Mechanism of action of Orthosiphon stamineus against non-alcoholic fatty liver disease: Insights from systems pharmacology and molecular docking approaches

Non-alcoholic fatty liver disease (NAFLD) is one of the most common complications of a metabolic syndrome caused by excessive accumulation of fat in the liver. Orthosiphon stamineus also known as Orthosiphon aristatus is a medicinal plant with possible potential beneficial effects on various metabolic disorders. This study aims to investigate the in vitro inhibitory effects of O. stamineus on hepatic fat accumulation and to further use the computational systems pharmacology approach to identify the pharmacokinetic properties of the bioactive compounds of O. stamineus and to predict their molecular mechanisms against NAFLD. Methods: The effects of an ethanolic extract of O. stamineus leaves on cytotoxicity, fat accumulation and antioxidant activity were assessed using HepG2 cells. The bioactive compounds of O. stamineus were identified using LC/MS and two bioinformatics databases, namely the Traditional Chinese Medicine Integrated Database (TCMID) and the Bioinformatics Analysis Tool for the Molecular Mechanism of Traditional Chinese Medicine (BATMAN-TCM). Pathway enrichment analysis was performed on the predicted targets of the bioactive compounds to provide a systematic overview of the molecular mechanism of action, while molecular docking was used to validate the predicted targets. Results: A total of 27 bioactive compounds corresponding to 50 potential NAFLD-related targets were identified. O. stamineus exerts its anti-NAFLD effects by modulating a variety of cellular processes, including oxidative stress, mitochondrial β-oxidation, inflammatory signalling pathways, insulin signalling, and fatty acid homeostasis pathways. O. stamineus is significantly targeting many oxidative stress regulators, including JNK, mammalian target of rapamycin (mTOR), NFKB1, PPAR, and AKT1. Molecular docking analysis confirmed the expected high affinity for the potential targets, while the in vitro assay indicates the ability of O. stamineus to inhibit hepatic fat accumulation. Conclusion: Using the computational systems pharmacology approach, the potentially beneficial effect of O. stamineus in NAFLD was indicated through the combination of multiple compounds, multiple targets, and multicellular components.     

Climate Change: Effects on the Older Adult

The effects of climate change include floods, hurricanes, heat waves, and fires; these natural disasters can result in respiratory, cardiovascular, and psychological harm in older adults, who experience the highest morbidity and mortality during heat waves. Advanced practice registered nurses (APRNs) need education on preparing, assessing, and treating older adults for climate-change disasters, especially heat waves. This article will help APRNs understand the effects of climate-change events on the vulnerable older adults and advocates for the need to integrate health effects of climate change into curricula, practicums, policy, and research agendas.     

Phase 1/2 clinical trial of COVID-19 vaccine in Japanese participants: A report of interim findings

We initiated a randomized, placebo-controlled, phase 1/2 trial to evaluate the safety and immunogenicity of the S-268019-b recombinant protein vaccine, scheduled as 2 intramuscular injections given 21 days apart, in 60 randomized healthy Japanese adults. We evaluated 2 regimens of the S-910823 antigen (5 μg [n = 24] and 10 μg [n = 24]) with an oil-in-water emulsion formulation and compared against placebo (n = 12). Reactogenicity was mild in most participants. No serious adverse events were noted. For both regimens, vaccination resulted in robust IgG and neutralizing antibody production at days 36 and 50 and predominant T-helper 1-mediated immune reaction, as evident through antigen-specific polyfunctional CD4+ T-cell responses with IFN-γ, IL-2, and IL-4 production on spike protein peptides stimulation. Based on the interim analysis, the S-268019-b vaccine is safe, produces neutralizing antibodies titer comparable with that in convalescent serum from COVID-19-recovered patients. However, further evaluation of the vaccine in a large clinical trial is warranted.     

Le traumatisme psychique constitue une blessure du langage par atteinte des réseaux de significations

ObjectivesTrauma appears within the discourse of mentally injured people, materializing what we have recently defined as “post traumatic psycholinguistic syndrome” (SPLIT). Translating unspeakability, revival, and dissociation, this clinical entity associates three significant disturbances : traumatic anomia (missing words, reduction of the elocutionary flow, deictic gestures, etc.); linguistic repetitions (of words and phrases, verbal intrusions, echophrasias, etc.); and phrasal and discursive disorganization (incomplete sentences, tense discordance, dysfluence, lack of logical connectors, etc.). What are the causes of these semiological and psycholinguistic expressions? What are their psychological and/or neuropsychological processes? It is time to come up with a new concept intended to go beyond the previous models in order to better identify people suffering from post-traumatic mental disorders, to better organize and evaluate psychotherapeutic care, and also to help practitioners collaborate more effectively on these first two goals. But how to evoke, affirm, or speak out about the consequences of unspeakability? Nothing is more apparently contradictory than wanting to define the language void. How to account for the fractures of psychic trauma in discourse? Nothing is more uncertain than to try to organize the upheavals, the disorders caused by dissociation in language. Finally, how to specify the reiteration of the trauma using words and sentences without this modeling being dissociative or repetitive? Today, thanks to a psycholinguistic reading, essential dimensions of post-traumatic suffering, hitherto hidden, can be clarified. Why exactly does an event cause trauma in the life of a subject at a given moment in her/his existence? Why is a latency phase structured between the traumatic event and the return of reviviscences under the influence of a re-triggering factor? How to differentiate the notion of dissociation as a normal phenomenon from the so-called traumatic dissociation? How to explain the multiple clinical forms of post-traumatic psychological disorders?MethodsFrom Pierre's clinical history, we chronologically detail the structuring and the consequences of the signified reflection that are constitutive of the psychic trauma: the psycholinguistic tools here help to formulate a new etiopathogenic conception of trauma and its psychological consequences. Then, thanks to Jean's testimony, taking up the retrospective meaning of the clinical analysis from chronic repetition syndrome, we discover the phases of tension regarding signified knowledge, up to the network prior to the traumatic confrontation. Finally, illustrated by Karima's disorder, beyond depersonalization, we explain that the analysis of the disturbances of a singular signified network, and also of an attack on its familial and societal bases, testifies to individual and collective subjectivities.ResultsComing from the real world, and therefore also from the body, the stimuli made up of signals picked up by our senses combine to compose an event that can be objectified by its temporal, spatial, biological, and physico-chemical coordinates. These elements combine into a unit, which is then interpreted by the mind, which attributes meaning to this event, which has become subjective reality. But when the subject is not sufficiently prepared to be confronted with this meaning that appears to be in extreme contradiction with her/his previous cardinal networks of significations, it makes “too much sense:” this irreconcilable hyper-signified (that we call the traumatic signified) results in post-traumatic dissociation. In other words, it is an impossibility of concordance of a signified with certain systems of prior significations that constitutes the pathogenesis of the trauma; and a situation runs a greater risk of being traumatic when it contradicts, or, moreso, endangers some or all of the subject's cardinal meanings. This unbearable signified reflexively blocks the capacities of significations immediately pre- and post-trauma, then dissociates the psychic functions to varying degrees and intensities. The traumatic signified, rejected, becomes unattainable: the stimuli that led to its formation find themselves confined to the state of reviviscences, each replication of which attempts to cross the barrier of inconceivability. Limiting sensory compounds to their raw states without the possibility of representational integration, associative pathways remain blocked. The signifier is referred to a hypo-signifier confined to the infra-linguistic by its confusion with the referent, the “objective and material” components of the traumatic event. Dissociation is therefore only a symptomatic reaction, secondary to the trauma, which it reinforces once again by limiting any possibility of representing the trauma. This dissociation does not involve forgetting the traumatic signified but “protects” the adjacent networks of meanings from it as much as it “keeps” this hypersignified intact, therefore ultimately “protecting” it as well. The traumatic signified persists somewhere, and even ends up being found everywhere: when the networks of meanings turn out to be globally disturbed, the tightest links remain those of the traumatic hypersignified that ultimately governs all the networks of meanings.DiscussionOur insufficient knowledge prevents us from precisely qualifying the architecture of the signified idiosyncratic networks and their evolutionary capacities; we cannot predict, beforehand, the reaction of an individual confronted with a potentially psychotraumatic situation. For most clinical situations, we affirm that the psychological trauma occurs in a psychically healthy subject, that is, not suffering from any psychiatric illness or any obvious psychopathological conflict. Psychotherapy will make it possible to discover the signified, sometimes ancient, origins of a trauma occurring in a singular subject. How was this subjectivity constructed? Beyond individual subjectivity, the intensity of certain confrontations such as serious attacks or macrosocial catastrophes such as genocide, would seem to lead to psychological wounds in any individual, even at the scale of a population. While, throughout existence, each subject produces a system of significations in connection with a unique psychic construction, the latter persists – resulting from, and often remaining overseen by, the community essence of a base of signifying networks, which we call “societal subjectivity.” Here, the psychological trauma can correspond to an individual and “common” injury as a failure of a sharing, or of ancestral beliefs anchored in the collective memory, defining the culture. By the collapse of acquired certainties, the cognitive patterns transmitted by education, language, and everything that establishes one's belonging to a society, trauma shakes the networks of individual and group meanings. Horror has a higher traumatogenic risk, because it defeats the fundamentals of humankind, the foundations of a signified network common to a culture, or even to all cultures, to the human condition. This is the case with murder, rape, torture, wars, genocides. Testifying to an instinct for survival stemming from the biological foundations of every living being, the impossibility of “living death” appears to be anchored in our networks of meanings and is manifested by indescribability, traumatic as such: being deserted by the language collides with the condition of speaking. And yet, it remains possible to say something about it... As a path of progressive desocialization, the occasional loss of the community of language, followed by its lasting traumatic ravages, can be appeased by the reestablishment of a speech link, either within the mind of the subject alone, or promoted by the exchange with others, in a psychotherapeutic setting, for example.ConclusionWhere theoretical discourses have sometimes proved divisive, going beyond the symptoms of indescribability and dissociation, psychodynamic practice today offers to unite. Thanks to psycholinguistic listening, phenomena that have never been explained take on meaning: the singularity of traumatic perception, the chronology of disorders including the latency phase, factors that trigger reviviscences, and the diversity of chronic clinical forms. All these post-traumatic symptoms are consequential to a linguistic wound, a difficulty in accessing meaning, the undermining of two dimensions characterizing and constructing the human being. As much as it integrates extralinguistic determinants, if the traumatic signified is undoubtedly not only speech, language appears the optimal way to identify it as such, while in the same movement appeasing it. The traumatic hypersignified is discovered through clinical analysis and psychotherapy, through deferred action, through the attribution of meaning, through the retrospective reconstruction of an unstable “real,” through a changing narration eternally distancing itself from reviviscences. But what precisely are the mechanisms of effective therapies ? What are the intersubjective links called for in the discussion between patient and practitioner? Could the operations that we call “psychotherapy” be made up of mobilizations of the networks of meanings by speech acts?     

Artificial intelligence and clinical data suggest the T cell-mediated SARS-CoV-2 nonstructural protein intranasal vaccines for global COVID-19 immunity

Advanced computational methodologies suggested SARS-CoV-2, nonstructural proteins ORF1AB, ORF3a, as the source of immunodominant peptides for T cell presentation. T cell immunity is long-lasting and compatible with COVID-19 pathology. Based on the supporting clinical data, nonstructural SARS-CoV-2 protein vaccines could provide global immunity against COVID-19.     

SLC及其受体CCR7与Ⅰ期非小细胞肺癌淋巴结微转移的相关性

目的 探讨溶质载体蛋白（SLC）及其受体趋化因子受体7（CCR7）与I期非小细胞肺癌（NSCLC）淋巴结微转移的相关性。方法 选取2019年1月~2020年3月于我院就诊的I期NSCLC患者127例为研究对象，按照淋巴结微转移情况分为对照组92例和转移组35例，所有患者入院后均通过根治术切除病灶，通过免疫组化方式检测病灶中SLC7A11及CCR7含量，并收集患者临床资料、实验室检查资料及影像学检查资料。通过Logistic回归分析评价SLC7A11及CCR7与淋巴结微转移之间的关系。最后通过建立ROC曲线分析两者及其联合检测对NSCLC患者微淋巴结转移的预测价值。结果 两组患者SLC7A11及CCR7表达水平存在显著差异（P＜0.05）。转移组患者病灶直径、支气管受累及TLG显著高于对照组（P＜0.05）。病灶直径（OR=49.254,95%CI=11.062~507.604）是影响NSCLC淋巴结微转移的独立危险因素（P＜0.05）。SLC7A11（OR=8.622）及CCR7（OR=8.709）表达水平是影响NSCLC淋巴结微转移的独立因素（P＜0.05）。SLC7A11、CCR7及联合诊断对NSCLC淋巴结微转移具有较好的检测价值（均P＜0.05）。联合检测特异度显著高于 SLC7A11及CCR7单独检测（2=7.292，15.125；均P＜0.01）。结论 SLC家族的中SLC7A11及其受体CCR7与NSCLC患者微淋巴结转移显著相关。     

Case Report: Transient Stress Hyperglycemia in the Patient With ST-Elevation Myocardial Infarction

Transient stress hyperglycemia in the setting of acute myocardial infarction is a frequent phenomenon. Its transient nature should not dissuade the clinician from management of elevated blood glucose in a patient after an ST-elevation myocardial infarction. This case presents an adult patient after an ST-elevation myocardial infarction with transient stress hyperglycemia and the evidence used to identify optimal pharmacologic management and secondary prevention.     

Glucose starvation induces resistance to metformin through the elevation of mitochondrial multidrug resistance protein 1

Metformin, a drug for type 2 diabetes mellitus, has shown therapeutic effects for various cancers. However, it had no beneficial effects on the survival rate of human malignant mesothelioma (HMM) patients. The present study was performed to elucidate the underlying mechanism of metformin resistance in HMM cells. Glucose‐starved HMM cells had enhanced resistance to metformin, demonstrated by decreased apoptosis and autophagy and increased cell survival. These cells showed abnormalities in mitochondria, such as decreased ATP synthesis, morphological elongation, altered mitochondrial permeability transition pore and hyperpolarization of mitochondrial membrane potential (MMP). Intriguingly, Mdr1 was significantly upregulated in mitochondria but not in cell membrane. The upregulated mitochondrial Mdr1 was reversed by treatment with carbonyl cyanide m‐chlorophenyl hydrazone, an MMP depolarization inducer. Furthermore, apoptosis and autophagy were increased in multidrug resistance protein 1 knockout HMM cells cultured under glucose starvation with metformin treatment. The data suggest that mitochondrial Mdr1 plays a critical role in the chemoresistance to metformin in HMM cells, which could be a potential target for improving its therapeutic efficacy.