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Overweight and obese are risk factors for various diseases. In Taiwan, the combined prevalence of overweight and obesity has increased dramatically. Here, we conducted a genome-wide association study (GWAS) on four adiposity traits, including body-mass index (BMI), body fat percentage (BF%), waist circumference (WC), and waist-hip ratio (WHR), using the data for more than 21,000 subjects in Taiwan Biobank. Associations were evaluated between 6,546,460 single-nucleotide polymorphisms (SNPs) and adiposity traits, yielding 13 genome-wide significant (GWS) adiposity-associated trait-loci pairs. A known gene, FTO, as well as two BF%-associated loci (GNPDA2-GABRG1 [4p12] and RNU6-2-PIAS1 [15q23]) were identified as pleiotropic effects. Moreover, RALGAPA1 was found as a specific genetic predisposing factor to high BMI in a Taiwanese population. Compared to other populations, a slightly lower heritability of the four adiposity traits was found in our cohort. Surprisingly, we uncovered the importance of neural pathways that might influence BF%, WC and WHR in the Taiwanese (East Asian) population. Additionally, a moderate genetic correlation between the WHR and BMI (γg = 0.52; p = 2.37×10-9) was detected, suggesting different genetic determinants exist for abdominal adiposity and overall adiposity. In conclusion, the obesity-related genetic loci identified here provide new insights into the genetic underpinnings of adiposity in the Taiwanese population.
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Adiposidade/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Adulto , Bancos de Espécimes Biológicos , Estudos de Coortes , Feminino , Proteínas Ativadoras de GTPase/genética , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas do Tecido Nervoso/genética , Obesidade/genética , Sobrepeso/genética , Polimorfismo de Nucleotídeo Único , TaiwanRESUMO
Abnormal cancer metabolism causes hypoxia and immunosuppressive tumor microenvironment (TME), which limits the antitumor efficacy of photodynamic therapy (PDT). Herein, we report a photosensitizing nanoscale metal-organic layer (MOL) with anchored 3bromopyruvate (BrP), BrP@MOL, as a metabolic reprogramming agent to enhance PDT and antitumor immunity. BrP@MOL inhibited mitochondrial respiration and glycolysis to oxygenate tumors and reduce lactate production. This metabolic reprogramming enhanced reactive oxygen species generation during PDT and reshaped the immunosuppressive TME to enhance antitumor immunity. BrP@MOL-mediated PDT inhibited tumor growth by >90% with a 40% cure rate, rejected tumor re-challenge, and prevented lung metastasis. Further combination with immune checkpoint blockade potently regressed the tumors with >98% tumor inhibition and an 80% cure rate.
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Amel, the gene encoding the amelogenin protein involved in enamel formation, is highly alternatively spliced. When exon4 is excised, it can form a mature miRNA (miR-exon4) that has previously been suggested to indirectly regulate expression of the Runt-related transcription factor 2 (Runx2) involved in bone development in ameloblasts and osteoblasts. However, the precise mechanism of this regulation is unclear. In this study, we aimed to identify direct targets of miR-exon4. The transcription factor family nuclear factor I/A (NFI/A) is known to negatively regulate expression of Runx2 and is among the most highly predicted direct targets of miR-exon4 that link to Runx2. Immunostaining detected NFI/A in osteoblasts and ameloblasts in vivo, and reporter assays confirmed direct interaction of the Nfia 3'-UTR and miR-exon4. In addition, silencing of Nfia in MC3T3-E1-M14 osteoblasts resulted in subsequent downregulation of Runx2. In a monoclonal subclone (mi2) of MC3T3-E1 cells wherein mature miR-exon4 was functionally inhibited, we observed significantly downregulated Runx2 expression. We showed that NFI/A was significantly upregulated in mi2 cells at both mRNA and protein levels. Furthermore, quantitative proteomics and pathway analysis of gene expression in mi2 cells suggested that miR-exon4 could directly target Prkch (protein kinase C-eta), possibly leading to RUNX2 regulation through mechanistic target of rapamycin kinase activation. Reporter assays also confirmed the direct interaction of miR-exon4 and the 3'-UTR of Prkch, and Western blot analysis confirmed significantly upregulated mechanistic target of rapamycin kinase phosphorylation in mi2 cells. Taken together, we conclude that Nfia and Prkch expression negatively correlates with miR-exon4-mediated Runx2 regulation in vivo and in vitro, suggesting miR-exon4 directly targets Nfia and Prkch to regulate Runx2.
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Amelogenina/genética , Subunidade alfa 1 de Fator de Ligação ao Core/genética , MicroRNAs , Fatores de Transcrição NFI/metabolismo , Proteína Quinase C/metabolismo , Regiões 3' não Traduzidas , Animais , Diferenciação Celular , Linhagem Celular , Subunidade alfa 1 de Fator de Ligação ao Core/metabolismo , Éxons , Regulação da Expressão Gênica , Camundongos , MicroRNAs/genética , MicroRNAs/metabolismo , Fatores de Transcrição NFI/genética , Osteoblastos/metabolismo , Osteogênese/fisiologia , Sirolimo/metabolismoRESUMO
The development of smart nanosystems, which could overcome diverse biological barriers of nanomedicine transport, has received intense scientific interest in improving the therapeutic efficacies of traditional nanomedicines. However, the reported nanosystems generally hold disparate structures and functions, and the knowledge of involved biological barriers is usually scattered. There is an imperative need for a summary of biological barriers and how these smart nanosystems conquer biological barriers, to guide the rational design of the new-generation nanomedicines. This review starts from the discussion of major biological barriers existing in nanomedicine transport, including blood circulation, tumoral accumulation and penetration, cellular uptake, drug release, and response. Design principles and recent progress of smart nanosystems in overcoming the biological barriers are overviewed. The designated physicochemical properties of nanosystems can dictate their functions in biological environments, such as protein absorption inhibition, tumor accumulation, penetration, cellular internalization, endosomal escape, and controlled release, as well as modulation of tumor cells and their resident tumor microenvironment. The challenges facing smart nanosystems on the road heading to clinical approval are discussed, followed by the proposals that could further advance the nanomedicine field. It is expected that this review will provide guidelines for the rational design of the new-generation nanomedicines for clinical use.
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Nanomedicina , Neoplasias , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Portadores de Fármacos/química , Proteínas/uso terapêutico , Endossomos , Sistemas de Liberação de Medicamentos , Microambiente TumoralRESUMO
PURPOSE: To surmount the critical issues of indocyanine green (ICG), and thus achieving a precise surgical navigation of primary liver cancer after long-term transcatheter arterial embolization. METHODS: In this study, a facile and green pure-nanomedicine formulation technology is developed to construct carrier-free indocyanine green nanoparticles (nanoICG), and which subsequently dispersed into lipiodol via a super-stable homogeneous lipiodol formulation technology (SHIFT nanoICG) for transcatheter arterial embolization combined near-infrared fluorescence-guided precise hepatectomy. RESULTS: SHIFT nanoICG integrates excellent anti-photobleaching capacity, great optical imaging property, and specific tumoral deposition to recognize tumor regions, featuring entire-process enduring fluorescent-guided precise hepatectomy, especially in resection of the indiscoverable satellite lesions (0.6 mm × 0.4 mm) in rabbit bearing VX2 orthotopic hepatocellular carcinoma models. CONCLUSION: Such a simple and effective strategy provides a promising avenue to address the clinical issue of clinical hepatectomy and has excellent potential for a translational pipeline.
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Carcinoma Hepatocelular , Embolização Terapêutica , Neoplasias Hepáticas , Nanopartículas , Cirurgia Assistida por Computador , Animais , Carcinoma Hepatocelular/diagnóstico por imagem , Carcinoma Hepatocelular/cirurgia , Óleo Etiodado , Humanos , Verde de Indocianina , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/cirurgia , Imagem Óptica/métodos , Coelhos , Cirurgia Assistida por Computador/métodosRESUMO
Sanqi (Panax notoginseng (Burk.) F. H. Chen) is a precious traditional Chinese herbal medicine. During April of 2021, a root rot disease with approximate 15% incidence was observed on 2-year-old Sanqi plants in a field of Zhouning (27º12' N, 119°33' E), Fujian Province of China. The disease symptoms included severe stunting, leaf chlorosis, root rotting and necrosis, as the disease progressed, the whole plant gradually wilted and died. To recover the causal agent, symptomatic roots were excised, surface sterilized in 75% alcohol for 1.5 min, rinsed in sterilized water three times, dried, and placed on PARP selective medium (Jeffers and Martin 1986), and incubated at 20°C in dark. After 5 days, total of 26 Pythium-like isolates were obtained, and one representative isolate Py21-6 (available from the Institute of Plant Protection, Fujian Academy of Agricultural Sciences) was selected for further identification. Colonies of Py21-6 on PARP plate were white with dense, cottony, aerial, and transparent mycelia. Sporangia were terminal or intercalary, non-papillate, spherical, pyriform or ovoid, measuring 21.7 ± 2.8 × 19.3 ± 2.3 µm (n = 30). Zoospores were saucer-like, released out of sporangium after maturation, and dispersed quickly by swimming. Oogonia were spherical, terminal or occasionally intercalary. Oospores were globose, smooth and aplerotic. The dimensions of zoospores, oogonia, and oospores were 6.8 ± 0.7 µm, 21.6 ± 2.2 µm and 18.2 ± 2.7 µm (n = 30), respectively. Antheridia were bell-shaped or irregular, terminal, monoclinous, and usually one per oogonium. According to the morphological characteristics the isolate was initially identified as Pythium spp. (Van der Plaats-Niterink 1981, Yong et al. 2016). For further identification, DNA extracted from Py21-6, the cytochrome c oxidase subunit I (COI) gene and internal transcribed spacer (ITS) region were amplified and sequenced with primers FM55/FM52R (Long et al. 2012) and ITS1 /ITS4 (White et al. 1990), respectively. BLAST analysis of 680-bp COI (OM688194) and 728-bp ITS (OM663703) sequences revealed 99.86% and 99.99% similarity to Pythium vexans in GenBank (HQ708995 [COI], GU133572 [ITS]). Therefore, the pathogen was identified as P. vexans. In order to fulfill Koch's postulates, isolate Py21-6 was grown on Martin's liquid medium (Martin 1992) for 72 h to produce a spore suspensions of 106 oospores/ml, and the pathogenicity test was conducted by root-dip method. Three groups of 2-year-old Sanqi (15 plants per group) with root soaked for 20 min in oospore suspension were used for pathogenicity, and the other three groups (15 plants per group) with root dipped in sterilized water as control. All treated plants were replanted in (15-cm-diameter) pots (2 plants/pot) filled with mixture of sterilized soil: vermiculite: pearlite (2:1:1, v/v), maintained in greenhouse under 60% black shade cloth at 20 to 26°C with 80% relative humidity, and watered once every three days. After 21days, all inoculated plants showed the same symptoms observed on the original diseased plants in the field, whereas, the control plants remained symptomless. The same pathogen was successfully re-isolated from the inoculated plants, and identical to those of the originals based on morphological and sequence data. To our knowledge, this is the first report of P. vexans causing root rot on Sanqi in China (Farr and Rossman 2022). Root rot is one of the destructive diseases in Sanqi production, identification of the pathogen will be useful to develop effective field management strategies to control this disease.
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The recent outbreak of coronavirus disease 2019 (COVID-19) by SARS-CoV-2 has led to uptodate 24.3 M cases and 0.8 M deaths. It is thus in urgent need to rationalize potential therapeutic targets against the progression of diseases. An effective, feasible way is to use the pre-existing ΔORF6 mutant of SARS-CoV as a surrogate for SARS-CoV-2, since both lack the moiety responsible for interferon antagonistic effects. By analyzing temporal profiles of upregulated genes in ΔORF6-infected Calu-3 cells, we prioritized 55 genes and 238 ligands to reposition currently available medications for COVID-19 therapy. Eight of them are already in clinical trials, including dexamethasone, ritonavir, baricitinib, tofacitinib, naproxen, budesonide, ciclesonide and formoterol. We also pinpointed 16 drug groups from the Anatomical Therapeutic Chemical classification system, with the potential to mitigate symptoms of SARS-CoV-2 infection and thus to be repositioned for COVID-19 therapy.
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Tratamento Farmacológico da COVID-19 , Perfilação da Expressão Gênica , Fatores Imunológicos/farmacologia , SARS-CoV-2/imunologia , Transcriptoma/efeitos dos fármacos , COVID-19/imunologia , Linhagem Celular , Humanos , Transcriptoma/imunologiaRESUMO
Poly(ethylene glycol) (PEG) is well known to endow nanoparticles (NPs) with low-fouling and stealth-like properties that can reduce immune system clearance in vivo, making PEG-based NPs (particularly sub-100 nm) of interest for diverse biomedical applications. However, the preparation of sub-100 nm PEG NPs with controllable size and morphology is challenging. Herein, we report a strategy based on the noncovalent coordination between PEG-polyphenolic ligands (PEG-gallol) and transition metal ions using a water-in-oil microemulsion phase to synthesize sub-100 nm PEG NPs with tunable size and morphology. The metal-phenolic coordination drives the self-assembly of the PEG-gallol/metal NPs: complexation between MnII and PEG-gallol within the microemulsions yields a series of metal-stabilized PEG NPs, including 30-50 nm solid and hollow NPs, depending on the MnII/gallol feed ratio. Variations in size and morphology are attributed to the changes in hydrophobicity of the PEG-gallol/MnII complexes at varying MnII/gallol ratios based on contact angle measurements. Small-angle X-ray scattering analysis, which is used to monitor the particle size and intermolecular interactions during NP evolution, reveals that ionic interactions are the dominant driving force in the formation of the PEG-gallol/MnII NPs. pH and cytotoxicity studies, and the low-fouling properties of the PEG-gallol/MnII NPs confirm their high biocompatibility and functionality, suggesting that PEG polyphenol-metal NPs are promising systems for biomedical applications.
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Nanopartículas Metálicas , Nanopartículas , Interações Hidrofóbicas e Hidrofílicas , Tamanho da Partícula , PolietilenoglicóisRESUMO
BACKGROUND: Autophagy is a conserved catabolic process, which plays an important role in regulating tumor cell motility and degrading protein aggregates. Chemotherapy-induced autophagy may lead to tumor distant metastasis and even chemo-insensitivity in the therapy of hepatocellular carcinoma (HCC). Therefore, a vast majority of HCC cases do not produce a significant response to monotherapy with autophagy inhibitors. RESULTS: In this work, we developed a biomimetic nanoformulation (TH-NP) co-encapsulating Oxaliplatin (OXA)/hydroxychloroquine (HCQ, an autophagy inhibitor) to execute targeted autophagy inhibition, reduce tumor cell migration and invasion in vitro and attenuate metastasis in vivo. The tumor cell-specific ligand TRAIL was bioengineered to be stably expressed on HUVECs and the resultant membrane vesicles were wrapped on OXA/HCQ-loaded PLGA nanocores. Especially, TH-NPs could significantly improve OXA and HCQ effective concentration by approximately 21 and 13 times in tumor tissues compared to the free mixture of HCQ/OXA. Moreover, the tumor-targeting TH-NPs released HCQ alkalized the acidic lysosomes and inhibited the fusion of autophagosomes and lysosomes, leading to effective blockade of autophagic flux. In short, the system largely improved chemotherapeutic performance of OXA on subcutaneous and orthotopic HCC mice models. Importantly, TH-NPs also exhibited the most effective inhibition of tumor metastasis in orthotopic HCCLM3 models, and in the HepG2, Huh-7 or HCCLM3 metastatic mice models. Finally, we illustrated the enhanced metastasis inhibition was attributed to the blockade or reverse of the autophagy-mediated degradation of focal adhesions (FAs) including E-cadherin and paxillin. CONCLUSIONS: TH-NPs can perform an enhanced chemotherapy and antimetastatic effect, and may represent a promising strategy for HCC therapy in clinics.
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Antineoplásicos/farmacologia , Autofagia/efeitos dos fármacos , Materiais Biomiméticos/química , Nanopartículas/química , Animais , Antineoplásicos/química , Antineoplásicos/metabolismo , Antineoplásicos/uso terapêutico , Caderinas/metabolismo , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Portadores de Fármacos/química , Liberação Controlada de Fármacos , Adesões Focais/química , Adesões Focais/efeitos dos fármacos , Adesões Focais/metabolismo , Humanos , Hidroxicloroquina/química , Hidroxicloroquina/metabolismo , Hidroxicloroquina/farmacologia , Hidroxicloroquina/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/secundário , Camundongos , Neoplasias/patologia , Oxaliplatina/química , Oxaliplatina/metabolismo , Oxaliplatina/farmacologia , Oxaliplatina/uso terapêutico , Paxilina/metabolismo , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/químicaRESUMO
Neuroinflammation has been well recognized as a key pathological event in acute glaucoma. The medical therapy of acute glaucoma mainly focuses on lowering intraocular pressure (IOP), while there are still scarce anti-inflammatory agents in the clinical treatment of acute glaucoma. Here we reported that ß,3α,5α-trihydroxy-androst-6-one (sterone), a novel synthetic polyhydric steroid, blocked neuroinflammation mediated by microglia/macrophages and alleviated the loss of retinal ganglion cells (RGCs) caused by acute intraocular hypertension (AIH). The results showed that sterone significantly inhibited the morphological changes, the up-regulation of inflammatory biomarker ionized calcium-binding adapter molecule 1 (Iba-1), and the mRNA increase of proinflammatory tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), and interleukin-6 (IL-6) induced by lipopolysaccharide (LPS) in BV2 microglia and RAW264.7 macrophages. Moreover, immunofluorescence and western blotting analysis revealed that sterone markedly abrogated the nuclear translocation and phosphorylation of nuclear factor-κB (NF-κB) p65 subunit. Furthermore, sterone significantly suppressed the inflammatory microglial activation and RGCs' reduction caused by retinal ischemia/reperfusion (I/R) injury in a rat AIH model. These results suggest sterone may be a potential candidate in the treatment of acute glaucoma caused by microglial activation-mediated neuroinflammatory injury.
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Microglia/efeitos dos fármacos , Microglia/metabolismo , Fármacos Neuroprotetores/farmacologia , Hipertensão Ocular/metabolismo , Hipertensão Ocular/fisiopatologia , Células Ganglionares da Retina/efeitos dos fármacos , Células Ganglionares da Retina/metabolismo , Esteroides/farmacologia , Doença Aguda , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Contagem de Células , Sobrevivência Celular/efeitos dos fármacos , Modelos Animais de Doenças , Glaucoma/tratamento farmacológico , Glaucoma/etiologia , Glaucoma/metabolismo , Glaucoma/fisiopatologia , Lipopolissacarídeos/efeitos adversos , Camundongos , Estrutura Molecular , NF-kappa B/metabolismo , Fármacos Neuroprotetores/síntese química , Hipertensão Ocular/tratamento farmacológico , Hipertensão Ocular/etiologia , Células RAW 264.7 , Ratos , Traumatismo por Reperfusão/etiologia , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologia , Esteroides/síntese químicaRESUMO
Objective To observe changes of serum neuron specific enolase (NSE) level in children patients with epilepsy by additional use of ilepcimide (piperine derivative). Methods Totally 107 epilepsy children patients were assigned to the test group (77 cases) and the control group (30 cases) ac- cording to random digit table. Children patients in the control group received anti-epileptic Western drugs only. Those in the test group additionally took ilepcimide, 5 mg/kg per day as initial dose, taken in two times. The dose was gradually added to those without control of epilepsy attack. Added dose within a week should not exceed 10 mg/kg per day. The therapeutic course for all was one year. Electoencephalo- gram (EEG) was performed before treatment, half a year after treatment, and one year after treatment, respectively. Serum NSE level was detected using electrochemiluminescence. Efficacy was assessed after 1-year treatment. Results The total effective rate was 65. 0% (50177) in the test group, with statistical difference as compared with that in the control group [30. 0% (9/30), P <0. 01 ]. Compared with before treatment, serum NES-level obviously decreased in the test group after 0. 5-year treatment and 1- year treatment respectively (P <0. 05, P <0. 01). Besides, serum NES level was lower after 1-year treatment than after 0. 5-year treatment (P <0. 05, P <0. 01). There was no statistical difference in serum NES level between the test group and the control group at each time point (P >0. 05). Results of EEG were obviously superior in the test group (3 with normal range EEG, 5 critically abnormal EEG, 69 abnormal EEG) to the control group (2 with normal range EEG and 75 abnormal EEG) after 1-year treatment, with statistical difference (Z= -2. 33, P <0. 05). There was no statistical difference in EEG results of the control group between before treatment (all abnormal EEG) and after 1-year treatment (3 critically abnormal EEG and 27 abnormal EEG) (Z = -1. 732, P > 0. 05). Conclusion Adding ilepcimide (piperine derivative) for epilepsy children patients could lower serum NSE level and the frequency of seizures, and improve results of EEG.
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Medicamentos de Ervas Chinesas , Epilepsia , Fosfopiruvato Hidratase , Piperidinas , Criança , Eletroencefalografia , Epilepsia/tratamento farmacológico , Humanos , Fosfopiruvato Hidratase/sangue , Fosfopiruvato Hidratase/efeitos dos fármacos , Piperidinas/farmacologia , ConvulsõesRESUMO
Bioremediation is an effective process for the removal and recovery of heavy metal ions from aqueous solutions. In this study, red algae Porphyra leucosticta was examined to remove Cd(II) and Pb(II) ions from wastewater through biological enrichment and biological precipitation. The experimental parameters that affect the bioremediation process such as pH, contact time and biomass dosage were studied. The maximum bioremediation capacity of metal ions was 31.45 mg/g for Cd(II) and 36.63 mg/g for Pb(II) at biomass dosage 15 g/L, pH 8.0 and contact time 120 minutes containing initial 10.0 mg/L of Cd(II) and 10.0 mg/L of Pb(II) solution. Red algae Porphyra leucosticta biomass was efficient at removing metal ions of 10.0 mg/L of Cd(II) and 10.0 mg/L of Pb(II) solution with bioremediation efficiency of 70% for Cd(II) and 90% for Pb(II) in optimal conditions. At the same time, the removal capacity for real industrial effluent was gained at 75% for 7.6 mg/L Cd(II) and 95% for 8.9 mg/L Pb(II). In conclusion, it is demonstrated that red algae Porphyra leucosticta is a promising, efficient, cheap and biodegradable sorbent biomaterial for reducing heavy metal pollution in the environment and wastewater.
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Cádmio/metabolismo , Chumbo/metabolismo , Porphyra/metabolismo , Poluentes Químicos da Água/metabolismo , Biodegradação Ambiental , Biomassa , Concentração de Íons de Hidrogênio , Íons , Cinética , Metais , Metais Pesados , Rodófitas , Soluções , Águas ResiduáriasRESUMO
OBJECTIVE: To investigate the clinical features in children with tuberous sclerosis complex (TSC)-associated cardiac rhabdomyomas (CRM). METHODS: The clinical data of 15 children with TSC complicated by CRM were collected. The clinical features of the patients were analyzed, and TSC gene mutations were detected. RESULTS: Eleven cases (73%) developed multiple CRM. The majority of the tumors were located in the left and right ventricles. Most tumors presented as a round-like hyperechogenic mass with a clear margin on echocardiography. Arrhythmias occurred in 3 patients and 2 patients experienced heart failure. Gene mutation tests were performed in 2 patients, and pathogenic mutations were detected in both patients, which were TSC1 mutation and TSC2 mutation, respectively. Three patients were followed up for 6 to 38 months, and their CRM shrank or regressed spontaneously. CONCLUSIONS: TSC-associated CRM is generally multiple. Heart failure and arrhythmias may occur in some patients. Echocardiography is important for diagnosis of CRM. TSC-associated CRM has an inclination to spontaneous regression. TSC can be diagnosed at a molecular genetic level by TSC gene mutation detection.
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Neoplasias Cardíacas/complicações , Rabdomioma/complicações , Esclerose Tuberosa/etiologia , Pré-Escolar , Feminino , Neoplasias Cardíacas/genética , Hemodinâmica , Humanos , Lactente , Recém-Nascido , Masculino , Mutação , Rabdomioma/genética , Proteína 2 do Complexo Esclerose Tuberosa , Proteínas Supressoras de Tumor/genéticaRESUMO
This article reviews the present indicators, trends, and recent solutions and strategies to tackle major global and country problems in safety and health at work. The article is based on the Yant Award Lecture of the American Industrial Hygiene Association (AIHA) at its 2013 Congress. We reviewed employment figures, mortality rates, occupational burden of disease and injuries, reported accidents, surveys on self-reported occupational illnesses and injuries, attributable fractions, national economic cost estimates of work-related injuries and ill health, and the most recent information on the problems from published papers, documents, and electronic data sources of international and regional organizations, in particular the International Labor Organization (ILO), World Health Organization (WHO), and European Union (EU), institutions, agencies, and public websites. We identified and analyzed successful solutions, programs, and strategies to reduce the work-related negative outcomes at various levels. Work-related illnesses that have a long latency period and are linked to ageing are clearly on the increase, while the number of occupational injuries has gone down in industrialized countries thanks to both better prevention and structural changes. We have estimated that globally there are 2.3 million deaths annually for reasons attributed to work. The biggest component is linked to work-related diseases, 2.0 million, and 0.3 million linked to occupational injuries. However, the division of these two factors varies depending on the level of development. In industrialized countries the share of deaths caused by occupational injuries and work-related communicable diseases is very low while non-communicable diseases are the overwhelming causes in those countries. Economic costs of work-related injury and illness vary between 1.8 and 6.0% of GDP in country estimates, the average being 4% according to the ILO. Singapore's economic costs were estimated to be equivalent to 3.2% of GDP based on a preliminary study. If economic losses would take into account involuntary early retirement then costs may be considerably higher, for example, in Finland up to 15% of GDP, while this estimate covers various disorders where work and working conditions may be just one factor of many or where work may aggravate the disease, injury, or disorders, such as traffic injuries, mental disorders, alcoholism, and genetically induced problems. Workplace health promotion, services, and safety and health management, however, may have a major preventive impact on those as well. Leadership and management at all levels, and engagement of workers are key issues in changing the workplace culture. Vision Zero is a useful concept and philosophy in gradually eliminating any harm at work. Legal and enforcement measures that themselves support companies and organizations need to be supplemented with economic justification and convincing arguments to reduce corner-cutting in risk management, and to avoid short- and long-term disabilities, premature retirement, and corporate closures due to mismanagement and poor and unsustainable work life. We consider that a new paradigm is needed where good work is not just considered a daily activity. We need to foster stable conditions and circumstances and sustainable work life where the objective is to maintain your health and work ability beyond the legal retirement age. We need safe and healthy work, for life.
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Acidentes de Trabalho/prevenção & controle , Acidentes de Trabalho/estatística & dados numéricos , Doenças Profissionais/economia , Doenças Profissionais/prevenção & controle , Acidentes de Trabalho/tendências , Efeitos Psicossociais da Doença , Humanos , Mortalidade/tendências , Local de TrabalhoRESUMO
Introduction: Chronic kidney disease (CKD) is worldwide healthcare burden with growing incidence and death rate. Emerging evidence demonstrated the compositional and functional differences of gut microbiota in patients with CKD. As such, gut microbial features can be developed as diagnostic biomarkers and potential therapeutic target for CKD. Methods: To eliminate the outcome bias arising from factors such as geographical distribution, sequencing platform, and data analysis techniques, we conducted a comprehensive analysis of the microbial differences between patients with CKD and healthy individuals based on multiple samples worldwide. A total of 980 samples from six references across three nations were incorporated from the PubMed, Web of Science, and GMrepo databases. The obtained 16S rRNA microbiome data were subjected to DADA2 processing, QIIME2 and PICRUSt2 analyses. Results: The gut microbiota of patients with CKD differs significantly from that of healthy controls (HC), with a substantial decrease in the microbial diversity among the CKD group. Moreover, a significantly reduced abundance of bacteria Faecalibacterium prausnitzii (F. prausnitzii) was detected in the CKD group through linear discriminant analysis effect size (LEfSe) analysis, which may be associated with the alleviating effects against CKD. Notably, we identified CKD-depleted F. prausnitzii demonstrated a significant negative correlation with three pathways based on predictive functional analysis, suggesting its potential role in regulating systemic acidbase disturbance and pro-oxidant metabolism. Discussion: Our findings demonstrated notable alterations of gut microbiota in CKD patients. Specific gut-beneficial microbiota, especially F. prausnitzii, may be developed as a preventive and therapeutic tool for CKD clinical management.
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Microbioma Gastrointestinal , RNA Ribossômico 16S , Insuficiência Renal Crônica , Microbioma Gastrointestinal/genética , Humanos , RNA Ribossômico 16S/genética , Insuficiência Renal Crônica/microbiologia , Bactérias/classificação , Bactérias/genética , Bactérias/isolamento & purificação , Fezes/microbiologia , Filogenia , Faecalibacterium prausnitzii/genética , Biodiversidade , Disbiose/microbiologiaRESUMO
Three new ruthenium(II) complexes-[Ru(bpy)2(adppz)](ClO4)2, [Ru(dmb)2(adppz)](ClO4)2, and [Ru(dmp)2(adppz)](ClO4)2 (bpy is 2,2'-bipyridine, adppz is 7-aminodipyrido[3,2-a:2',3'-c]phenazine, dmb is 4,4'-dimethyl-2,2'-bipyridine, and dmp is 2,9-dimethyl-1,10-phenanthroline)-were synthesized. [Ru(dmp)2(adppz)](ClO4)2 exhibits higher cytotoxicity than cisplatin toward A549, MG-63, and SKBR-3 cells. The apoptosis and cellular uptake were studied by fluorescence microscopy. [Ru(dmp)2(adppz)](ClO4)2 enhances the level of reactive oxygen species (ROS) and decreases the mitochondrial membrane potential. These complexes induce cell cycle arrest in S phase in BEL-7402 cells, and inhibit the antiproliferation of SKBR-3 cells at G0/G1 phase. Western blotting analysis shows that [Ru(dmp)2(adppz)](ClO4)2 induces apoptosis in BEL-7402 cells through activation of caspase 3, caspase 7, and procaspase 7 and ROS-mediated mitochondrial dysfunction pathways.
Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Complexos de Coordenação/química , Complexos de Coordenação/farmacologia , Rutênio/química , Rutênio/farmacologia , 2,2'-Dipiridil/química , 2,2'-Dipiridil/farmacologia , Apoptose/efeitos dos fármacos , Western Blotting , Linhagem Celular Tumoral , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Fenantrolinas/química , Fenantrolinas/farmacologia , Fenazinas/química , Fenazinas/farmacologia , Piridinas/química , Piridinas/farmacologia , Espécies Reativas de Oxigênio/metabolismoRESUMO
Although sonodynamic therapy (SDT) has shown promise for cancer treatment, the lack of efficient sonosensitizers (SSs) has limited the clinical application of SDT. Here, a new strategy is reported for designing efficient nano-sonosensitizers based on 2D nanoscale metal-organic layers (MOLs). Composed of Hf-oxo secondary building units (SBUs) and iridium-based linkers, the MOL is anchored with 5,10,15,20-tetra(p-benzoato)porphyrin (TBP) sensitizers on the SBUs to afford TBP@MOL. TBP@MOL shows 14.1- and 7.4-fold higher singlet oxygen (1 O2 ) generation than free TBP ligands and Hf-TBP, a 3D nanoscale metal-organic framework, respectively. The 1 O2 generation of TBP@MOL is enhanced by isolating TBP SSs on the SBUs of the MOL, which prevents aggregation-induced quenching of the excited sensitizers, and by triplet-triplet Dexter energy transfer between excited iridium-based linkers and TBP SSs, which more efficiently harnesses broad-spectrum sonoluminescence. Anchoring TBP on the MOL surface also enhances the energy transfer between the excited sensitizer and ground-state triplet oxygen to increase 1 O2 generation efficacy. In mouse models of colorectal and breast cancer, TBP@MOL demonstrates significantly higher SDT efficacy than Hf-TBP and TBP. This work uncovers a new strategy to design effective nano-sonosensitizers by facilitating energy transfer to efficiently capture broad-spectrum sonoluminescence and enhance 1 O2 generation.
Assuntos
Neoplasias , Porfirinas , Terapia por Ultrassom , Camundongos , Animais , Irídio , Porfirinas/farmacologia , Oxigênio Singlete , Oxigênio , Neoplasias/tratamento farmacológicoRESUMO
The diabetic wound is a prevalent and serious complication of diabetes, which easily deteriorates due to susceptibility to infection and difficulty in healing, causing a high risk of amputation and economic burden to patients. Bacterial infection, persistent excessive inflammation, and cellular and angiogenesis disorders are the main reasons for the difficulty of diabetic wound healing. In this study, glycerol monooleate (GMO) was used to prepare lyotropic liquid crystal hydrogel (LLC) containing the natural antimicrobial peptide LL37 and carbenoxolone (CBX) to achieve antibacterial, anti-inflammation, and healing promotion for the treatment of diabetic wounds. The shear-thinning properties of the LLC precursor solution allowed it to be administered in the form of a spray, which perfectly fitted the shape of the wound and transformed into a gel after absorbing wound exudate to act as a wound protective barrier. The faster release of LL37 realized rapid sterilization of wounds, controlled the source of inflammation, and accelerated wound healing. The inflammatory signaling pathway was blocked by the subsequently released CBX, and the spread of the inflammatory response was inhibited and then further weakened. In addition, CBX down-regulated connexin (Cx43) to assist LL37 to promote cell migration and proliferation better. Combined with the pro-angiogenic effect of LL37, the healing of diabetic wounds was significantly accelerated. All these advantages made LL37-CBX-LLC a promising approach for the treatment of chronic diabetic wounds.
RESUMO
Current oxidative stress amplifying strategies for immunogenic cell death (ICD) promotion are mainly restricted to immune tolerance induced by adaptive cellular antioxidation, limited tumor-selectivity, and tumoral immunosuppression. Herein, a facile and efficient scenario of genetically engineering transferrin-expressing cell membrane nanovesicle encapsulated IR820-dihydroartemisinin nanomedicine (Tf@IR820-DHA) was developed to boost a-PD-L1-mediated immune checkpoint blocking (ICB) via synergetic triple stimuli-activated oxidative stress-associated ICD. We demonstrate that the engineered transferrin of Tf@IR820-DHA has excellent tumor targeting and Fe(III)-loading properties and thus delivered Fe(III) and IR820-DHA nanoparticles (NPs) to the lesion location effectively. We found that the self-carrying Fe(III)-mediated programmable catalysis of DHA and glutathione (GSH) depletion generated plenty of reactive oxygen species (ROS). Moreover, DHA also acted as an immunomodulator to decrease the number of T regulatory cells, thereby remodeling the tumor immune microenvironment and achieving double T cell activation. Furthermore, the IR820 molecule served as a competent sonosensitizer to produce ROS under ultrasound activation and guide precise immunotherapy via fluorescent/photoacoustic (FL/PA) imaging. Through its three-pronged delivery of stimuli-activated oxidative stress (DHA-induced chemodynamic therapy, catalysis-conferred GSH depletion, and IR820-mediated sonodynamic therapy), Tf@IR820-DHA caused high levels of targeted ICD. This significantly increased the proportions of IFN-γ-secreting T cells (CD4+ T and CD8+ T) and enhanced a-PD-L1-mediated ICB against primary and distant tumors, which represents a promising approach for cancer nanoimmunotherapy.