Hepatotoxicity Comparison of Crude and Licorice-Processed Euodiae Fructus in Rats With Stomach Excess-Cold Syndrome

In recent years, drug-induced liver injury (DILI) has become an important issue of public health. Euodiae Fructus (EF) is a commonly used herb with mild toxicity in clinic, and large doses of EF can cause significant liver damage. Licorice processing might reduce the hepatotoxicity of CEF (crude EF), but up to now, studies on the hepatotoxicity of EF have been hardly reported, let alone its material basis and mechanism of detoxification by licorice processing. This work firstly established a stomach excess-cold syndrome animal model induced by intragastric administration of cold Zhimu (Anemarrhena asphodeloides Bge). Secondly, multiple approaches and indexes were used to evaluate the hepatotoxicity of the drugs in the rats including general behavior, biochemical analysis, protein expressions, and histopathological examination. Thirdly, the hepatotoxicity of three doses of three CEF and LPEF (licorice-processed EF) extracts was systematically investigated, and the hepatotoxicity differences were analyzed and compared comprehensively among the three extracts, three doses, and CEF and LPEF. Finally, the connotation of detoxification of EF by licorice processing was preliminarily discussed according to the changes in toxic components after processing, toxicological characteristics, and TCM (traditional Chinese medicine) theory. All extracts of EF were found to have dose-dependent hepatotoxicity, and the toxicity was in the descending order of water extract, ethanol extract, and volatile oil. The hepatotoxic mechanism of EF may be related to peroxidation damage, inflammatory factor, and mitochondrial injury. The CEF hepatotoxicity can be significantly reduced by licorice processing. EF should be safe for short-term use at pharmacopeial dose under the guidance of the TCM theory. The detoxification mechanism is probably related to the reduction of toxic components and antagonistic action of licorice.

Extracellular Vesicles Physiological Role and the Particular Case of Disease-Spreading Mechanisms in Polyglutamine Diseases

Recent research demonstrated pathological spreading of the disease-causing proteins from one focal point across other brain regions for some neurodegenerative diseases, such as Parkinson’s and Alzheimer’s disease. Spreading mediated by extracellular vesicles is one of the proposed disease-spreading mechanisms. Extracellular vesicles are cell membrane-derived vesicles, used by cells for cell-to-cell communication and excretion of toxic components. Importantly, extracellular vesicles carrying pathological molecules, when internalized by “healthy” cells, may trigger pathological pathways and, consequently, promote disease spreading to neighboring cells. Polyglutamine diseases are a group of genetic neurodegenerative disorders characterized by the accumulation of mutant misfolded proteins carrying an expanded tract of glutamines, including Huntington’s and Machado–Joseph disease. The pathological spread of the misfolded proteins or the corresponding mutant mRNA has been explored. The understanding of the disease-spreading mechanism that plays a key role in the pathology progression of these diseases can result in the development of effective therapeutic approaches to stop disease progression, arresting the spread of the toxic components and disease aggravation. Therefore, the present review’s main focus is the disease-spreading mechanisms with emphasis on polyglutamine diseases and the putative role played by extracellular vesicles in this process.

Toxin-like peptides in plasma, urine and faecal samples from COVID-19 patients

Background: SARS-CoV-2 that causes COVID-19 disease and led to the pandemic currently affecting the world has been broadly investigated. Different studies have been performed to understand the infection mechanism, and the involved human genes, transcripts and proteins. In parallel, numerous clinical extra-pulmonary manifestations co-occurring with COVID-19 disease have been reported and evidence of their severity and persistence is increasing. Whether these manifestations are linked to other disorders co-occurring with SARS-CoV-2 infection, is under discussion. In this work, we report the identification of toxin-like peptides in COVID-19 patients by application of the Liquid Chromatography Surface-Activated Chemical Ionization – Cloud Ion Mobility Mass Spectrometry. Methods: Plasma, urine and faecal samples from COVID-19 patients and control individuals were analysed to study peptidomic toxins’ profiles. Protein precipitation preparation procedure was used for plasma, to remove high molecular weight proteins and efficiently solubilize the peptide fraction; in the case of faeces and urine, direct peptide solubilization was employed. Results: Toxin-like peptides, almost identical to toxic components of venoms from animals, like conotoxins, phospholipases, phosphodiesterases, zinc metal proteinases, and bradykinins, were identified in samples from COVID-19 patients, but not in control samples. Conclusions: The presence of toxin-like peptides could potentially be connected to SARS-CoV-2 infection. Their presence suggests a possible association between COVID-19 disease and the release in the body of (oligo-)peptides almost identical to toxic components of venoms from animals. Their involvement in a large set of heterogeneous extra-pulmonary COVID-19 clinical manifestations, like neurological ones, cannot be excluded. Although the presence of each individual symptom is not selective of the disease, their combination might be related to COVID-19 by the coexistence of the panel of the here detected toxin-like peptides. The presence of these peptides opens new scenarios on the aetiology of the COVID-19 clinical symptoms observed up to now, including neurological manifestations.

A MORTE NA PERSPECTIVA BIOLÓGICA E ESPIRITUAL NA RELAÇÃO DE UM FENÔMENO NATURAL CELULAR

A morte biológica é um processo que se relaciona com uma série de ações biológicas celulares sinalizadoras. Na busca de compreensão da alma é possível sugerirmos proposições que possam interagir e integrar os corpos físico e espiritual. Perante proteínas celulares responsáveis pela proteção celular e eliminação de componentes tóxicos, buscamos objetivar uma associação entre as perspectivas filosóficas, inclusive na religião para o processo de morte. A morte deve ser compreendida como condição natural para os seres vivos, e que desencadeia a esperança na própria vida. Na morte programada e prevista pelas células biológicas, seja por motivo de saúde ou até mesmo a finalização de um tempo de vida, as etiquetas químicas da morte entram em ação. Morte e vida estão em íntima relação biológica e espiritual. É nesse sentido que a morte também é um fator de manutenção das tradições e preocupações humanas para uma evolução biológica e divina. Palavras-chave: A Morte Biológica. E Espiritual. Fenômeno Natural Celular. Abstract Biological death is a process that is related to a series of signaling cellular biological actions. In the search for understanding the soul, it is possible to suggest propositions that can interact and integrate the physical and spiritual bodies. Faced with cellular proteins responsible for cellular protection and elimination of toxic components, we seek to aim at an association between philosophical perspectives, including religion for the process of death. Death must be understood as a natural condition for living beings, which triggers hope in life itself. In programmed and predicted death by biological cells, whether for health reasons or even the end of a lifetime, the chemical labels of death come into play. Death and life are in an intimate biological and spiritual relationship. It is in this sense that death is also a factor in maintaining human traditions and concerns for a biological and divine evolution. Keywords: Biological Death. And Spiritual. Signaling Cellular biological Actions.

Toxin-like peptides in plasma, urine and faecal samples from COVID-19 patients

Background: SARS-CoV-2 that causes COVID-19 disease and led to the pandemic currently affecting the world has been broadly investigated. Different studies have been performed to understand the infection mechanism, and the involved human genes, transcripts and proteins. In parallel, numerous clinical extra-pulmonary manifestations co-occurring with COVID-19 disease have been reported and evidence of their severity and persistence is increasing. Whether these manifestations are linked to other disorders co-occurring with SARS-CoV-2 infection, is under discussion. In this work, we report the identification of toxin-like peptides in COVID-19 patients by application of the Liquid Chromatography Surface-Activated Chemical Ionization – Cloud Ion Mobility Mass Spectrometry. Methods: Plasma, urine and faecal samples from COVID-19 patients and control individuals were analysed to study peptidomic toxins’ profiles. Protein precipitation preparation procedure was used for plasma, to remove high molecular weight proteins and efficiently solubilize the peptide fraction; in the case of faeces and urine, direct peptide solubilization was employed. Results: Toxin-like peptides, almost identical to toxic components of venoms from animals, like conotoxins, phospholipases, phosphodiesterases, zinc metal proteinases, and bradykinins, were identified in samples from COVID-19 patients, but not in control samples. Conclusions: The presence of toxin-like peptides could potentially be connected to SARS-CoV-2 infection. Their presence suggests a possible association between COVID-19 disease and the release in the body of (oligo-)peptides almost identical to toxic components of venoms from animals. Their involvement in a large set of heterogeneous extra-pulmonary COVID-19 clinical manifestations, like neurological ones, cannot be excluded. Although the presence of each individual symptom is not selective of the disease, their combination might be related to COVID-19 by the coexistence of the panel of the here detected toxin-like peptides. The presence of these peptides opens new scenarios on the aetiology of the COVID-19 clinical symptoms observed up to now, including neurological manifestations.

A New Produced Water Management Policy for the Energy Sector of Trinidad and Tobago

A Produced Water (PW) Management framework is presented, forming part of an Upstream Effluent Management (UEM) Policy. It addresses the minimization and ultimate elimination of treated and untreated PW discharge by utilization of an integrated management approach to ensure Zero Harmful Discharge (ZHD) to the environment. This approach targeted legislative reform, sustainable PW management practices, monitoring and evaluation, research and development and sustainable production patterns. A Cabinet-appointed Upstream Effluent Management Committee was established for evaluating the status of the upstream, oil and gas, effluent management practices including that of PW and providing recommendations on the way forward. This included determining the challenges in meeting relevant environmental standards; evaluating Best Available Technology (BAT) or Best Practicable Environmental Options (BPEO) for local use and benchmarking local standards against international best practices. Ultimately, a UEM Policy, inclusive of a PW Management Policy, and a revised Water Pollution Rules 2019 (WPR) were developed, submitted and approved by the Cabinet of Trinidad and Tobago. Emerging from data evaluation and committee consultations, it was found that parameters from PW streams, such as Chemical Oxygen Demand (COD), Phenols and Ammoniacal Nitrogen were regularly out of compliance with local permissible limits. Additionally, it was noted that PW management was known to be generally costly, in terms of monitoring, treatment and disposal operations. As such the UEM Committee recommended that measures be taken to facilitate better PW management including, amendments to the Water Pollution Rules 2001 (as amended) and the TTS 547:1998, Specification for the Effluent From Industrial Processes Discharged into the Environment; to focus more on toxic components such as BTEX (Benzene, Toluene, Ethylbenzene and Xylene) and PAH (Polycyclic Aromatic Hydrocarbons); improvement of the chemical evaluation and approval process by the Ministry of Energy and Energy Industries (MEEI) to include a pre-screening step; and the establishment of National Ambient Water Quality Standards, which have been included in the revised WPR. The WPR also encourages re-use as a beneficial discount through the revised annual permit calculation. In addition, Environmental Risk Assessments (ERA) are to be utilized to evaluate the physical, biological and socio-economic environmental standing of the marine environment of Trinidad and Tobago, so as to comprehensively deduce the full impacts of effluent discharge. Trinidad and Tobago has been in oil and gas operations for over 100 years and this integrated management approach for PW introduces a set of novel strategies and tools, geared towards moving in a more environmentally sustainable direction. The approach envisages the use of a more industry-specific regulation that focuses on the toxic components. Furthermore, this method acknowledges that "not-one-size-fits-all" and so, based on the ERA results for the specific geographic marine jurisdictions surrounding Trinidad and Tobago; it encourages more environmentally sustainable and cost effective management.

Glycyrrhiza Uralensis Promote the Metabolism of Toxic Components of Aconitum Carmichaeli by CYP3A and Alleviate the Development of Chronic Heart Failure

BackgroundCHF is a common clinical critical disease with high mortality and short survival. Aconitum, as "the first drug of choice for invigorating Yang and saving lives", has been widely used for the treatment of heart failure. However, toxic components of Aconitum can easily lead to serious arrhythmia, respiratory depression, shock and even death [1, 2]. ObjectiveTo investigate the mechanisms of Glycyrrhizae reducing the toxicity of Aconitum.Method A High Performance Liquid Chromatography (HPLC) method for the determination of aconitine (AC), mesaconitine (MA) and hypaconitine (HA) was established; The effect of Glycyrrhiza on CYP3A1 / 2 mRNA expression was detected by RT-PCR; SD rats were given Aconitum and compatibility of Glycyrrhizae and Aconitum by gavage respectively, the blood concentration of toxic components were determined by LC-MS / MS; The CHF rat model was established by intraperitoneal injection of adriamycin (2.5 mg / kg), and were randomly divided into model, Aconitum, the compatibility of Glycyrrhizae and Aconitum and Captopril group. After 4 weeks of gavage, the levels of BNP, Ang II and ALD in blood were detected by ELISA, and the contents of adenosine monophosphate (ATP, ADP and AMP) in myocardium were determined by HPLC.Result AC, MA and HA produced three, three and two metabolites respectively; Ketoconazole significantly inhibited the metabolites of AC, MA and HA; Glycyrrhiza induced CYP3A gene expression, and significantly promoted the metabolism of toxic components of Aconitum; The level of ALD in the compatibility of Glycyrrhizae and Aconitum group was significantly lower than that in Aconitum group. After intervention with the compatibility of Glycyrrhizae and Aconitum, ATP increased significantly, ADP decreased significantly.Conclusion Glycyrrhiza promoted the metabolism of toxic components of Aconitum by up regulating the expression of CYP3A, and reduced the content of BNP, Ang II and ALD, improved the energy metabolism disorder of myocardium, alleviated the development of CHF.

Pyrrolizidine-Derived Alkaloids: Highly Toxic Components in the Seeds of Crotalaria cleomifolia Used in Popular Beverages in Madagascar

Seeds of Crotalaria cleomifolia (Fabaceae) are consumed in Madagascar in preparation of popular beverages. The investigation of extracts from the seeds of this species revealed the presence of high amounts of alkaloids from which two pyrrolizidine-derived alkaloids were isolated. One of them was fully characterized by spectroscopic and spectrometric methods, which was found to be usaramine. Owing to the high toxicity of these alkaloids, issuing a strong warning among populations consuming the seeds of Crotalaria cleomifolia must be considered.