’s diverse values, beliefs and worldviews, (ii) a shift towards more trusted relationships among stakeholders to enable two-way knowledge exchange, (iii) economic incentives that encourage behavioural changes necessary for achieving desired sustainability outcomes, and (iv) stronger regulations that simultaneously focus on ocean and human health. We contend that these changes will provide improved outcomes for both oceans and society over the United Nations Decade of Ocean Science.
Graphic abstractGinsenoside compound K (CK) with a wide range of pharmacological activities has been widely used in the healthcare product industry. However, the application of CK is limited by low productivity and difficult separation. The purpose of this study is to convert ginsenoside Rb1 into CK by improving conversion efficiency in novel “green” reaction medium-deep eutectic solvent (DES). Talaromyces purpureogenus was selected from ginseng rhizosphere soil to produce β-glucosidase with high activity and purity to transform ginsenosides, and Mn2+ was found to be an enzyme promoter. Among the DES based on choline chloride as hydrogen-bond receptor, choline chloride:ethylene glycol (ChCl:EG = 2:1) was the most promising solvent in maintaining enzyme activity and stability. In the presence of 30% v/v ChCl:EG = 2:1, the half-life of β-glucosidase was increased by 96%, the solubility of F2 was increased by 120%, and CK yield was increased by 54% compared with those in the buffer. Fourier transform infrared, circular dichroism, and fluorescence spectroscopy confirmed that DES did not destroy the structure and conformation of β-glucosidase. In addition, 80.6% CK conversion was obtained at 60 °C, pH 4.5, 48 h and 8 mM Rb1, which provided a feasible method for efficiently producing CK.
Graphic abstractBoron is an important element for plants, humans, and animals in limited amounts. However, excess amounts can cause adverse effects in both humans and plants, necessitating its removal from certain systems. Boron compounds are used in many industrial applications, including in developing sectors like alternative energy technology; as a result, the need for this element is increasing and industries are looking towards boron recovery for the sustained use of this element in their products. While the literature on boron removal strategies is abundant, there is a relative lack of studies on boron recovery, with no review papers having yet addressed this topic. In this review, both boron removal and recovery techniques involving conventional approaches and membrane processes are examined to juxtapose the states of the science in these two related—and increasingly important—processes.
Graphical abstractThis article presents a machine learning workflow allowing to construct spectrophotometric equations predicting nitrate and nitrite concentrations within microalgae culture samples. First, numerous samples with various nitrate and nitrite concentrations (in mixture or separated) were drawn from cultures. Their UV absorbance spectra were recorded with a tabletop spectrophotometer before being analyzed using ion chromatography. Then, the data collected were used to construct a machine leaning model based on partial least square regression. From a practical perspective, the best model involves 3 wavelengths to quantify both nitrate and nitrite within the samples. The proposed equations can readily be used (LoQ of 0.5 mg L??1, uncertainty of ± 10%). They greatly shorten the time to obtain sample nitrate and nitrite concentrations compared to ion chromatography while retaining adequate accuracy. Furthermore, the workflow is presented step-wise, with emphasis on relevant details so that other scholars may deploy in their own laboratory to best suit their own needs. Finally, the data and source files are made available in an online repository.
Model generation workflow and associated data management.