Synthesis of narrow-spectrum anti-mycobacterial molecules without effect on the diversity of gut microbiota in mice based on the structure of rifampicin.

Rifampicin (RIF) is a broad-spectrum antimicrobial agent that is also a first-line drug for treating tuberculosis (TB). Based on the naphthyl ring structure of RIF this study synthesized 16 narrow-spectrum antimicrobial molecules that were specifically anti-Mycobacterium tuberculosis (Mtb). The most potent candidate was 2-((6-hydroxynaphthalen-2-yl) methylene) hydrazine-1-carbothioamide (compound 3c) with minimum inhibitory concentration (MIC) of 1 µg/mL against Mtb. Synergistic anti-Mtb test indicated that none of the combinations of 3c with the major anti-TB drugs are antagonistic. Consistent with RIF, compound 3c induced large amounts of reactive oxygen radicals (ROS) in the cells of Mtb. The killing kinetics of compound 3c and RIF are very similar. Furthermore, molecular docking showed that compound 3c was able to access the RIF binding pocket of the ß subunit of Mtb RNA polymerase (RNAP). Experiments in mice showed that compound 3c increased the variety of intestinal flora in mice, while RIF significantly decreased the diversity of intestinal flora in mice. In addition, compound 3c is non-toxic to animal cells with a selection index (SI) much more than 10. The evidence from this study suggests that the further development of 3c could contribute to the development of novel drug for TB treatment.

Reverse Separation of Carbon Dioxide and Acetylene in Two Isostructural Copper Pyridine-Carboxylate Frameworks.

Separating acetylene from carbon dioxide is important but highly challenging due to their similar molecular shapes and physical properties. Adsorptive separation of carbon dioxide from acetylene can directly produce pure acetylene but is hardly realized because of relatively polarizable acetylene binds more strongly. Here, we reverse the CO2 and C2H2 separation by adjusting the pore structures in two isoreticular ultramicroporous metal-organic frameworks (MOFs). Under ambient conditions, copper isonicotinate (Cu(ina)2), with relatively large pore channels shows C2H2-selective adsorption with a C2H2/CO2 selectivity of 3.4, whereas its smaller-pore analogue, copper quinoline-5-carboxylate (Cu(Qc)2) shows an inverse CO2/C2H2 selectivity of 5.6. Cu(Qc)2 shows compact pore space that well matches the optimal orientation of CO2 but is not compatible for C2H2. Neutron powder diffraction experiments confirmed that CO2 molecules adopt preferential orientation along the pore channels during adsorption binding, whereas C2H2 molecules bind in an opposite fashion with distorted configurations due to their opposite quadrupole moments. Dynamic breakthrough experiments have validated the separation performance of Cu(Qc)2 for CO2/C2H2 separation.

Synthesis, antimycobacterial evaluation, and molecular docking study of 1,2,4-triazole derivatives.

Fifteen 1,2,4-triazole derivatives were synthesised in this study and their MIC values against Mycobacterium tuberculosis (Mtb) ranged from 2 to 32 µg/mL. Furthermore, their antimycobacterial activity was positively correlated with the KatG enzyme docking score. Among the 15 compounds, compound 4 showed the strongest bactericidal activity with an MIC of 2 µg/mL. The selectivity index of compound 4 is more than 10, indicating that the compound has low toxicity to animal cells and has the potential to become a drug. Molecular docking indicates that compound 4 can bind firmly to the Mtb KatG active site. The experimental results showed that compound 4 inhibited Mtb KatG and caused the accumulation of ROS in Mtb cells. We speculate that compound 4 causes the accumulation of ROS by inhibiting KatG, and ROS produces oxidative destruction, leading to the death of Mtb. This study provides a new idea for the development of novel anti-Mtb drugs.

Identification and Gene Expression Analysis of the Pheromone Biosynthesis Activating Neuropeptide Receptor (PBANR) From the Ostrinia furnacalis (Lepidoptera: Pyralidae).

Pheromonal communication is important in insect mate finding and reproduction. Identifying components of pest insect pheromone system is a first step to disrupt pest insect reproduction. In this study, we identified and cloned the pheromone biosynthesis activating neuropeptide receptor (PBANR) from the Asian corn borer, Ostrinia furnacalis (Guenée) (Lepidoptera: Pyralidae), which is one of the most damaging pests of corn and other crops in parts of Asia and Australia. The O. furnacalis PBANR (OstfuPBANR) gene has an ORF of 1,086 bp and encoded 362 amino acids with seven transmembrane domains and had a high sequence identity to known lepidopteran PBANRs. Expression analysis showed that OstfuPBANR was highly expressed in the pheromone glands compared with other tissues, consistent with other studies. Interestingly, OstfuPBANR was expressed higher in the larval stages compared to the pupal or adult stages, suggesting that OstfuPBANR may have broad functions in larva beyond adult pheromone synthesis.

[Treating irritable bowel syndrome with diarrhea patients by yigan fupi decoction: a randomized controlled trial].

OBJECTIVE: To evaluate the efficacy and safety of Yigan Fupi Decoction (YFD) in the treatment of irritable bowel syndrome with diarrhea (IBS-D) patients. METHODS: A randomized controlled clinical trail was carried out in patients with IBS-D. All patients were randomly assigned to the treatment group (58 cases, treated with YFD) and the control group (58 cases, treated with Pinaverium Bromide Tablet). The treatment course was 4 weeks for all patients. The total effective rate, the stool property and state, the quality of life (QOL), and TCM syndrome efficacy were assessed by IBS bowel symptom severity scale (IBS-BSS), IBS defecation state questionnaire (IBS-DSQ), IBS quality of life questionnaire (IBS-QOL), and traditional Chinese medicine pattern curative effect scoring system (TCM-PES) before and after treatment. RESULTS: There was no statistical difference in the total effective rate between the two groups (82.76% vs. 77.59%, P > 0.05). The treatment group was superior in the total IBS-BSS integral to the control group (P < 0.05). The total effective rate of improving the stool property was better in the treatment group than in the control group (81.03% vs. 72.41%, P < 0.05). Besides, the number of days for emergent defecation among 10 days was less in the treatment group than in the control group (P < 0.05). The improvement of the total IBS-QOL integral and the total integral of TCM syndrome were better in the treatment group than in the control group (P < 0.01). The total effective rate of TCM-PES was better in the treatment group than in the control group (84.48% vs. 70.69%, P < 0.05). CONCLUSION: YFD was effective in the treatment of IBS-D patients of Gan-qi invading Pi syndrome, and could effectively relieve bowel symptoms, improve the stool property and the defecation frequency, elevate their QOL, and attenuate Gan-qi invading Pi syndrome with favorable safety and compliance.

19 Schiff bases as antimycobacterial agents: synthesis, molecular docking and a plausible mechanism of action.

Aim: To discover novel anti-Mycobacterium tuberculosis (Mtb) drugs, 19 compounds were synthesized; their anti-Mtb effects were evaluated and mechanisms of action were preliminarily explored. Materials & methods: The compounds were synthesized and their anti-Mtb activity was elucidated using resazurin microtiter assays. The plausible target of the potential compound was investigated by microimaging techniques, gas chromatography-mass spectrometry analysis and molecular docking. Results: 19 compounds inhibited Mtb growth with minimum inhibitory concentrations ranging from 1 to 32 µg/ml. Compounds 1-17 showed inhibition of Mtb KatG enzyme. Compound 19, the most potent, might be an inhibitor of Pks13 polyketide synthase. Conclusion: This study suggests that 2-((6-fluoropyridin-3-yl)methylene) hydrazine-1-carbothioamide (19) is a potential anti-Mtb lead compound with a novel mechanism of action.

Globally, more than 1.6 million people die of tuberculosis (TB) and about 11 million new cases occur each year. The emergence of drug-resistant Mycobacterium tuberculosis (Mtb) has made it difficult to effectively treat TB. Therefore, 19 drugs were synthesized and assayed in the laboratory to verify whether they could inhibit the growth of Mtb. All compounds exhibit anti-Mtb effects at relatively low concentrations. Among them, compound 19 had a strong anti-Mtb effect, and its bactericidal effect on Mtb even exceeded that of isoniazid. In addition, it was preliminarily determined that compound 19 is a novel inhibitor of a key enzyme in the biosynthesis of Mtb cell walls. These findings demonstrate a potential new treatment option for TB but more research is needed to confirm the safety of these drugs.

Reexamination of the π-bond strengths within H2C=XHn systems: a theoretical study.

The accurate determination of π-bond energies, D(π), in doubly-bonded species has been an important issue in theoretical chemistry. The procedure using the divalent state stabilization energy defined by Walsh has been suggested, and the procedure seems to be conceptually reasonable and applicable to all kinds of doubly-bonded species. Therefore, the aim of this study was to examine whether the procedure could be a reliable methodology for estimating the D(π) values for a variety of H(2)C=XH(n) species. To achieve a higher accuracy, the D(π) values were estimated at QCISD(T)/6-311++G(3df,2p) level of theory combined with isogyric correction. The D(π) values estimated in this work were in excellent agreement with the extant literature values. On the other hand, in determining accurate D(π) values for doubly bonded species, especially in species with lone-pair electrons such as H(2)C=O, it has been found that consideration of highly sophisticated electron correlation effects could be important. However, sufficiently accurate D(π) values have been obtainable at QCISD(T) or CCSD(T) levels with a 6-311++G(3df,2p) basis set on geometries at relatively inferior correlated levels such as MP2 and B3LYP levels with a 6-31+G(d) basis set.

Elastic Differential Evolution for Automatic Data Clustering.

In many practical applications, it is crucial to perform automatic data clustering without knowing the number of clusters in advance. The evolutionary computation paradigm is good at dealing with this task, but the existing algorithms encounter several deficiencies, such as the encoding redundancy and the cross-dimension learning error. In this article, we propose a novel elastic differential evolution algorithm to solve automatic data clustering. Unlike traditional methods, the proposed algorithm considers each clustering layout as a whole and adapts the cluster number and cluster centroids inherently through the variable-length encoding and the evolution operators. The encoding scheme contains no redundancy. To enable the individuals of different lengths to exchange information properly, we develop a subspace crossover and a two-phase mutation operator. The operators employ the basic method of differential evolution and, in addition, they consider the spatial information of cluster layouts to generate offspring solutions. Particularly, each dimension of the parameter vector interacts with its correlated dimensions, which not only adapts the cluster number but also avoids the cross-dimension learning error. The experimental results show that our algorithm outperforms the state-of-the-art algorithms that it is able to identify the correct number of clusters and obtain a good cluster validation value.

Disseminated Tuberculosis Associated Hemophagocytic Lymphohistiocytosis in a Pregnant Woman With Evans syndrome: A Case Report and Literature Review.

Background: Tuberculosis (TB) is a leading cause of morbidity and mortality in underdeveloped and developing countries. Disseminated TB may induce uncommon and potentially fatal secondary hemophagocytic lymphohistiocytosis (HLH). Timely treatment with anti-tuberculosis therapy (ATT) and downmodulation of the immune response is critical. However, corticosteroid treatment for TB-associated HLH remains controversial. Herein, we report a successful case of disseminated TB-associated HLH in a pregnant woman with Evans syndrome accompanied by a literature review. Case Presentation: A 26-year-old pregnant woman with Evans syndrome was transferred to the Third Affiliated Hospital of Sun Yat-Sen University because of severe pneumonia. She presented with cough, fever, and aggravated dyspnea. Nested polymerase chain reaction for Mycobacterium tuberculosis (M. tuberculosis) complex in sputum was positive. Sputum smear sample for acid-fast bacilli was also positive. Metagenome next-generation sequencing (mNGS) of the bronchoalveolar lavage fluid identified 926 DNA sequence reads and 195 RNA sequence reads corresponding to M. tuberculosis complex, respectively. mNGS of blood identified 48 DNA sequence reads corresponding to M. tuberculosis. There was no sequence read corresponding to other potential pathogens. She was initially administered standard ATT together with a low dose of methylprednisolone (40 mg/day). However, her condition deteriorated rapidly with high fever, acute respiratory distress syndrome, pancytopenia, and hyperferritinemia. Bone marrow smears showed hemophagocytosis. And caseating tuberculous granulomas were found in the placenta. A diagnosis of disseminated TB-associated HLH was made. Along with the continuation of four drug ATT regimen, therapy with a higher dose of methylprednisolone (160 mg/day) combined with immunoglobulin and plasma exchange was managed. The patient's condition improved, and she was discharged on day 19. Her condition was good at follow-up with the continuation of the ATT. Conclusions: Clinicians encountering patients with suspected TB accompanied by unexplainable inflammation not responding to ATT should consider complications with HLH. Timely administration of ATT combined with corticosteroids may result in a favorable outcome.

Bioaccumulation of Cadmium Affects Development, Mating Behavior, and Fecundity in the Asian Corn Borer, Ostrinia furnacalis.

Heavy metal pollution is becoming an increasingly serious problem in agricultural ecosystems. Heavy metals such as cadmium (Cd) accumulate in the food chain and may lead to detrimental effects on the physiological functions of living organisms, including herbivorous insects. One such example is the Asian Corn Borer, Ostrinia furnacalis (Lepidoptera: Pyralidae). However, how Cd can affect the development and reproduction of O. furnacalis is largely unknown. In this study, we exposed larvae of O. furnacalis to a diet containing Cd and investigated the effects of Cd on the development, mating behavior, and fecundity of the insect. We showed that Cd accumulates in the larvae and inhibits development by extending larval and pupal duration and decreasing the survival rate. The excretion of Cd through multiple routes during the larval and pupal stages resulted in low levels of residual Cd in the adult insects, which were not fed with Cd. However, the mating behavior and fecundity of these insects were significantly affected, compared to control insects. This suggests that the bioaccumulation of heavy metals such as Cd has long lasting and detrimental effects on O. furnacalis over the entire life cycle, affecting fecundity, even when specimens are only exposed at an early life stage.

[Comparative study on Jinghua Weikang Capsule and famotidine in treating duodenal ulcer].

OBJECTIVE: To compare the effect and security of Jinghua Weikang Capsule (JWC) and famotidine in treating duodenal ulcer. METHODS: Two hundred patients with duodenal ulcer were randomly divided into the treated group treated with JWC, 160 mg 3 times per day and the control group treated with famotidine 20 mg twice per day, both by orally taking before meal for 4 weeks, 100 cases in each group. Changes of symptom score, adverse reaction, helicobacter pylori (Hp) infection and endoscopic figure before and after treatment were observed. RESULTS: The general remission rate and the ulcer healing rate in the treated group were equal to those in the control group respectively (both P > 0.05). Symptoms including belly ache, sour regurgitation and abdominal distension were ameliorated after therapy in both groups (all P < 0.05). The effect in relieving anorexia and eructation and Hp eradication rate were significantly higher in the treated group than those in the control group (all P< 0.05), while the incidence rate of adverse reaction in the treated group was remarkably lower than that in the control group (P < 0.05). CONCLUSION: JWC is an effective and safe remedy in treating duodenal ulcer, especially for symptom amelioration and Hp eradication, so it is worthy of expanding clinically.

Investigation on effects of the nourishing kidney and eliminating toxicity decoction on immunological imbalance of Th1, Th17 and Treg in HBV transgenic mice.

OBJECTIVE: To study the immune mechanism of nourishing kidney and eliminating toxicity decoction (NKETD) on Chronic Hepatitis B (CHB), we detected the serum concentrations of IFN-γ (the characteristic cytokine of Th1), IL-17A (the characteristic cytokine of Th17) and the quantitative proportion of CD(+) 4CD(+) 25 foxp3 Treg to CD(+) 4 Treg in HBV transgenic mice. METHODS: The HBV transgenic mice were randomly divided into six groups: high-dose group, middle-dose group, low-dose group, lamivudine group, model control group and normal mice control group. The serum concentrations of IFN-γ and IL-17A in mice were measured by ELISA method and the ratio of CD(+) 4CD(+) 25 foxp3 Treg to CD(+) 4 Treg was detected by Flow Cytometry Method (FCM). RESULTS: The decoction could increase the serum concentration of IFN-γ and decrease that of IL-17A in HBV transgenic mice. The higher the dose was, the more significantly the concentration of IFN-γ increased. And high-dose decoction could decrease the serum concentration of IL-17A in HBV transgenic mice significantly and continuously while middle-dose and low-dose decoction had no significant effects. However, there wasn't statistically significant variation on the ratio of CD(+) 4CD(+) 25 foxp3 Treg to CD(+) 4 Treg in HBV transgenic mice. CONCLUSION: The decoction could treat CHB by regulating the immune function by promoting the generation of Th1 and/or enhancing its function while inhibiting Th17. The immune regulation by decoction had more significant effects than lamivudine.

Plasma copeptin levels are associated with prognosis of severe acute pancreatitis.

Copeptin reflects the individual stress level, and is correlated with outcomes of critical illness. This study was designed to evaluate its relationship with disease severity, local complications, organ failure and mortality of severe acute pancreatitis (SAP). Seventy-eight SAP patients and 78 sex- and age-matched healthy individuals were recruited. Plasma samples were obtained on admission from SAP patients and at study entry from healthy individuals. Copeptin concentration was determined using enzyme-linked immunosorbent assay. Plasma copeptin level was obviously higher in patients than in healthy individuals, was identified as an independent predictor of local complications, organ failure and in-hospital mortality, was highly associated with traditional predictors of disease severity and mortality including the Acute Physiology and Chronic Health Care Evaluation II score, Ranson score, multiple organ dysfunction score, sequential organ failure assessment score, and predicted local complications, organ failure, and in-hospital mortality of SAP patients with high areas under receiver operating characteristic curve. Furthermore, its predictive value was similar to the traditional predictors'. However, it could not improve these traditional predictors' predictive values. Therefore, increased plasma copeptin level is associated with disease severity and identified as a novel prognostic marker of local complications, organ failure and mortality after SAP.