Dead Cas(t) light on new life: CRISPRa-mediated reprogramming of somatic cells into neurons.

Overexpression of exogenous lineage-specific transcription factors could directly induce terminally differentiated somatic cells into target cell types. However, the low conversion efficiency and the concern about introducing exogenous genes limit the clinical application. With the rapid progress in genome editing, the application of CRISPR/dCas9 has been expanding rapidly, including converting somatic cells into other types of cells in vivo and in vitro. Using the CRISPR/dCas9 system, direct neuronal reprogramming could be achieved by activating endogenous genes. Here, we will discuss the latest progress, new insights, and future challenges of the application of the dCas9 system in direct neuronal reprogramming.

Hepatotoxicity of food-borne mycotoxins: molecular mechanism, anti-hepatotoxic medicines and target prediction.

Mycotoxins are metabolites produced by fungi. The widespread contamination of food and feed by mycotoxins is a global food safety problem and a serious threat to people's health. Most food-borne mycotoxins have strong hepatotoxicity. However, no effective methods have been found to prevent or treat Mycotoxin- Induced Liver Injury (MILI) in clinical and animal husbandry. In this paper, the molecular mechanisms and potential anti-MILI medicines of six food-borne MILI are reviewed, and their targets are predicted by network toxicology, which provides a theoretical basis for further study of the toxicity mechanism of MILI and the development of effective strategies to manage MILI-related health problems in the future and accelerate the development of food safety.

Further insight into the potential toxicity of zearalenone-14-glucoside based on toxicokinetics, tissue distribution, transformation, and excretion in rats.

Bioaccumulation and biotransformation are critical factors that affect the release of easily metabolizable chemicals to cause human toxicity. The glucoside-type modified mycotoxin Zearalenone-14-Glucoside (Z14G) has attracted global attention for its high occurrence in foodstuffs and the potential threat to humans as its high rate of transformation into parent forms. Given the limited toxicokinetics information, this study assessed the absorption, distribution, biotransformation and excretion of Z14G, aiming to define the potential risk of Z14G. The toxicokinetics of Z14G were assessed after intravenous (IV) or oral administration (PO) in SD rats at doses of 10 mg/kg·b.w. In addition, comparative work with the parent mycotoxin ZEN was performed in parallel. The determination of Z14G and its metabolites (ZEN, α-zearalenol, ß-zearalenol, α-zearalanol, ß-zearalanol) proceeded with a sensitive UHPLC-MS/MS method. Our research indicated that Z14G readily disappeared from the blood, and distributed throughout the tissues via transformation into its parent form ZEN, and excreted primarily through urine. More importantly, the metabolite α-ZEL was observed in most analyzed tissue, urine and feces samples. Overall, our findings highlight the importance of biotransformation with regard to Z14G, providing critical insight for the health risk assessment of co-exposure of humans to glucoside-type modified mycotoxins.

A highly parallel DTT/MB-DNA/Au electrochemical biosensor for trace Hg monitoring by using configuration occupation approach and SECM.

Environmental pollution and medicine safety have aroused increasing public concerns due to human health. Amongst various contaminants, mercury is of special attention owing to their environmental persistence and biogeochemical recycling and ecological risks. Herein, a simple and highly parallel electrochemical biosensor for Hg determination was designed and investigated. The proposed biosensor was prepared and compared between (1) DTT/MB-DNA/Au with configuration occupation approach and (2) MCH/MB-DNA/Au with passivation approach. According to the combined results of scanning electrochemical microscope (SECM) and Randles-Sevcik equation, the DTT modified electrode exhibited high uniformity on DNA distribution and superb stability on electron transfer in Hg2+ detection. Evidentially, the response value of proposed DTT/MB-DNA/Au was increased from 57.518% to 97.607%, while RSD% between duplicate runs had dropped from 22.658% to 0.223% (n = 3). Moreover, the increased proportion of effective working area was 467.380% compared with general sensors. Besides, DTT concentration, DNA concentration as well as assembly time were optimized, utilizing electrochemical impedance spectroscopy (EIS), Cyclic Voltammetry (CV) and Square Wave Anode Stripping Voltammetry (SWASV). This optimized biosensor exhibited an excellent selectivity toward Hg2+ over Cu2+, As2+, Cd2+, Pb2+, Cr3+, Ni2+ and Zn2+ etc., and the stability of DTT/MB-DNA/Au were at least two times better even after 3 days under room temperature. Also, a linear relation was observed between the peak current and Hg2+concentrations in a range from 0.25 nM to 2.00 µM with a detection limit of 53.00 pM under optimal conditions. Finally, DTT/MB-DNA/Au was applied for plants and medical products analysis. In all, this optimized DTT/MB-DNA/Au with advantages of high repeatability and sensitivity would provide a new insight into the design and application of biosensor for reliable sensing in safeguarding plant protection and medicinal safety.

Identification of the downstream molecules of agrin/Dok-7 signaling in muscle.

The development of the neuromuscular junction depends on signaling processes that involve protein phosphorylation. Motor neuron releases agrin to activate muscle protein Dok-7, a key tyrosine kinase essential for the formation of a mature and functional neuromuscular junction. However, the signaling cascade downstream of Dok-7 remains poorly understood. In this study, we combined the clustered regularly interspaced short palindromic repeats/Cas9 technique and quantitative phosphoproteomics analysis to study the tyrosine phosphorylation events triggered by agrin/Dok-7. We found tyrosine phosphorylation level of 36 proteins increased specifically by agrin stimulation. In Dok-7 mutant myotubes, however, 13 of the 36 proteins failed to be enhanced by agrin stimulation, suggesting that these 13 proteins are Dok-7-dependent tyrosine-phosphorylated proteins, could work as downstream molecules of agrin/Dok-7 signaling. We validated one of the proteins, Anxa3, by in vitro and in vivo assays. Knocking down of Anxa3 in the cultured myotubes inhibited agrin-induced AChR clustering, whereas reduction of Anxa3 in mouse muscles induced abnormal postsynaptic development. Collectively, our phosphoproteomics analysis provides novel insights into the complicated signaling network downstream of agrin/Dok-7.

[Health risk assessment of exogenous harmful pollutants in Chinese medicine: a review].

In recent years, the quality and safety problems have been limiting the internationalization of Chinese medicine. The pollutants in Chinese medicine, particularly the exogenous harmful pollutants mainly including mycotoxins, pesticide residues, heavy metals, harmful elements, and sulfur dioxide, are of high risks for people. Therefore, the World Health Organization(WHO) and relevant national organizations have clearly defined the maximum residue limits(MRLs) of such pollutants. Chinese Pharmacopoeia(2020 edition, volume Ⅳ) also demonstrates the detection methods, MRLs and preliminary risk assessment methods for four typical exogenous harmful pollutants in Chinese medicine. Therefore, continuous optimization of the health risk assessment system can further help further raise the quality and safety of Chinese medicine. This paper reviews the research on the health risk assessment of four typical exogenous harmful pollutants in Chinese medicine and discusses the problems of and challenges for the assessment system, which is expected to lay a scientific basis for the establishment of the risk warning mode and response measures suitable for specific types of Chinese medicine.

Long noncoding RNA MEG3 silencing protects against hypoxia-induced pheochromocytoma-12 cell injury through inhibition of TIMP2 promoter methylation.

Hypoxia is a common pathological process caused by insufficient oxygen. Long noncoding RNAs (lncRNAs) have been proven to participate in this pathology. Hypoxia is reported to significantly reduce the secretion of tissue inhibitor of metalloproteinase 2 (TIMP2) and TIMP2 induces pheochromocytoma-12 (PC12) cell cycle arrest. Thus, our study aimed to explore the mechanism by which lncRNA maternally expressed gene 3 (MEG3) was implicated in hypoxia-induced PC12 cell injury through TIMP2 promoter methylation. To elucidate the potential biological significance of MEG3 and the regulatory mechanism between MEG3 and TIMP2, a hypoxia-induced PC12 cell injury model was generated. The hypoxia-exposed cells were subjected to a series of overexpression plasmids and short hairpin RNAs, followed by the measurement of levels of MEG3, TIMP2, lactate dehydrogenase (LDH), malondialdehyde (MDA), superoxide dismutase (SOD), reactive oxygen species (ROS), Bcl-2-associated X protein, B-cell lymphoma-2, and caspase-3, as well as the changes in MMP, cell proliferation, apoptosis, and cell cycle progression. On the basis of the findings, MEG3 was upregulated in hypoxia-injured PC12 cells. MEG3 recruited methylation proteins DNMT3a, DNMT3b, and MBD1 and accelerated TIMP2 promoter methylation, which in turn inhibited its expression. Moreover, PC12 cells following MEG3 silencing and TIMP2 overexpression exhibited significantly decreased levels of LDH, MDA, and ROS along with cell apoptosis, yet increased SOD and MMP levels, as well as cell cycle entry to the S phase and cell proliferation. In conclusion, MEG3 silencing suppresses hypoxia-induced PC12 cell injury by inhibiting TIMP2 promoter methylation. This study may provide novel therapeutic targets for hypoxia-induced injury.

Design of single-porphyrin donors toward high open-circuit voltage for organic solar cells via an energy level gradient-distribution screening strategy of fragments: a theoretical study.

Open-circuit voltage (VOC) is a key factor for improving the power conversion efficiency (PCE) of bulk heterojunction (BHJ) organic solar cells (OSCs). At present, increasing attention has been devoted towards modifying π bridges in single-porphyrin small molecule donors with an A-π-D-π-A configuration to reduce the highest occupied molecular orbital (HOMO) levels and improve the VOC of devices. However, how to screen the π bridges is a key issue. In this work, nine π bridges were screened by the HOMO level gradient-distribution strategy of fragments (electron-donating donor (D), π bridges, and electron-withdrawing acceptor (A)), where fragments meeting the requirements were combined into five novel small molecule donors. Meanwhile, in order to test whether the strategy is beneficial to increasing VOC, [6,6]-phenyl C61-butyric acid methyl ester (PC61BM) was selected as the acceptor material. The energy levels of all molecules were compared and the photoelectric properties (i.e., energy gap, energy driving force, reorganization energy, intermolecular charge transfer rate, charge recombination rate, and VOC) of the five small molecules were studied. The results showed that the HOMO levels of porphyrin donors could be significantly lowered via this strategy, and VOC was raised without losing the short-circuit current (JSC) and fill factor (FF) of the devices. Meanwhile, the designed five small molecules could be used as donor candidates to improve the performance of OSCs.

Nicotinic Acetylcholine Receptor Alpha7 Subunit Mediates Vagus Nerve Stimulation-Induced Neuroprotection in Acute Permanent Cerebral Ischemia by a7nAchR/JAK2 Pathway.

BACKGROUND The role of nicotinic acetylcholine receptor alpha7 subunit (a7nAchR) in the treatment of acute cerebral ischemia by VNS has not been thoroughly clarified to date. Therefore, this study aimed to investigate the specific role of a7nAchR and explore whether this process is involved in the mechanisms of VNS-induced neuroprotection in rats undergoing permanent middle cerebral artery occlusion (PMCAO) surgery. MATERIAL AND METHODS Rats received a7nAChR antagonist (A) or antagonist placebo injection for control (AC), followed by PMCAO and VNS treatment, whereas the a7nAChR agonist (P) was utilized singly without VNS treatment but only with PMCAO pretreatment. The rats were randomly divided into 6 groups: sham PMCAO, PMCAO, PMCAO+VNS, PMCAO+VNS+A, PMCAO+VNS+AC, and PMCAO+P. Neurological function and cerebral infarct volume were measured to evaluate the level of brain injury at 24 h after PMCAO or PMCAO-sham. Moreover, the related proteins levels of a7nAChR, p-JAK2, and p-STAT3 in the ischemic penumbra were assessed by Western blot analysis. RESULTS Rats pretreated with VNS had significantly improved neurological function and reduced cerebral infarct volume after PMCAO injury (p<0.05). In addition, VNS enhanced the levels of a7nAchR, p-JAK2, and p-STAT3 in the ischemic penumbra (p<0.05). However, inhibition of a7nAchR not only attenuated the beneficial neuroprotective effects induced by VNS, but also decreased levels of p-JAK2 and p-STAT3. Strikingly, pharmacological activation of a7nAchR can partially substitute for VNS-induced beneficial neurological protection. CONCLUSIONS These results suggest that a7nAchR is a pivotal mediator of VNS-induced neuroprotective effects on PMCAO injury, which may be related to suppressed inflammation via activation of the a7nAchR/JAK2 anti-inflammatory pathway.

Overexpression of Long Non-Coding RNA TUG1 Promotes Colon Cancer Progression.

BACKGROUND Colon cancer is one of the most prevalent and deadly cancers worldwide. It is still necessary to further define the mechanisms and explore therapeutic targets of colon cancer. Dysregulation of long noncoding RNAs (lncRNAs) has been shown to be correlated with diverse biological processes, including tumorigenesis. This study aimed to characterize the biological mechanism of taurine-upregulated gene 1 (TUG1) in colon cancer. MATERIAL AND METHODS qRT-PCR was used to analyze the expression level of TUG1 and p63 in 75 colon cancer tissues and the matched adjacent non-tumor tissue. In vitro, cultured colon cancer cell lines HCT-116 and LoVo were used as cell models. TUG1 and p63 were silenced via transferring siRNA into HCT-116 or LoVo. The effects of TUG1 were investigated by examining cell proliferation, apoptosis, and migration. RESULTS Among the 75 colon cancer cases, the expression of TUG1 was significantly higher in colon cancer tissues compared with the matched adjacent non-tumor tissue, while p63 expression was lower in the tumor tissue. In HCT-116 and LoVo, the expression of TUG1 was significantly increased by p63 siRNA transfection. Furthermore, down-regulation of TUG1 by siRNA significantly inhibited the cell proliferation and promoted colon cancer cell apoptosis. In addition, inhibition of TUG1 expression significantly blocked the cell migration ability of colon cancer cells. CONCLUSIONS LncRNA TUG1 may serve as a potential oncogene for colon cancer. Overexpressed TUG1 may contribute to promoting cell proliferation and migration in colon cancer cells.

A hybridization-induced charge-transfer state energy arrangement reduces nonradiative energy loss in organic solar cells.

Here, we explain why the Energy Gap Law and the energy inversion related to the charge-transfer state have opposite effects on the trend of nonradiative energy loss of organic solar cells. The root is the existing condition of energy inversion. There is indeed a certain probability of energy inversion, but it will eventually be implicit or explicit as determined by the hybridization, which depends on the electron-withdrawing unit of the donor, giving rise to different stacking sites. The triplet-state hybridization leads to an explicit characteristic, while singlet-state hybridization leads to an implicit characteristic.

Twenty-four-hour urinary aldosterone predicts inappropriate left ventricular mass index in patients with primary aldosteronism.

OBJECTIVE: Primary aldosteronism (PA) is associated with inappropriate left ventricular hypertrophy (LVH) in relation to a given gender and body size. There is no ideal parameter to predict the presence of LVH or inappropriate LVH in patients with PA. We investigate the performance of 24-hour urinary aldosterone level, plasma renin activity and aldosterone-to-renin ratio on this task. METHODS: We performed echocardiography in 106 patients with PA and 31 subjects with essential hypertension (EH) in a tertiary teaching hospital. Plasma renin activity, aldosterone concentration, and 24-hour urinary aldosterone level were measured. RESULTS: Only 24-hour urinary aldosterone was correlated with left ventricular mass index (LVMI) and excess LVMI among these parameters. The multivariate analysis revealed the urinary aldosterone level as an independent predictor for LVMI and excess LVMI. Analyzing the ability of urinary aldosterone, plasma aldosterone concentration, and plasma aldosterone-to-renin ratio to identify the presence of LVH (ROC AUC = 0.701, 0.568, 0.656, resp.) and the presence of inappropriate LV mass index (defined as measured LVMI in predicting LVMI ratio >135%) (ROC area under curve = 0.61, 0.43, 0.493, resp.) revealed the better performance of 24-hour urinary aldosterone. CONCLUSIONS: In conclusion, 24-hour urinary aldosterone level performed better to predict the presence of LVH and inappropriate LVMI in patients with PA.

Microbiota Alters and Its Correlation with Molecular Regulation Underlying Depression in PCOS Patients.

Depression is one of the complications in patients with polycystic ovary syndrome (PCOS) that leads to considerable mental health. Accumulating evidence suggests that human gut microbiomes are associated with the progression of PCOS and depression. However, whether microbiota influences depression development in PCOS patients is still uncharacterized. In this study, we employed metagenomic sequencing and transcriptome sequencing (RNA-seq) to profile the composition of the fecal microbiota and gene expression of peripheral blood mononuclear cells in depressed women with PCOS (PCOS-DP, n = 27) in comparison to mentally healthy women with PCOS (PCOS, n = 18) and compared with healthy control (HC, n = 27) and patients with major depressive disorder (MDD, n = 29). Gut microbiota assessment revealed distinct patterns in the relative abundance in the PCOS-DP compared to HC, MDD, and PCOS groups. Several gut microbes exhibited uniquely and significantly higher abundance in the PCOS-DP compared to PCOS patients, inducing EC Ruminococcus torques, Coprococcus comes, Megasphaera elsdenii, Acidaminococcus intestini, and Barnesiella viscericola. Bacteroides eggerthii was a potential gut microbial biomarker for the PCOS-DP. RNA-seq profiling identified that 35 and 37 genes were significantly elevated and downregulated in the PCOS-DP, respectively. The enhanced differential expressed genes (DEGs) in the PCOS-DP were enriched in pathways involved in signal transduction and endocrine and metabolic diseases, whereas several lipid metabolism pathways were downregulated. Intriguingly, genes correlated with the gut microbiota were found to be significantly enriched in pathways of neurodegenerative diseases and the immune system, suggesting that changes in the microbiota may have a systemic impact on the expression of neurodegenerative diseases and immune genes. Gut microbe-related DEGs of CREB3L3 and CCDC173 were possible molecular biomarkers and therapeutic targets of women with PCOS-DP. Our multi-omics data indicate shifts in the gut microbiome and host gene regulation in PCOS patients with depression, which is of possible etiological and diagnostic importance.

Distribution Characteristics of Nutritional Elements and Combined Health Risk of Heavy Metals in Medicinal Tea from Genuine Producing Area of China.

The development of the medicinal tea (MT) system has promoted the health awareness in the whole world, and the nutritional elements are also an important resource of health care delivery except for the medicinal components. Among various medicinal teas, Astragalus membranaceus (AM), Zingiberaceae rhizome (ZR), and Lonicera japonica (LJ) were the most popular ingredients in China. However, except for the nutrition value, MT was inevitably contaminated with heavy metals due to the special planting environment and processing system. This study was aimed to investigate the distribution characteristics of nutrition elements and combined health risk of heavy metals in MT sample, referring to the maximum residue limit (MRL), estimated daily intake (EDI), total target hazard quotients (TTHQs), and lifetime cancer risk (LCR). Furthermore, the bioaccessibility of gastrointestinal phase and bioavailability of human colon adeno carcinoma cell line were selected for elaborating the exact damage degree to human digestive system. The results showed that, the nutritional elements of Na, Se, K, Ca, and Mn were very rich in MT, but a total of 50% of MT were contaminated by Cr, Hg, and Cd in raw material. Although the cumulative lifetime cancer risk can be accepted under the bioaccessibility (26.62-99.27%), the heavy metals of Cr, As, Hg, and Fe in AM and LJ posed a slight threaten of non-carcinogenic risk to consumers. This study will give an exactly assessment of multiple elements in digestive system, thus further to predict the potential health risk under the consumption of MT products.

[Discussion on the location of Dazhui (GV 14) and Yaoyangguan (GV 3)].

Since the anatomical location of acupoints was recorded in The latest Practice of Western Acupuncture in 1915, and Lecture Notes on Advanced Acupuncture in 1931, the Japanese acupuncture works of Chinese translation version, the location of Dazhui (GV 14) (under the spinous process of the 7th cervical vertebra) and Yaoyangguan (GV 3) (under the spinous process of the 4th lumbar vertebra) had rarely been questioned for nearly a century. In order to confirm the above statement, the writers have reviewed ancient literature, combined with the modern anatomical knowledge and searched the evidences from the core arguments of the acupuncture Mingtang chart and the bronze acupuncture statue. It is believed that Dazhui （GV 14） should be positioned under the spinous process of the 1st thoracic vertebra, and Yaoyangguan（GV 3） be under the spinous process of the 5th lumbar vertebra. Accordingly, all of the other acupoints of these meridians should be moved down by 1 vertebra, i.e. those on the governor vessel from Dazhui (GV 14) to Yaoyangguan (GV 3), those on the 1st lateral line of the bladder meridian of foot-taiyang from Dazhu (BL 11) to Baihuanshu (BL 30) and those on the 2nd lateral line of the bladder meridian from Fufen (BL 41) to Zhibian (BL 54).

Energy differences as descriptors for the correlation between JSC and VOC in nonfullerene organic photovoltaics.

ITIC-series nonfullerene organic photovoltaics (NF OPVs) have realized the simultaneous increases of the short-circuit current density (JSC) and open-circuit voltage (VOC), called the positive correlation between JSC and VOC, which could improve the power conversion efficiency (PCE). However, it is complicated to predict the formation of positive correlation in devices through simple calculations of single molecules due to their dimensional differences. Here, a series of symmetrical NF acceptors blended with the PBDB-T donor were chosen to establish an association framework between the molecular modification strategy and positive correlation. It can be found that the positive correlation is modification site-dependent following the energy variation at the different levels. Furthermore, to illustrate a positive correlation, the energy gap differences (ΔEg) and the energy level differences of the lowest unoccupied molecular orbitals (ΔELUMO) between the two changed acceptors were proposed as two molecular descriptors. Combined with the machine learning model, the accuracy of the proposed descriptor is more than 70% for predicting the correlation, which verifies the reliability of the prediction model. This work establishes the relative relationship between two molecular descriptors with different molecular modification sites and realizes the prediction of the trend of efficiency. Therefore, future research should focus on the simultaneous enhancement of photovoltaic parameters for high-performance NF OPVs.

CRISPRa-based activation of Fgf21 and Fndc5 ameliorates obesity by promoting adipocytes browning.

BACKGROUND: Skeletal muscle-secreted myokines widely participate in lipids metabolism through autocrine, paracrine and endocrine actions. The myokines represented by FGF21 and Irisin can promote the browning of adipocytes and serve as promising targets for treating obesity. Although recombinant myokines replacement therapy and AAV (adeno-associated virus)-based myokines overexpression have shown a definite effect in ameliorating obesity, novel myokine activation strategies with higher efficacy and safety are still in pressing need. This study aimed to evaluate the therapeutic potential of a novel CRISPR-based myokines activation strategy in obesity treatments. METHODS: In this study, we used lentivirus and a single AAV vector containing dCas9-VP64 with a single-guide RNA to selectively activate Fgf21 and Fndc5 expression in skeletal muscles both in vitro and in vivo. The activation efficacy of the CRISPRa system was determined by qRT-PCR, Western blotting and ELISA. The treatment effect of CRISPR-based myokines activation was tested in 3T3-L1-derived adipocytes and diet-induced obese (DIO) mice (male C57BL/6 mice, induced at 6-week-old for 10 weeks). RESULTS: The virus upregulates myokines expression in both mRNA and protein levels of muscle cells in vitro and in vivo. Myokines secreted by muscle cells promoted browning of 3T3-L1-derived adipocytes. In vivo activation of myokines by AAVs can reduce body weight and fat mass, increase the adipocytes browning and improve glucose tolerance and insulin sensitivity in DIO mice. CONCLUSIONS: Our study provides a novel CRISPR-based myokines activation strategy that can ameliorate obesity by promoting adipocytes browning.

Fatal hemophagocytic lymphohistiocytosis-induced multiorgan dysfunction secondary to Burkholderia pseudomallei sepsis: A case report.

BACKGROUND: Burkholderia pseudomallei (B. pseudomallei) is a short, straight, medium-sized Gram-negative bacterium that mostly exists alone, without a capsule or spores, has more than three flagella at one end, and actively moves. B. pseudomallei confers high morbidity and mortality, with frequent granulocytopenia in B. pseudomallei sepsis-related deaths. However, mortality may be related to hemophagocytic lymphohistiocytosis (HLH) secondary to B. pseudomallei infection. CASE SUMMARY: A 12-year-old female was referred from a local hospital to the pediatric intensive care unit with suspected septic shock and fever, cough, dyspnea, and malaise. After admission, supportive symptomatic treatments including fluid resuscitation, anti-infective therapy, mechanical ventilation, and a vasoactive drug maintenance cycle were carefully initiated. The patient became unconscious, her blood pressure could not be maintained even under the exposure of vasoactive drugs, and she experienced cardiorespiratory arrest. The patient died due to ineffective high-quality in-hospital cardiopulmonary resuscitation. A subsequent bone marrow smear examination revealed extensive phagocytosis, and the blood culture was positive for B. pseudomallei. Family history revealed a sibling death from B. pseudomallei sepsis 5 years earlier. CONCLUSION: The higher mortality rate in patients with B. pseudomallei sepsis may be related to secondary HLH after infection, wherein multiorgan dysfunction syndrome may be directly related to infection or immune damage caused by secondary HLH. Patients with B. pseudomallei can be asymptomatic and can become an infective source.

Extensive myocardial calcification in critically ill patients receiving extracorporeal membrane oxygenation: A case report.

BACKGROUND: Myocardial calcification is a rare complication in critically ill patients. The prognosis of myocardial calcifications in critically ill patients is very poor if not treated in a timely manner. We describe a rare case of acute extensive myocardial calcifications due to acute myocarditis after receiving extracorporeal membrane oxygenation (ECMO) support. CASE SUMMARY: We report a 17-year-old male patient who developed extensive myocardial calcifications while receiving prolonged ECMO support for severe myocarditis and cardiogenic shock. Extensive myocardial calcifications were confirmed by chest computed tomography (CT). Myocardial calcifications were observed in the left ventricle walls on CT examination 10 days after admission. The patient was then discharged with heart function class II on the NYHA classification. Two years later, the patient was still alive with adequate quality of life. We then included this patient and 7 other cases retrieved from the PubMed, Cochrane Library, EMBASE, and MEDLINE databases in our study, in order to provide a reference for the clinical diagnosis and treatment of this disease. CONCLUSION: Multiple causes including prolonged hemodynamic failure, profound acidosis, high vasopressor doses, and acute renal failure may jointly lead to extensive myocardial calcifications. The precise role of ECMO support in the timing and frequency of acute myocardial calcifications deserves further investigation.

Zearalenone-14-Glucoside Is Hydrolyzed to Zearalenone by ß-Glucosidase in Extracellular Matrix to Exert Intracellular Toxicity in KGN Cells.

As one of the most important conjugated mycotoxins, zearalenone-14-glucoside (Z14G) has received widespread attention from researchers. Although the metabolism of Z14G in animals has been extensively studied, the intracellular toxicity and metabolic process of Z14G are not fully elucidated. In this study, the cytotoxicity of Z14G to human ovarian granulosa cells (KGN) and the metabolism of Z14G in KGN cells were determined. Furthermore, the experiments of co-administration of ß-glucosidase and pre-administered ß-glucosidase inhibitor (Conduritol B epoxide, CBE) were used to clarify the mechanism of Z14G toxicity release. Finally, the human colon adenocarcinoma cell (Caco-2) metabolism model was used to verify the toxicity release mechanism of Z14G. The results showed that the IC50 of Z14G for KGN cells was 420 µM, and the relative hydrolysis rate of Z14G on ZEN was 35% (25% extracellular and 10% intracellular in KGN cells). The results indicated that Z14G cannot enter cells, and Z14G is only hydrolyzed extracellularly to its prototype zearalenone (ZEN) by ß-glucosidase which can exert toxic effects in cells. In conclusion, this study demonstrated the cytotoxicity of Z14G and clarified the toxicity release mechanism of Z14G. Different from previous findings, our results showed that Z14G cannot enter cells but exerts cytotoxicity through deglycosylation. This study promotes the formulation of a risk assessment and legislation limit for ZEN and its metabolites.