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Morinda officinalis oligosaccharides (MOO) are an oral drug approved in China for the treatment of depression in China. However, MOO is hardly absorbed so that their anti-depressant mechanism has not been elucidated. Here, we show that oral MOO acted on tryptophan → 5-hydroxytryptophan (5-HTP) → serotonin (5-HT) metabolic pathway in the gut microbiota. MOO could increase tryptophan hydroxylase levels in the gut microbiota which accelerated 5-HTP production from tryptophan; meanwhile, MOO inhibited 5-hydroxytryptophan decarboxylase activity, thus reduced 5-HT generation, and accumulated 5-HTP. The raised 5-HTP from the gut microbiota was absorbed to the blood, and then passed across the blood–brain barrier to improve 5-HT levels in the brain. Additionally, pentasaccharide, as one of the main components in MOO, exerted the significant anti-depressant effect through a mechanism identical to that of MOO. This study reveals for the first time that MOO can alleviate depression via increasing 5-HTP in the gut microbiota. Up-regulating gut microbiota tryptophan hydroxylase levels and down-regulating 5-hydroxytryptophan decarboxylase activity is the molecular mechanism of action of the anti-depressant drug Morinda officinalis oligosaccharides. [Display omitted] [ABSTRACT FROM AUTHOR]

Due to the considerable calcium carbonate content, eggshell can serve as an effective, cheap, and efficient adsorbent in treating contaminated water. The removal of bismuth (Bi) ion by 0.45 µm pulverized chicken eggshells was investigated and the effects of various factors including contact time, initial pH, adsorbent dosage, initial Bi ion concentration, and temperature were studied. The optimal removal efficiency of Bi ions (50 mg/L) was 891.29 mg/g by treating with 6.25 g/L eggshells at pH 8 for 45 min at 40°C. Results obtained by scanning electron micrograph, energy dispersive spectrum and Fourier transform infrared spectroscopy analysis yielded the adsorption capacity based on the interaction of the alcohol hydroxyl group, methyl group and carbonyl functional groups present on the pulverized eggshell with Bi ion. The adsorption kinetics were better described by the pseudosecond-order kinetic model (R² = 0.9999) compared with the pseudo-first-order model (R² = 0.7633). The adsorption was endothermic. The equilibrium data fitted better with the Langmuir model than the Freundlich and Temkin isotherm models. Based on proposed mechanism, the adsorption of Bi ions onto the eggshell followed the electrostatic interaction and cation exchange principle. Moreover, the Bi ion removal efficiency decreased by the presence of coexisting ions (Mg2+ and Zn2+), and the highest decrease of 326.58 and 379.22 mg/g was determined with the presence of 100 mg/L Mg2+ and 100 mg/L Zn2+, respectively. Overall, the pulverized eggshell is a potentially low-cost adsorbent for treatment of Bi wastewater. [ABSTRACT FROM AUTHOR]

SARS-CoV-2 has caused tens of thousands of infections and more than one thousand deaths. There are currently no registered therapies for treating coronavirus infections. Because of time consuming process of new drug development, drug repositioning may be the only solution to the epidemic of sudden infectious diseases. We systematically analyzed all the proteins encoded by SARS-CoV-2 genes, compared them with proteins from other coronaviruses, predicted their structures, and built 19 structures that could be done by homology modeling. By performing target-based virtual ligand screening, a total of 21 targets (including two human targets) were screened against compound libraries including ZINC drug database and our own database of natural products. Structure and screening results of important targets such as 3-chymotrypsin-like protease (3CLpro), Spike, RNA-dependent RNA polymerase (RdRp), and papain like protease (PLpro) were discussed in detail. In addition, a database of 78 commonly used anti-viral drugs including those currently on the market and undergoing clinical trials for SARS-CoV-2 was constructed. Possible targets of these compounds and potential drugs acting on a certain target were predicted. This study will provide new lead compounds and targets for further in vitro and in vivo studies of SARS-CoV-2, new insights for those drugs currently ongoing clinical studies, and also possible new strategies for drug repositioning to treat SARS-CoV-2 infections. Twenty structures including 19 SARS-CoV-2 targets and one human target were built by homology modeling. Library of ZINC drug database, natural products, 78 anti-viral drugs were screened against these targets plus human ACE2. This study provides drug repositioning candidates and targets for further in vitro and in vivo studies of SARS-CoV-2. Image 1 [ABSTRACT FROM AUTHOR]

Ricin is a highly toxic type 2 ribosome-inactivating protein (RIP) which is extracted from the seeds of castor beans. Ricin is considered a potential bioterror agent and no effective antidote for ricin exists so far. In this study, by structural modification of a retrograde transport blocker Retro-2cycl, a series of novel compounds were obtained. The primary screen revealed that compound 27 has an improved anti-ricin activity compare to positive control. In vitro pre-exposure evaluation in Madin–Darby Canine Kidney (MDCK) cells demonstrated that 27 is a powerful anti-ricin compound with an EC 50 of 41.05 nmol/L against one LC (lethal concentration, 5.56 ng/mL) of ricin. Further studies surprisingly indicated that 27 confers post-exposure activity against ricin intoxication. An in vivo study showed that 1 h post-exposure administration of 27 can improve the survival rate as well as delay the death of ricin-intoxicated mice. A drug combination of 27 with monoclonal antibody mAb4C13 rescued mice from one LD (lethal dose) ricin challenge and the survival rate of tested animals is 100%. These results represent, for the first time, indication that small molecule retrograde transport blocker confers both in vitro and in vivo post-exposure protection against ricin and therefore provides a promising candidate for the development of anti-ricin medicines. A series of compound with retrograde transport block activity were synthesized based on the structure of Retro-2cycl. One novel compound, 27 , demonstrated improved in vitro and in vivo anti-ricin activity compare to positive control (94). The combination of 27 with mAb4C13 rescued mice from one LD (lethal dose) ricin challenge and achieved a survival rate of 100%. Image 1 [ABSTRACT FROM AUTHOR]

Dopamine neurons in the Substantia nigra (SN) play crucial roles in control of voluntary movement. Extensive degeneration of this neuronal population is the cause of Parkinson's disease (PD). Many factors have been linked to SN DA neuronal survival, including neuronal pacemaker activity (responsible for maintaining basal firing and DA tone) and mitochondrial function. Dln-101, a naturally occurring splice variant of the human ghrelin gene, targets the ghrelin receptor (GHSR) present in the SN DA cells. Ghrelin activation of GHSR has been shown to protect SN DA neurons against 1-methyl-4-phenyl-1,2,5,6 tetrahydropyridine (MPTP) treatment. We decided to compare the actions of Dln-101 with ghrelin and identify the mechanisms associated with neuronal survival. Histologial, biochemical, and behavioral parameters were used to evaluate neuroprotection. Inflammation and redox balance of SN DA cells were evaluated using histologial and real-time PCR analysis. Designer Receptors Exclusively Activated by Designer Drugs (DREADD) technology was used to modulate SN DA neuron electrical activity and associated survival. Mitochondrial dynamics in SN DA cells was evaluated using electron microscopy data. Here, we report that the human isoform displays an equivalent neuroprotective factor. However, while exogenous administration of mouse ghrelin electrically activates SN DA neurons increasing dopamine output, as well as locomotion, the human isoform significantly suppressed dopamine output, with an associated decrease in animal motor behavior. Investigating the mechanisms by which GHSR mediates neuroprotection, we found that dopamine cell-selective control of electrical activity is neither sufficient nor necessary to promote SN DA neuron survival, including that associated with GHSR activation. We found that Dln101 pre-treatment diminished MPTP-induced mitochondrial aberrations in SN DA neurons and that the effect of Dln101 to protect dopamine cells was dependent on mitofusin 2, a protein involved in the process of mitochondrial fusion and tethering of the mitochondria to the endoplasmic reticulum. Taken together, these observations unmasked a complex role of GHSR in dopamine neuronal protection independent on electric activity of these cells and revealed a crucial role for mitochondrial dynamics in some aspects of this process. • Dln101 is a human splice-variant of the ghrelin gene with different expression pattern. • Ghrelin and Dln101 display equivalent levels of neuroprotection of SN DA cells. • Modulation of electrical activity of SN DA cells is not relevant for neuroprotection. • Mitochondrial fusion protein 2 (MFN 2) blocks DLN101-induced mitochondrial fusion in SN DA neurons and prevents DLN101-induced neuroprotection. [ABSTRACT FROM AUTHOR]

The conflict of interests between the government and the enterprise plays a critical role in the effect of water pollution control. In order to resolve that conflict, corresponding government policy should be made. However, the current policies are all limited to the pollution tax or the incentive mechanism, respectively. This paper presents a principal-agent model taking the both policies into consideration. The optimal ration of water pollution control amount under the given policy is investigated. The relationships among the optimal ration of water pollution control amount and the awards proportion for water pollution control and the pollution tax rate are presented. An example is given to illustrate the idea of the proposed model and the effectiveness of the designed algorithm, which shows that incentive policy and pollution tax both have positive influence on enterprise's reduction in water pollution. Further, it proves that the government applied the combined policy of water pollution control incentive policy and pollution tax charging is better than applying any of them separately. The enterprise's optimal strategy of water pollution control adaptive to the government supervision can be obtained from the proposed model. [ABSTRACT FROM AUTHOR]

Summary Hypothalamic pro-opiomelanocortin (POMC) neurons regulate energy and glucose metabolism. Intracellular mechanisms that enable these neurons to respond to changes in metabolic environment are ill defined. Here we show reduced expression of activated dynamin-related protein (pDRP1), a mitochondrial fission regulator, in POMC neurons of fed mice. These POMC neurons displayed increased mitochondrial size and aspect ratio compared to POMC neurons of fasted animals. Inducible deletion of DRP1 of mature POMC neurons ( Drp1 fl/fl -POMC-cre:ER T2 ) resulted in improved leptin sensitivity and glucose responsiveness. In Drp1 fl/fl -POMC-cre:ER T2 mice, POMC neurons showed increased mitochondrial size, ROS production, and neuronal activation with increased expression of Kcnj11 mRNA regulated by peroxisome proliferator-activated receptor (PPAR). Furthermore, deletion of DRP1 enhanced the glucoprivic stimulus in these neurons, causing their stronger inhibition and a greater activation of counter-regulatory responses to hypoglycemia that were PPAR dependent. Together, these data unmasked a role for mitochondrial fission in leptin sensitivity and glucose sensing of POMC neurons. [ABSTRACT FROM AUTHOR]

Paradoxically, glucose, the primary driver of satiety, activates a small population of anorexigenic pro-opiomelanocortin (POMC) neurons. Here, we show that lactate levels in the circulation and in the cerebrospinal fluid are elevated in the fed state and the addition of lactate to glucose activates the majority of POMC neurons while increasing cytosolic NADH generation, mitochondrial respiration, and extracellular pyruvate levels. Inhibition of lactate dehydrogenases diminishes mitochondrial respiration, NADH production, and POMC neuronal activity. However, inhibition of the mitochondrial pyruvate carrier has no effect. POMC-specific downregulation of Ucp2 (Ucp2 PomcKO ), a molecule regulated by fatty acid metabolism and shown to play a role as transporter in the malate-aspartate shuttle, abolishes lactate- and glucose-sensing of POMC neurons. Ucp2 PomcKO mice have impaired glucose metabolism and are prone to obesity on a high-fat diet. Altogether, our data show that lactate through redox signaling and blocking mitochondrial glucose utilization activates POMC neurons to regulate feeding and glucose metabolism. [Display omitted] • The redox metabolite, lactate, plays a role in regulating POMC neuronal activity • Redox sensing by POMC neurons regulates POMC activity through mitochondrial oxidation • UCP2-dependent redox sensing in POMC neurons regulates food intake Yoon et al. show that lactate affects redox signaling in the hypothalamic anorexigenic POMC neurons and, by driving their activity, regulates feeding and peripheral glucose metabolism, a mechanism that depends on mitochondrial mechanisms related to uncoupling protein 2 (UCP2) and lipid utilization. [ABSTRACT FROM AUTHOR]

Four single nucleotide polymorphisms (SNPs) have been reported to be associated with thyroid cancer risk in two genome-wide association studies (GWASs) and were validated in a Chinese population. Because of a lack of further clinical and functional evidence, the clinical significances of these SNPs remain unknown. Four GWAS-identified SNPs of papillary thyroid cancer (PTC), rs965513, rs944289, rs966423 and rs2439302, were genotyped in a case-control study of 838 patients with PTC and 501 patients with benign thyroid tumor (BTT) from the Chinese Han population. The associations between these SNPs, clinicopathologic features, and the outcome of the PTC patients were examined. The CT and CT + TT genotypes of rs966423 were more common in PTC patients with extrathyroidal extension and more advanced T stage. The TC and TC + CC genotypes and the C allele of rs944289 were significantly less frequent in patients with multifocal disease. No correlation was observed between GWAS-identified SNPs and disease persistence of PTC after a short-term follow-up. Significantly different allele distributions between the PTC and BTT groups were observed for all four selected SNPs. Individuals with more than five risk alleles were 8.84-fold (95% CI 3.23–24.17) more likely to suffer from PTC compared with those with zero or 1 risk allele. GWAS-identified SNPs affect the individual predisposition to PTC without interacting with existing Hashimoto thyroiditis and BTT lesions. GWAS-identified SNPs were associated with certain clinicopathologic features of PTC, and may contribute to identifying PTC patients with different clinical patterns. Large prospective studies are required to further evaluate the diagnostic and prognostic power of these genetic markers. [ABSTRACT FROM AUTHOR]