A Redox-active Phenothiazine-based Pd2L4-type Coordination Cage and Its Isolable Crystalline Polyradical Cations.

Polyradical cages are of great interest because they show very fascinating physical and chemical properties, but many challenges remain, especially for their synthesis and characterization. Herein, we present the synthesis of a polyradical cation cage 14•+ through post-synthetic oxidation of a redox-active phenothiazine-based Pd2L4-type coordination cage 1. It's worth noting that 1 exhibits excellent reversible electrochemical and chemical redox activity due to the introduction of a bulky 3,5-di-tert-butyl-4-methoxyphenyl substituent. The generation of 14•+ through reversible electrochemical oxidation is investigated by in situ UV-vis-NIR and EPR spectroelectrochemistry. Meanwhile, chemical oxidation of 1 can also produce 14•+ which can be reversibly reduced back to the original cage 1, and the process is monitored by EPR and NMR spectroscopies. Eventually, we succeed in the isolation and single crystal X-ray diffraction analysis of 14•+, whose electronic structure and conformation are distinct to original 1. The magnetic susceptibility measurements indicate the predominantly antiferromagnetic interactions between the four phenothiazine radical cations in 14•+. We believe that our study including the facile synthesis methodology and in situ spectroelectrochemistry will shed some light on the synthesis and characterization of novel polyradical systems, opening more perspectives for developing functional supramolecular cages.

Coprococcus eutactus screened from healthy adolescent attenuates chronic restraint stress-induced depression-like changes in adolescent mice: Potential roles in the microbiome and neurotransmitter modulation.

The onset of depression commonly occurs in adolescence; therefore, depressive prevention and intervention are pivotal during this period. It is becoming evident that neurotransmitter imbalance and gut microbiota dysbiosis are prominent causes of depression. However, the underlying links and mechanisms remain poorly understood. In this study, with 16S ribosomal RNA gene sequencing, genus Coprococcus markedly differentiated between the healthy and unmedicated depressive adolescents. Based on this, transplantation of Coprococcus eutactus (C.e.) was found to dramatically ameliorate the chronic restraint stress (CRS) induced depression-like changes and prevent synaptic loss and glial-stimulated neuroinflammation in mice. The Ultra-high performance liquid chromatography tandem mass spectrometry analysis (UHPLC-MS/MS) further showed that neurotoxic neurotransmitters in kynurenine pathway (KP) such as 3-hydroxykynurenine (3-HK) and 3-hydroxyanthranilic acid (3-HAA) decreased in mouse brains, mechanistically deciphering the transfer of the tryptophan metabolic pathway to serotonin metabolic signaling in the brain after C.e. treatment, which was also verified in the colon. Molecularly, blockage of KP activities mediated by C.e. was ascribed to the restraint of the limit-step enzymes responsible for kynurenine, 3-HK, and quinolinic acid generation. In the colon, C.e. treatment significantly recovered goblet cells and mucus secretion in CRS mice which may ascribe to the rebalance of the disordered gut microbiota, especially Akkermansia, Roseburia, Rikenella, Blautia, and Alloprevotella. Taken together, the current study reveals for the first time the beneficial effects and potential mechanisms of C.e. in ameliorating CRS-induced depression, unraveling the direct links between C.e. treatment and neurotransmitter rebalance, which may provide efficacious therapeutic avenues for adolescent depressive intervention.

The fusion of multi-omics profile and multimodal EEG data contributes to the personalized diagnostic strategy for neurocognitive disorders.

BACKGROUND: The increasing prevalence of neurocognitive disorders (NCDs) in the aging population worldwide has become a significant concern due to subjectivity of evaluations and the lack of precise diagnostic methods and specific indicators. Developing personalized diagnostic strategies for NCDs has therefore become a priority. RESULTS: Multimodal electroencephalography (EEG) data of a matched cohort of normal aging (NA) and NCDs seniors were recorded, and their faecal samples and urine exosomes were collected to identify multi-omics signatures and metabolic pathways in NCDs by integrating metagenomics, proteomics, and metabolomics analysis. Additionally, experimental verification of multi-omics signatures was carried out in aged mice using faecal microbiota transplantation (FMT). We found that NCDs seniors had low EEG power spectral density and identified specific microbiota, including Ruminococcus gnavus, Enterocloster bolteae, Lachnoclostridium sp. YL 32, and metabolites, including L-tryptophan, L-glutamic acid, gamma-aminobutyric acid (GABA), and fatty acid esters of hydroxy fatty acids (FAHFAs), as well as disturbed biosynthesis of aromatic amino acids and TCA cycle dysfunction, validated in aged mice. Finally, we employed a support vector machine (SVM) algorithm to construct a machine learning model to classify NA and NCDs groups based on the fusion of EEG data and multi-omics profiles and the model demonstrated 92.69% accuracy in classifying NA and NCDs groups. CONCLUSIONS: Our study highlights the potential of multi-omics profiling and EEG data fusion in personalized diagnosis of NCDs, with the potential to improve diagnostic precision and provide insights into the underlying mechanisms of NCDs. Video Abstract.

The effects of Chinese proprietary medicine and vaccination on patients with COVID-19: a retrospective study in Macao.

BACKGROUND: COVID-19 is continuing to ravage globally and has resulted in a huge health and financial burden. Chinese proprietary medicines, such as Lianhua Qingwen (LHQW) and Huoxiang Zhengqi (HXZQ) capsules, have been recommended for non-high-risk patients with COVID-19 in China. Based on this, we described the baseline information, using status of LHQW and HXZQ capsules and inoculation history of quarantined patients in the second half of 2022 in Macao. Additionally, we analyzed the underlying association among medicines administration, vaccination and COVID-19 indices, in order to explore novel clues for the regular control and prevention of local epidemic situation in the future. METHODS: A total of 976 patients in Macao quarantine hotels from June to August 2022 were included in the present study, of which, 857 subjects were followed-up for prognosis evaluation. During quarantine, the baseline demographic information, including sex, age, BMI, occupation and personal habits were collected. Additionally, the inoculation history, medicine employment status and cycle threshold (Ct) values were also reported. We interviewed the patients for collection of their symptoms at the beginning and end of quarantine, as well as prognostic ones. Basic statistical description of baseline information, vaccination history and medication were displayed. Chi-squared test or with continuous correction test was employed for comparison of dichotomous data between two or multiple groups. Binary logistic regression was applied to reveal the correlation between potential risk factors and Ct values or prognosis symptoms. We also used Cox regression model to identify the effect of different types of vaccine products on Ct value altering rate. RESULTS: Patients who were female (52.0%), engaged in service industry (31.8%), from Macao native (65.8%), never took physical exercises (33.6%) and preferred irritated diet (59.5%) enjoyed more dominant proportions. Over 80% of participants were inoculated and 74.6% of them chose inactivated COVID-19 vaccine produced by China National Biotech Group (CNBG). Participants used LHQW capsules accounted for 92.1% and the duration of medicating lasted for one to two weeks. All of the reported symptoms were significantly ameliorated after quarantine and the duration of quarantine was concentrated on 21 days. People with different age, sex, occupation and region had different choices of HXZQ administration and vaccination. Additionally, middle dose (4-5 boxes) of LHQW capsules exhibited evidently negative association with positive Ct values (adjusted, - 0.037 ± 0.19, p = 0.04). Two doses of CNBG and one dose of mRNA vaccine had obvious protective effect on reducing Ct positive rate (p = 0.041). Meanwhile, symptoms after quarantine were significantly positive correlated with those in prognosis (adjusted, 1.38 ± 0.18, p < 0.0001). CONCLUSION: Our study found that the administration of LHQW capsules was beneficial for Ct value turning negative, meanwhile, certain mixed inoculation may be the promoting factor to reduce the positive rate of Ct value. These findings provide data basis for the Chinese proprietary medicine treatment and mixed vaccination applying for prevention and control of local COVID-19 epidemic in the future.

Microbiome and tryptophan metabolomics analysis in adolescent depression: roles of the gut microbiota in the regulation of tryptophan-derived neurotransmitters and behaviors in human and mice.

BACKGROUND: Adolescent depression is becoming one of the major public health concerns, because of its increased prevalence and risk of significant functional impairment and suicidality. Clinical depression commonly emerges in adolescence; therefore, the prevention and intervention of depression at this stage is crucial. Recent evidence supports the importance of the gut microbiota (GM) in the modulation of multiple functions associated with depression through the gut-brain axis (GBA). However, the underlying mechanisms remain poorly understood. Therefore, in the current study, we aimed to screen the microbiota out from healthy and depressive adolescents, delineate the association of the targeted microbiota and the adolescent depression, address the salutary effects of the targeted microbiota on anti-depressive behaviors in mice involving the metabolism of the tryptophan (Trp)-derived neurotransmitters along the GBA. RESULTS: Here, we found the gut microbiota from healthy adolescent volunteers, first diagnosis patients of adolescent depression, and sertraline interveners after first diagnosis displayed significant difference, the relative abundance of Faecalibacterium, Roseburia, Collinsella, Blautia, Phascolarctobacterium, Lachnospiraceae-unclassified decreased in adolescent depressive patients, while restored after sertraline treatment. Of note, the Roseburia abundance exhibited a high efficiency in predicting adolescent depression. Intriguingly, transplantation of the fecal microbiota from healthy adolescent volunteers to the chronic restraint stress (CRS)-induced adolescent depressed mice significantly ameliorated mouse depressive behaviors, in which the Roseburia exerted critical roles, since its effective colonization in the mouse colon resulted in remarkably increased 5-HT level and reciprocally decreased kynurenine (Kyn) toxic metabolites quinolinic acid (Quin) and 3-hydroxykynurenine (3-HK) levels in both the mouse brain and colon. The specific roles of the Roseburia were further validated by the target bacteria transplantation mouse model, Roseburia intestinalis (Ri.) was gavaged to mice and importantly, it dramatically ameliorated CRS-induced mouse depressive behaviors, increased 5-HT levels in the brain and colon via promoting tryptophan hydroxylase-2 (TPH2) or -1 (TPH1) expression. Reciprocally, Ri. markedly restrained the limit-step enzyme responsible for kynurenine (indoleamine2,3-dioxygenase 1, IDO1) and quinolinic acid (3-hydroxyanthranilic acid 3,4-dioxygenase, 3HAO) generation, thereby decreased Kyn and Quin levels. Additionally, Ri. administration exerted a pivotal role in the protection of CRS-induced synaptic loss, microglial activation, and astrocyte maintenance. CONCLUSIONS: This study is the first to delineate the beneficial effects of Ri. on adolescent depression by balancing Trp-derived neurotransmitter metabolism and improving synaptogenesis and glial maintenance, which may yield novel insights into the microbial markers and therapeutic strategies of GBA in adolescent depression. Video Abstract.

Extended phenothiazines: synthesis, photophysical and redox properties, and efficient photocatalytic oxidative coupling of amines.

Herein we successfully developed a ring-fusion approach to extend the conjugation length of phenothiazines and synthesized a series of novel extended phenothiazines 1-5. The intriguing π-conjugation length-dependent photophysical and redox properties of 1-5, and their photocatalytic performance towards visible-light-driven oxidative coupling reactions of amines were systematically investigated. The results indicated that this series of extended phenothiazines exhibited continuous red shifts of light absorption with increasing numbers of fused rings. As compared with the conventional phenothiazine (PTZ), all the extended phenothiazines displayed reversible redox behavior and maintained a strong excited-state reduction potential as well. Consequently, 3, 4 and 5 with longer effective conjugation lengths could efficiently catalyze the oxidative coupling of amines to imines under visible-light irradiation; by comparison, the shorter 1, 2 and PTZ could only catalyze such reactions in the presence of UV light. Moreover, 3 showed superior catalytic performance which can result in better yields within a shorter reaction time, and in a broad substrate scope. Finally, a direct and efficient conversion of amines to imines under sunlight in an air atmosphere was successfully realized. We believe that our study including the new phenothiazine modification methodology and the newly developed extended phenothiazine-based photocatalysts will open up a new way to develop novel phenothiazine-based materials for optoelectronic and catalytic applications.

Links Between Gut Dysbiosis and Neurotransmitter Disturbance in Chronic Restraint Stress-Induced Depressive Behaviours: the Role of Inflammation.

Accumulating evidence has shown that inflammation, the gut microbiota, and neurotransmitters are closely associated with the pathophysiology of depression. However, the links between the gut microbiota and neurotransmitter metabolism remain poorly understood. The present study aimed to investigate the neuroinflammatory reactions in chronic restraint stress (CRS)-induced depression and to delineate the potential links between the gut microbiota and neurotransmitter metabolism. C57BL/6 mice were subjected to chronic restraint stress for 5 weeks, followed by behavioural tests (the sucrose preference test, forced swim test, open field test, and elevated plus maze) and analysis. The results showed that CRS significantly increased interleukin-1 beta (IL-1ß), interleukin-2 (IL-2), interleukin-6 (IL-6), and tumour necrosis factor α (TNFα) levels and decreased brain-derived neurotrophic factor (BDNF) expression, accompanied by the activation of IkappaB-alpha-phosphorylation-nuclear factor kappa-B (IκBα-p-NF-κB) signalling in the mouse hippocampus. In addition, the neurotransmitter metabolomics results showed that CRS resulted in decreased levels of plasma 5-hydroxytryptamine (5-HT), dopamine (DA), and noradrenaline (NE) and their corresponding metabolites, and gut microbiota faecal metabolites with the 16S rRNA gene sequencing indicated that CRS caused marked microbiota dysbiosis in mice, with a significant increase in Helicobacter, Lactobacillus, and Oscillibacter and a decrease in Parabacteroides, Ruminococcus, and Prevotella. Notably, CRS-induced depressive behaviours and the disturbance of neurotransmitter metabolism and microbiota dysbiosis can be substantially restored by dexamethasone (DXMS) administration. Furthermore, a Pearson heatmap focusing on correlations between the microbiota, behaviours, and neurotransmitters showed that Helicobacter, Lactobacillus, and Oscillibacter were positively correlated with depressive behaviours but were negatively correlated with neurotransmitter metabolism, and Parabacteroides and Ruminococcus were negatively correlated with depressive behaviours but were positively correlated with neurotransmitter metabolism. Taken together, the results suggest that inflammation is involved in microbiota dysbiosis and the disturbance of neurotransmitter metabolism in CRS-induced depressive changes, and the delineation of the potential links between the microbiota and neurotransmitter metabolism will provide novel strategies for depression treatment.

Involvement of the microbiota-gut-brain axis in chronic restraint stress: disturbances of the kynurenine metabolic pathway in both the gut and brain.

Emerging evidence suggests that the gut microbiota may interact with the host brain and play pivotal roles in the pathogenesis of neuropsychiatric disorders. However, the mechanism underlying reciprocal interactions along the microbiota-gut-brain axis in depression remains unclear. In this study, a murine model of chronic restraint stress (CRS) was established to investigate the metabolic signaling of tryptophan (Trp) neurotransmission at the intestinal and central levels in depression. The results showed that CRS mice displayed depression- and anxiety-like behaviors. Additionally, kynurenine (Kyn) and its metabolites, an important Trp metabolic pathway, were strongly activated in the brain. Intriguingly, the Kyn toxic signaling was exacerbated in the gut, especially in the colon. Indoleamine 2,3-dioxygenase (IDO), a rate-limiting enzyme responsible for Kyn metabolic pathway initiation, was significantly upregulated in the brain and gut in CRS mice compared with control mice, promoting transfer of Trp metabolic pathway to Kyn signaling. Additionally, administration of IDO inhibitor, 1-methyl-tryptophan (1-MT), partially rescued CRS-induced depression- and anxiety-like changes. Moreover, the enhanced intestinal permeability mediated by CRS allowed toxic metabolites to "leak" into the bloodstream. The microbiome profiles of CRS mice displayed obviously altered taxonomic composition and negative correlations were observed between Enterorhabdus, Parabacteroides and Kyn levels in the brain. Reciprocal crosstalk between the brain and gut was further validated by citalopram treatment, IDO inhibitor and microbiota intervention, which counteracted depression-like behavior, Kyn metabolic signaling and microbiota composition in CRS mice. Meanwhile, Parabacteroides treatment affected Trp metabolism in mouse hippocampus, manifesting as elevated concentration of 5-HT as well as ratio of 5-HT to Trp. These results suggest that long-term stress disrupts Kyn metabolism and endocrine function along the gut-brain axis, accompanied by the disrupted homeostasis of certain microbiota, which collectively contribute to the development of depression-like behavior.

Bisphenol F induces nonalcoholic fatty liver disease-like changes: Involvement of lysosome disorder in lipid droplet deposition.

Epidemiological studies have demonstrated that the general population's exposure to bisphenol A (BPA) substitutes is ubiquitous. Bisphenol F (BPF), one of the main BPA substitutes, is increasingly replacing BPA in plastics for food and beverage applications. Accumulating evidence suggests that BPA exposure is associated with nonalcoholic fatty liver disease (NAFLD)-like changes. However, the potential effects of BPF on lipid homeostasis remain poorly understood. In the present study, an epidemiological analysis with LC-MS-MS revealed that the BPF concentrations in the serum of NAFLD patients were significantly higher than those in a control group. Supporting this result, using Oil Red O, BODIPY 493/503, LipidTox Deep Red staining and gas chromatography-time-of-flight mass spectrometry (TOF-MS) assays, we found that BPF exposure induced NAFLD-like changes, with obvious lipid droplet deposition, triglyceride (TG) and fatty acids increase in mouse livers. Meanwhile, lipid droplet deposition and TG increase induced by BPF were also observed in HepG2 cells, accompanied by autophagic flux blockade, including autophagosome accumulation and the decreased degradation of SQSTM1/p62. Using adenoviruses dual-reporter plasmid RFP-GFP-LC3, RFP-GFP-PLIN2 transfection, AO staining, and EGFR degradation assays, we demonstrated that BPF treatment impaired lysosomal degradative capacity, since BPF treatment obviously impaired lysosomal acidification, manifested as decreased lysosomal hydrolase cathepsin L (CTSL) and mature cathepsin D (CTSD) in HepG2 and mouse liver issues. Additionally, v-ATPase D, a multi-subunit enzyme that mediates acidification of eukaryotic intracellular organelles, significantly decreased after BPF exposure in both the vitro and in vivo studies. This study ascertained a novel mechanism involving dysfunctional of lysosomal degradative capacity induced by BPF, which contributes to lipophagic disorders and causes lipid droplet deposition. This work provides evidence that lysosomes may be a target organelle where BPF exerts its potential toxicity; therefore, novel intervention strategies targeting lysosome are promising for BPF-induced NAFLD-like changes.