Perilla frutescens L. alleviates trimethylamine N-oxide-induced apoptosis in the renal tubule by regulating ASK1-JNK phosphorylation.

Trimethylamine N-oxide (TMAO) is associated with overall mortality in patients with chronic kidney disease (CKD). Previous findings suggest that P. frutescens (L.) can alleviate renal injury, but its effects and mechanisms underlying alleviation of TMAO-induced kidney damage remain unclear. In this study, a TMAO injury model, in vivo and in vitro, was established to clarify the effects and mechanisms of P. frutescens in alleviating TMAO-induced kidney injury. The results show that TMAO (60 mM/L) can induce the activation of apoptosis signal-regulating kinase 1 (ASK1)-c-Jun N-terminal kinase (JNK), thus aggravating downstream cell apoptosis in vitro. The study also found that P. frutescens aqueous extract (PFAE) (5 mg/mL) can inhibit TMAO-induced apoptosis by downregulating ASK1-JNK phosphorylation. In the in vivo experiments, it was demonstrated that TMAO can increase the levels of blood urea nitrogen and cystatin C, aggravating renal tubular epithelial apoptosis. The results also show that PFAE can reduce TMAO-induced renal damage by inhibiting ASK1-JNK phosphorylation in vivo. Our findings confirmed that P. frutescens can alleviate TMAO-induced renal tubule apoptosis by regulating ASK1-JNK phosphorylation, indicating that P. frutescens may be an effective treatment for alleviating TMAO damage in CKD.

Latent Sex Differences in CaMKII-nNOS Signaling That Underlie Antidepressant-Like Effects of Yueju-Ganmaidazao Decoction in the Hippocampus.

Previous studies have demonstrated that Yueju-Ganmaidazao (YG) decoction induces rapid antidepressant-like effects, and the antidepressant response is mostly dependent on the suppression of nitric oxide-cyclic guanosine monophosphate signaling in male mice. This study aimed to investigate the sex difference mediated by calcium/calmodulin-dependent protein kinase II (CaMKII)-neuronal nitric oxide synthase (nNOS) signaling involved in the antidepressant-like effect of YG in mice. We found that the immobility times in the tail suspension test (TST) were found to be decreased after the single injection of YG in male and female mice with the same dosage. Additionally, chronic administration for 4 days of subthreshold dosage of YG and escitalopram (ES) also significantly decreased the immobility time in mice of both sexes. Chronic subthreshold dosage of YG and ES in LPS-treated mice and in chronic unpredictable stress (CUS) mice both decreased the immobility time, which was increased by stress. Meanwhile, in CUS-treated mice, sucrose preference test, forced swimming test, and open field test were applied to further confirm the antidepressant-like effects of YG and ES. Moreover, CUS significantly decreased the expression of nNOS and CaMKII, and both YG and ES could enhance the expression in the hippocampus of female mice, which was opposite to that in male mice, while endothelial nitric oxide synthase expression was not affected by stress or drug treatment neither in male mice nor in female mice. Finally, subthreshold dosage of YG combined with 7-nitroindazole (nNOS inhibitor) induced the antidepressant-like effects both in female and in male mice, while the single use of YG or 7-NI did not display any effect. However, pretreatment with KN-93 (CaMKII inhibitor) only blocked the antidepressant-like effect of high-dosage YG in female mice. Meanwhile, in CUS mice, chronic stress caused NR1 overexpression and inhibited cAMP response element binding protein action, which were both reversed by YG and ES in male and female mice, implying that YG and ES produced the same antidepressant-like effect in mice of both sexes. The study revealed that chronic treatment with a subthreshold dose of YG also produced antidepressant-like effects in female mice, and these effects depended on the regulation of the CaMKII-nNOS signaling pathway.

Association of sleep quality before and after SARS-CoV-2 infection with clinical outcomes in hospitalized patients with COVID-19 in China.

Sleep is believed to benefit the host defense against pathogens. We aimed to investigate the association of sleep quality with clinical outcomes among hospitalized patients with COVID-19. We conducted a prospective cohort study in 205 adult hospitalized patients with diagnosed moderate COVID-19, with follow-up until hospital discharge or death. Pittsburgh Sleep Quality Index (PSQI) assessed sleep quality before and after infection. The primary outcome was the incidence of severe or critical pneumonia, and the secondary outcomes were duration of hospital stay and laboratory measurements during the follow up. Among the 205 included hospitalized patients, 185 (90.2 %) experienced poorer sleep quality after infection than before according to the PSQI score, and 25 (12.2 %) developed severe or critical pneumonia during follow-up. In Cox regression models, the adjusted hazard ratio of developing severe or critical pneumonia associated with each 1 score increment in the PSQI score before and after infection was 1.23 (95% CI: 1.09, 1.39) and 1.35 (95 % CI: 1.08, 1.67), respectively. Poorer sleep quality was also significantly associated with a prolonged hospital stay and more serious dysregulations in immune system indicated by several laboratory markers. Poorer sleep quality, either in the daily time or after infection with SARS-CoV-2, was associated with worse clinical outcomes. These findings highlight the importance of good sleep in confronting the emerging pandemic of COVID-19.

Association between sleep structure and amnesic mild cognitive impairment in patients with insomnia disorder: a case-control study.

STUDY OBJECTIVES: To examine the association between sleep structure and amnesic mild cognitive impairment (aMCI) in patients with insomnia disorder. METHODS: A total of 256 patients with insomnia disorder were diagnosed by neurologists, 45 of whom were diagnosed with aMCI according to the Petersen criteria, and 45 participants with intact cognition were chosen as controls matched for age and education. A case-control study was conducted to compare sleep structure between aMCI and control patients with insomnia disorder. We evaluated self-reported sleep problems by the Insomnia Severity Index and objective sleep features by polysomnography. Logistic regression models were used to estimate the associations between sleep parameters and aMCI in patients with insomnia disorder. RESULTS: There was no significant difference in Insomnia Severity Index scores between the aMCI and control groups. In the logistic regression after adjustment for covariates, people with a longer sleep duration (adjusted odds ratio [aOR] = 0.56, 95% confidence interval [CI]: 0.36-0.89), greater sleep efficiency (aOR = 0.50, 95% CI: 0.32-0.77), and a higher percentage of total sleep time in stage 3 of non-rapid eye movement sleep (N3%) (aOR = 0.02, 95% CI: 0.01-0.15) have a lower relative probability of having aMCI. By contrast, higher N1% (aOR = 2.28, 95% CI: 1.36-3.82) and wake after sleep onset (aOR = 1.31, 95% CI: 1.11-1.55) may be risk factors for aMCI in patients with insomnia. CONCLUSIONS: In patients with insomnia disorder, sleep duration, sleep fragmentation, sleep efficiency, N1% and N3% were independently associated with the presence of aMCI. In the clinical setting, if patients with insomnia show much more serious abnormalities in these sleep indices, clinicians should pay attention to their cognitive function. In-depth research would also be worthwhile to elaborate the causality between sleep and cognitive decline.

Synthesis of novel 2-methyl-3-furyl sulfide flavor derivatives as efficient preservatives.

Foodborne microbial infestation seriously threatens food security, and the development of low-risk food preservatives is highly needed in food production. For discovering novel flavor molecules with antiseptic function, novel 2-methyl-3-furyl sulfide flavor derivatives were synthesized and evaluated. A wide range of 2-methyl-3-furyl sulfide derivatives were synthesized by reactions of 2-methyl-3-furyl disulfide with cyclic ethers, amides, ketones, and epoxides. All of these compounds have special aroma characteristics and low aroma thresholds. The antimicrobial activity of these compounds against test foodborne bacterial or fungal strains (Escherichia coli, Bacillus subtilis, Staphylococcus aureus, Salmonella paratyphi, Listeria monocytogenes, Vibrio parahemolyticus, Penicillium italicum, Aspergillus niger, Mucor racemosus, Rhizopus oryzae) was examined. It was found that fifteen compounds (3a, 3b, 3d, 3e, 3f, 3g, 3h, 3i, 3j, 3k, 3l, 3m, 5a, 5b, 5f) have antimicrobial activity against different foodborne bacterial or fungal strains. Significantly, the antimicrobial activity of the flavor compounds (3b, 3d, 3e, 3i, 3j, 3l, 3m) is better than that of the control group (penicillin, amphotericin B and thiram), and they are promising preservatives for food production.

Selective Formation of Ser-His Dipeptide via Phosphorus Activation.

The Ser-His dipeptide is the shortest active peptide. This dipeptide not only hydrolyzes proteins and DNA but also catalyzes the formation of peptides and phosphodiester bonds. As a potential candidate for the prototype of modern hydrolase, Ser-His has attracted increasing attention. To explore if Ser-His could be obtained efficiently in the prebiotic condition, we investigated the reactions of N-DIPP-Ser with His or other amino acids in an aqueous system. We observed that N-DIPP-Ser incubated with His can form Ser-His more efficiently than with other amino acids. A synergistic effect involving the two side chains of Ser and His is presumed to be the critical factor for the selectivity of this specific peptide formation.

Evolutionary relationships between seryl-histidine dipeptide and modern serine proteases from the analysis based on mass spectrometry and bioinformatics.

Seryl-histidine dipeptide (Ser-His) has been recognized as the shortest peptide with hydrolysis cleavage activity; however, its protein cleavage spectrum has not yet been fully explored. Here, four differently folded proteins were treated with Ser-His, and the digestion products were evaluated with high-resolution mass spectrometry. The cleavage efficiency and cleavage propensity of Ser-His against these protein substrates were calculated at both the primary and secondary sequence levels. The above experiments show that Ser-His cleaves a broad spectrum of substrate proteins of varying secondary structures. Moreover, Ser-His could cleave at all 20 amino acids with different efficiencies according to the protein, which means that Ser-His has the original digestion function of serine proteases. Furthermore, we collected and compared the catalytic sites and cleavage sites of 340 extant serine proteases derived from 17 representative organisms. A consensus motif Ser-[X]-His was identified as the major pattern at the catalytic sites of serine proteases from all of the organisms represented except Danio rerio, which uses Ser-Lys instead. This finding indicates that Ser-His is the core component of the serine protease catalytic site. Moreover, our analysis revealed that the cleavage sites of modern serine proteases have become more specific over the evolutionary history of this family. Based on the above analysis results, it could be found that Ser-His is likely the original serine protease and maybe the evolutionary core of modern serine proteases.

Synthesis of Enantioenriched Pyrrolidines via Gold-Catalyzed Tandem Cycloisomerization/Hydrogenation of Chiral Homopropargyl Sulfonamides.

A novel gold-catalyzed tandem cycloisomerization/hydrogenation of chiral homopropargyl sulfonamides has been developed. Various enantioenriched pyrrolidines can be obtained in excellent yields and excellent enantioselectivities by combination of chiral tert-butylsulfinimine chemistry with gold catalysis. Importantly, this represents the first example of a pyrrolidine synthesis from homopropargyl sulfonamide.

Atom-economic generation of gold carbenes: gold-catalyzed formal [3+2] cycloaddition between ynamides and isoxazoles.

The generation of gold carbenes via the gold-catalyzed intermolecular reaction of nucleophiles containing relatively labile N-O or N-N bonds with alkynes has received considerable attention during recent years. However, this protocol is not atom-economic as the reaction produces a stoichiometric amount of pyridine or quinoline waste, the cleaved part of the N-O or N-N bonds. In this article, we disclose an unprecedented gold-catalyzed formal [3+2] cycloaddition between ynamides and isoxazoles, allowing rapid and practical access to a wide range of synthetically-useful 2-aminopyrroles. Most importantly, mechanistic studies and theoretical calculations revealed that this reaction presumably proceeds via an α-imino gold carbene pathway, thus providing a strategically novel, atom-economic route to the generation of gold carbenes. Other significant features of this approach include the use of readily-available starting materials, high flexibility, simple procedure, mild reaction conditions, and in particular, no need to exclude moisture or air ("open flask").

Efficient and practical synthesis of enantioenriched 2,3-dihydropyrroles through gold-catalyzed anti-Markovnikov hydroamination of chiral homopropargyl sulfonamides.

A direct gold-catalyzed 5-endo-dig cycloisomerization of chiral homopropargyl sulfonamides has been developed. A range of enantioenriched 2,3-dihydropyrroles are readily accessed by utilizing this approach. Importantly, this gold-catalyzed cycloisomerization reaction proceeds through an anti-Markovnikov addition by using a catalytic base as the additive, which completely suppresses the undesired dimerization.

Practical, modular, and general synthesis of 3-coumaranones through gold-catalyzed intermolecular alkyne oxidation strategy.

A gold-catalyzed intermolecular alkyne oxidation for the preparation of 3-coumaranones has been developed. Using 8-isopropylquinoline N-oxides as oxidants, the reactions of o-ethynylanisoles afford versatile 3-coumaranones in moderate to good isolated yields. The synthetic utility of this chemistry is also indicated by the synthesis of the natural product sulfuretin.

Gold-catalyzed tandem cycloisomerization/functionalization of in situ generated α-oxo gold carbenes in water.

A gold-catalyzed tandem cycloisomerization/functionalization of in situ generated α-oxo gold carbenes in water has been developed, which provides ready access to highly functionalized indole derivatives from o-alkynyl anilines and ynamides. Importantly, gold serves dual catalytic roles to mediate both the cycloisomerization of o-alkynyl anilines and the intermolecular oxidation of ynamides at the same time, thus providing a new type of concurrent tandem catalysis. The use of readily available starting materials, a simple procedure, and mild reaction conditions are other notable features of this method.

Gold-catalyzed intermolecular oxidation of o-alkynylbiaryls: an easy and practical access to functionalized fluorenes.

A novel gold-catalyzed intermolecular oxidation of o-alkynylbiaryls has been developed. A variety of functionalized fluorenes are readily accessed by utilizing this non-diazo approach, thus providing a viable alternative to synthetically useful fluorenes.

Flexible and practical synthesis of 3-oxyindoles through gold-catalyzed intermolecular oxidation of o-ethynylanilines.

A novel gold-catalyzed intermolecular oxidation of o-ethynylanilines has been developed. A range of functionalized 3-oxyindoles are readily accessed by utilizing this strategy. Importantly, this gold-catalyzed oxidative process outcompetes the typical indole formation.

Gold-catalyzed intermolecular oxidation of chiral homopropargyl sulfonamides: a reliable access to enantioenriched pyrrolidin-3-ones.

A gold-catalyzed intermolecular oxidation of chiral homopropargyl sulfonamides has been developed, which provides a reliable access to synthetically useful chiral pyrrolidin-3-ones with excellent ee, by combining the chiral tert-butylsulfinimine chemistry and gold catalysis. This methodology has also been used in the facile synthesis of natural product (-)-irniine. The use of readily available starting materials, a broad substrate scope, a simple procedure and the mild nature of this reaction render it a viable alternative for the synthesis of enantioenriched pyrrolidin-3-ones.

The utilization status of aspirin for the secondary prevention of ischemic stroke.

BACKGROUND: The present study was aimed to investigate the usage of aspirin for the secondary prevention of ischemic stroke, evaluate the correlated factors, and analyze the reasons for not taking and irregularly taking aspirin. METHODS: The patients in this group were all stroke survivors who have formerly been diagnosed with a cerebral infarction or transient ischemic attack (TIA) in our hospital. We investigated their use of aspirin over a three-year period following their hospitalization. According to the patients' aspirin usage, they were divided into treatment and non-treatment groups. In addition, the reasons for not taking or irregularly taking aspirin were analyzed in the two groups. RESULTS: A total of 1240 patients were studied, including 367 (29.60%) in the treatment group and 873 (70.40%) cases in the non-treatment group. In addition, 201 (16.20%) cases in the treatment group had been regularly taking aspirin (50 - 325 mg of aspirin daily) for 1 to 3 years or longer. The results demonstrated that the main reasons for not taking aspirin in this study were related to patients' concerns regarding the side effects of taking aspirin (46.45%), as well as the doctors' inadequacy in informing their patients to take aspirin (38.71%). The major reasons for patients to irregularly take aspirin were that the doctors did not notify the length of aspirin usage to their patients (41.57%), and that doctors did not prescribe aspirin upon the patients' follow-up visit (26.51%). CONCLUSION: The most effective way to increase patient's compliance for aspirin consumption is to promote the guidelines for stroke treatment and to relay these advances in stroke therapy to the patient.