Hydroxygenkwanin suppresses peritoneal metastasis in colorectal cancer by modulating tumor-associated macrophages polarization.

Peritoneal metastasis is an important cause of high mortality and poor prognosis in colorectal cancer (CRC) patients. Therefore, the development of compounds with unique anti-CRC Peritoneal metastasis activities is urgently needed to improve the survival of CRC patients. Hydroxygenkwanin (HGK),a natural flavonoid compound, have been shown to display anti-inflammatory, antioxidant, antitumor, and immunoregulatory effects. Here, we employed CRC peritoneal metastasis mouse model with MC38 cells to examine the antitumor activity of HGK. The result showed that HGK not only inhibited peritoneal metastasis, but also significantly increased the proportion of M1-like macrophages while decreasing the proportion of M2-like macrophages within the tumor microenvironment (TME). Furthermore, we demonstrated that the inhibitory effect of HGK on peritoneal metastasis of CRC depended on macrophages in vitro and in vivo. Moreover, we revealed that HGK promoted the polarization of TAMs into M1-like macrophages and inhibited their polarization into M2-like macrophages in a LPS- or IL-4-induced bone marrow-derived macrophages (BMDMs) model and co-culture system. Finally, we also investigated the regulatory mechanism of HGK on TAMs polarization that HGK may active p-STAT5, p-NF-κB signaling in M1-like macrophages and inhibit p-STAT6, JMJD3, PPARγ expression in M2-like macrophages. Taken together, our findings suggest that HGK is a natural candidate for effective prevention of peritoneal metastasis in colorectal cancer, which provides a potential strategy for clinical treatment of colorectal cancer.

Functional connectivity of the amygdala subregions and the antidepressant effects of repeated ketamine infusions in major depressive disorder.

BACKGROUND: Amygdala subregion-based network dysfunction has been determined to be centrally implicated in major depressive disorder (MDD). Little is known about whether ketamine modulates amygdala subarea-related networks. We aimed to investigate the relationships between changes in the resting-state functional connectivity (RSFC) of amygdala subregions and ketamine treatment and to identify important neuroimaging predictors of treatment outcomes. METHODS: Thirty-nine MDD patients received six doses of ketamine (0.5 mg/kg). Depressive symptoms were assessed, and magnetic resonance imaging (MRI) scans were performed before and after treatment. Forty-five healthy controls underwent one MRI scan. Seed-to-voxel RSFC analyses were performed on the amygdala subregions, including the centromedial amygdala (CMA), laterobasal amygdala (LBA), and superficial amygdala subregions. RESULTS: Abnormal RSFC between the left LBA and the left precuneus in MDD patients is related to the therapeutic efficacy of ketamine. There were significant differences in changes in bilateral CMA RSFC with the left orbital part superior frontal gyrus and in changes in the left LBA with the right middle frontal gyrus between responders and nonresponders following ketamine treatment. Moreover, there was a difference in the RSFC of left LBA and the right superior temporal gyrus/middle temporal gyrus (STG/MTG) between responders and nonresponders at baseline, which could predict the antidepressant effect of ketamine on Day 13. CONCLUSIONS: The mechanism by which ketamine improves depressive symptoms may be related to its regulation of RSFC in the amygdala subregion. The RSFC between the left LBA and right STG/MTG may predict the response to the antidepressant effect of ketamine.

Altered regional brain activity moderating the relationship between childhood trauma and depression severity.

OBJECTIVE: Childhood trauma (CT) is a major environmental risk factor for an adverse course and treatment outcome of major depressive disorder (MDD). Evidence suggests that an altered regional brain activity may play a crucial role in the relationship between CT and MDD. This study aimed to clarify the relationship between CT, regional brain activity, and depression severity. METHODS: In this study, 96 patients with MDD and 82 healthy controls (HCs) participated. Regional brain activity was measured using the fractional amplitude of low-frequency fluctuation (fALFF) and regional homogeneity (ReHo). These measures were compared between the MDD and HC groups, and the values of different brain regions were extracted as moderators. RESULTS: Increased fALFF and ReHo values were observed in the left middle temporal gyrus in the MDD group compared with the HC group (p < 0.001). Furthermore, the fALFF and ReHo values moderated the positive correlation between the Childhood Trauma Questionnaire (CTQ) score, 17-item Hamilton Depression Rating Scale (HAMD-17) total score, and retardation factor score in the MDD group (all, p < 0.05). Finally, as the fALFF and ReHo values increased, the positive correlations between CTQ, HAMD-17 total, and retardation dimension scores became stronger. CONCLUSION: Our study highlighted the crucial role of altered brain function in connecting childhood maltreatment with depressive symptoms. Our findings indicate that an altered regional brain activity could explain the potential neurobiological mechanisms of MDD symptoms, offering the opportunity to function as a powerful diagnostic biomarker.

Sex differences in the effects of repeated ketamine infusions on bone markers in patients with unipolar and bipolar depression.

BACKGROUND: Patients with depression, especially women, are associated with low bone mineral density (BMD). Traditional antidepressants are associated with negative effects on BMD. Few studies have examined the effect of ketamine on BMD, and it remains unclear whether there are sex differences in the effects of ketamine on BMD in patients with depression. METHODS: A total of 102 patients with unipolar and bipolar depression were administered six infusions of intravenous ketamine over a 12-day period. Plasma levels of eight bone markers were examined at baseline, 24 h after the sixth infusion and again 2 weeks (Days 13 and 26). RESULTS: Linear mixed models showed all bone markers had significant time main effect (all p < 0.05). Compared with baseline, the whole sample showed increased levels of leptin and osteoprotegerin at Days 13 and 26, as well as Dickkopf-related protein 1 at Day 13, and decreased levels of osteocalcin, sclerostin, osteopontin, parathyroid hormone and fibroblast growth factor 23 at Days 13 and 26 (all p < 0.05). Females had a higher level of leptin at Days 13 and 26, and lower levels of osteocalcin and sclerostin at Day 13 than males (all p < 0.05). Increases of leptin were associated with depressive symptom improvements at Day 13 and Day 26 in females (both p < 0.05). In males, higher baseline osteocalcin levels were associated with greater depressive symptom improvement at Day 26 (ß = 0.414, p = 0.009). CONCLUSIONS: Our results suggest that repeated ketamine infusions may be associated with modulation of bone markers in patients with depression and present sex differences. Baseline osteocalcin level may be served as a predictor for the antidepressant effects of ketamine in males. Trial registration Data were derived from an open label clinical trial, which was registered at Chinese Clinical Trial Registry (ChiCTR-OOC-17012239). Registered 26 May 2017. http://www.chictr.org.cn.

Depression and low bone mineral density (BMD) are epidemiologically linked and traditional antidepressants may act as a risk factor for BMD. However, it is unclear whether the novel antidepressant, ketamine, has effects on bone markers in patients with depression and whether there are sex differences on these effects. Ketamine infusions may be associated with modulation of bone markers and may exert a positive effect on BMD in patients with depression, which present sex differences. The study results may inform potential strategies for prevention of low BMD during the treatment of depression. Clinicians should be aware of the bone markers because some of them may be associated antidepressant response.

Efficacy and safety of intermittent theta burst stimulation on adolescents and young adults with major depressive disorder: A randomized, double blinded, controlled trial.

BACKGROUND: Intermittent theta burst stimulation (iTBS) is a newer form of Repetitive Transcranial Magnetic Stimulation (rTMS) for depression. However, its efficacy and safety in adolescents and young adults with major depressive disorder (AYA-MDD) have not been well studied, especially when applied with a strategy that combines neuronavigation targeting and accelerated iTBS. METHODS: In this study, ninety patients were randomly assigned to twice-daily (two 600-pulse sessions spaced out by 10 min, n = 31), once-daily (one 600-pulse session, n = 29) or sham iTBS (no pulses, n = 30) groups for 10 treatment days. The primary outcome measure was the change in depression scores on the Hamilton Rating Scale for Depression (HAMD-17). Other clinical symptoms, such as anxiety, were also evaluated. RESULTS: Linear mixed model analysis found that scores on the HAMD-17 and its factors improved in all three groups, but these improvements did not significantly differ among groups. Other clinical symptoms such as anxiety also improved. Response and remission rates were relatively low and did not differ among groups at any time point. The most common adverse event was headache, and the proportion of participants who reported headache in the twice-daily and once-daily groups was significantly higher than that in the sham group. CONCLUSIONS: The current results indicated that twice-daily and once-daily iTBS under neuronavigation are safe and well tolerated in AYA-MDD, but the overall efficacy was not superior to that of sham treatment. We speculated several possible reasons such as the high placebo response of the young population, inadequate iTBS pulses and so on.

The core inflammatory factors in patients with major depressive disorder: a network analysis.

Introduction: The symptoms of major depressive disorder (MDD) vary widely. Psycho-neuro-inflammation has shown that MDD's inflammatory factors can accelerate or slow disease progression. This network analysis study examined the complex interactions between depressed symptoms and inflammatory factors in MDD prevention and treatment. Measures: We gathered participants' inflammatory factor levels, used the Hamilton Depression Scale (HAMD-17), and network analysis was used to analyzed the data. Network analysis revealed the core inflammatory (nodes) and their interactions (edges). Stability and accuracy tests assessed these centrality measures' network robustness. Cluster analysis was used to group persons with similar dimension depressive symptoms and examine their networks. Results: Interleukin-1ß (IL-1ß) is the core inflammatory factor in the overall sample, and IL-1ß-interleukin-4 (IL-4) is the strongest correlation. Network precision and stability passed. Network analysis showed significant differences between Cluster 1 (with more severe anxiety/somatization and sleep disruption) and Cluster 3 (with more severe retardation and cognitive disorders), as well as between Cluster 2 (with more severe anxiety/somatization, sleep disruption and body weight) and Cluster 3. IL-1ß is the core inflammatory factor in Cluster 1 and Cluster 2, while tumor necrosis factor alpha (TNF-α) in Cluster 3. Conclusion: IL-1ß is the central inflammatory factor in the network, and there is heterogeneity in the core inflammatory factor of MDD with specific depressive dimension symptoms as the main manifestation. In conclusion, inflammatory factors and their links should be prioritized in future theoretical models of MDD and may provide new research targets for MDD intervention and treatment.

Short-term cognitive effects of repeated-dose esketamine in adolescents with major depressive disorder and suicidal ideation: a randomized controlled trial.

BACKGROUND: Ketamine and its enantiomer have rapid and robust effects on depressive symptom and suicidal ideation. Little is known about their cognitive effects in adolescents. We aimed to evaluate the short-term effect of esketamine on cognition in adolescents with major depressive disorder (MDD) and suicidal ideation. METHOD: In this randomized-controlled trial, 51 participants aged 13-18 with MDD and suicidal ideation received three intravenous infusions of either esketamine (0.25 mg/kg) or midazolam (0.02 mg/kg). Four dimensions of the MATRICS Consensus Cognitive Battery (MCCB), including processing speed, working memory, verbal learning and visual learning, were assessed at Days 0, 6 and 12. RESULTS: In the linear mixed model, a significant time main effect (F = 12.803, P < 0.001), drug main effect (F = 6.607, P = 0.013), and interaction effect (F = 3.315, P = 0.041) was found in processing speed. Other dimensions including working memory and verbal learning showed significant time main effect (all P < 0.05), but no significant drug or interaction effect (all P > 0.05). Esketamine group showed improvement in processing speed from baseline to Days 6 and 12, and working memory from baseline to Day 12 (all P < 0.05). The generalized estimation equation showed no significant association between baseline cognition and antidepressant or antisuicidal effect (both P > 0.05). CONCLUSIONS: The present study suggested that three-dose subanesthetic esketamine infusions did not harm cognition among adolescents with MDD and suicidal ideation. Instead, esketamine may be associated with improvement in processing speed. TRIAL REGISTRATION: This trial was registered in the Chinese Clinical Trials Registry ( http://www.chictr.org.cn , ChiCTR2000041232).

Alterations of functional connectivity in young people with depression mediate the relationship between sleep quality and cognitive function.

BACKGROUND: Sleep disturbances is common in young people with depression, and poor sleep quality affects the ability to learn. In this study, we examined possible resting-state functional connectivity abnormalities between regions of interest, and clarified the relationship with depressive symptoms, sleep quality, and cognitive function. METHODS: Resting-state functional magnetic resonance imaging (fMRI) was collected on 42 healthy controls (HCs), 82 youth depressive patients (44 without sleep disturbances (NSD), and 38 with sleep disturbances (SD)). Regions of interest were defined by using Brainnetome Atlas. Functional connectivity was calculated, and its associations with depressive symptoms, sleep quality, and cognitive function were examined using correlation analysis and mediation analysis. RESULTS: The left and right caudal of cingulate gyrus, tongue and larynx region of postcentral gyrus were significant brain regions in NSD versus SD. The average functional connectivity between these regions was associated with poor sleep quality (r = 0.368, p = 0.001) and worse working memory (r = -0.256, p = 0.023) and mediated the relationship between sleep quality and working memory (c = -0.738, c' = -0.500). LIMITATION: Data consistency in this study was not good enough. This study did not monitor sleep rhythms to provide objective sleep-related data. CONCLUSION: The functional connectivity between the left and right caudal of cingulate gyrus with tongue and larynx region of postcentral gyrus may be the neural mechanism by which sleep disturbances affect working memory. This provides an intervention target for clinically improving cognitive function in young people with depression.

Mediating effect of subclinical inflammation on the process of morning hypertension leading to atrial fibrillation in community-based older adults.

BACKGROUND: The impacts and mechanisms of morning hypertension (MHT) on the risk of new-onset atrial fibrillation (AF) in the elderly have not been clarified. We aimed to investigate an association between MHT and new-onset AF and explore a mediating effect of subclinical inflammation on this association. METHODS: From 2008 to 2010, 1789 older adults aged ≥60 years were recruited in Shandong area, China. Morning blood pressure (BP) was assessed using 24-hour ambulatory BP monitoring. MHT was defined as BP ≥ 135/85 mm Hg during the period from wake time to 0900 a.m. Subclinical inflammation was assessed by hypersensitive C-reactive protein (hsCRP), tumor necrosis factor-alpha (TNF-α), systemic immune-inflammation index (SII), neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and galectin-3. New-onset AF was rated during the follow-up period. RESULTS: Over an average 129.0 [standard deviation (SD): 21.58] months of follow-up, the hazard ratio of new-onset AF in MHT patients was 1.39 (95% confidence interval: 1.01 to 1.91) compared with non-MHT participants (Padjusted = 0.027). The risk of new-onset AF was 1.17-fold with one-SD increment of morning systolic BP. Subclinical inflammation was significantly associated with new-onset AF. The hazard ratios of new-onset AF were 2.29, 2.04, 2.08, 2.08, 2.03, and 3.25 for one-SD increment in hsCRP, TNF-α, SII, NLR, PLR, and galectin-3, respectively (Padjusted < 0.001). The analysis showed that hsCRP, TNF-α, SII, NLR, PLR, and galectin-3 separately mediated the process of MHT inducing new-onset AF (Padjusted < 0.05). CONCLUSIONS: MHT is associated with an increased risk of new-onset AF. The subclinical inflammation might play a mediating role in this association.

Efficacy of repeated intravenous esketamine in adolescents with anxious versus non-anxious depression.

Background: Patients with anxious major depressive disorder (MDD) are more likely to have poorer outcomes than those with non-anxious MDD. However, the effect of esketamine on adolescents with anxious versus non-anxious MDD has remained unknown. Aims: We compared the efficacy of esketamine in adolescents with MDD and suicidal ideation, both anxious and non-anxious. Methods: Fifty-four adolescents with anxious (n=33) and non-anxious (n=21) MDD received three infusions of esketamine 0.25 mg/kg or active-placebo (midazolam 0.045 mg/kg) over 5 days, with routine inpatient care and treatment. Suicidal ideation and depressive symptoms were assessed using the Columbia Suicide Severity Rating Scale and the Montgomery-Åsberg Depression Rating Scale. Multiple-sample proportional tests were used to compare the differences between groups on treatment outcomes 24 hours after the final infusion (day 6, primacy efficacy endpoint) and throughout the 4-week post-treatment (days 12, 19 and 33). Results: In subjects who received esketamine, a greater number of patients in the non-anxious group than the anxious group achieved antisuicidal remission on day 6 (72.7% vs 18.8%, p=0.015) and day 12 (90.9% vs 43.8%, p=0.013), and the non-anxious group had a higher antidepressant remission rate compared with the anxious group on day 33 (72.7% vs 26.7%, p=0.045). No significant differences in treatment outcomes were observed between the anxious and non-anxious groups at other time points. Conclusions: Three infusions of esketamine as an adjunct to routine inpatient care and treatment had a greater immediate post-treatment antisuicidal effect in adolescents with non-anxious MDD than in those with anxious MDD; however, this benefit was temporary and was not maintained over time. Trial registration number: ChiCTR2000041232.

Effect of Repeated Intravenous Esketamine on Adolescents With Major Depressive Disorder and Suicidal Ideation: A Randomized Active-Placebo-Controlled Trial.

OBJECTIVE: Suicide is a major cause of death in adolescents with limited treatment options. Ketamine and its enantiomers have shown rapid anti-suicidal effects in adults with major depressive disorder (MDD), but their efficacy in adolescents is unknown. We conducted an active, placebo-controlled trial to determine the safety and efficacy of intravenous esketamine in this population. METHOD: A total of 54 adolescents (aged 13-18 years) with MDD and suicidal ideation were included from an inpatient setting and randomly assigned (1:1) to receive 3 infusions of esketamine (0.25 mg/kg) or midazolam (0.02mg/kg) over 5 days, with routine inpatient care and treatment. Changes from baseline to 24 hours after the final infusion (day 6) in the scores of the Columbia Suicide Severity Rating Scale (C-SSRS) Ideation and Intensity (primary outcome) and the Montgomery-Åsberg Depression Rating Scale (MADRS, key secondary outcome) were analyzed using linear mixed models. In addition, the 4-week clinical treatment response was a key secondary outcome. RESULTS: The mean changes in C-SSRS Ideation and Intensity scores from baseline to day 6 were significantly greater in the esketamine group than in the midazolam group (Ideation, -2.6 [SD = 2.0] vs -1.7 [SD = 2.2], p = .007; Intensity, -10.6 [SD = 8.4] vs -5.0 [SD = 7.4], p = .002), and the changes in MADRS scores from baseline to day 6 were significantly greater in the esketamine group than in the midazolam group (-15.3 [SD = 11.2] vs -8.8 [SD = 9.4], p = .004). The rates of anti-suicidal and antidepressant responses at 4 weeks posttreatment were 69.2% and 61.5% after esketamine, and were 52.5% and 52.5% after midazolam, respectively. The most common adverse events in the esketamine group were nausea, dissociation, dry mouth, sedation, headache, and dizziness. CONCLUSION: These preliminary findings indicate that 3-dose intravenous esketamine, added to routine inpatient care and treatment, was an effective and well-tolerated therapy for treating adolescents with MDD and suicidal ideation. CLINICAL TRIAL REGISTRATION INFORMATION: The efficacy and safety of esketamine combined with oral antidepressants in the treatment of major depressive disorder with suicidal ideation. http://www.chictr.org.cn. Chinese Clinical Trial Registry: ChiCTR2000041232. DIVERSITY & INCLUSION STATEMENT: We worked to ensure that the study questionnaires were prepared in an inclusive way. The author list of this paper includes contributors from the location and/or community where the research was conducted who participated in the data collection, design, analysis, and/or interpretation of the work. We actively worked to promote sex and gender balance in our author group.

Cyclohexenone Derivative and Drimane Sesquiterpenes from the Seagrass-Derived Fungus Aspergillus insuetus.

One new cyclohexenone derivative (1), and two undescribed drimane sesquiterpenes (2 and 3), together with another seven known drimane sesquiterpenes were isolated from a seagrass-derived fungus Aspergillus insuetus SYSU6925. Structures of these metabolites were elucidated by comprehensive spectroscopic analysis, including NMR analysis, mass spectrometry, and ECD calculations. Compounds 1-3, 5 and 7 displayed weak to moderate antifungal activities towards four phytopathogenic fungi, with Minimum inhibition concentration (MIC) values range from 50 to 200 µg/mL. Compound 1, a rare cyclohexenone derivative with n-propyl group exhibited more potent inhibitory activities (MIC, 50 µg/mL) against F. oxysporum than positive control (Triadimefon). Compounds 2 and 3 also exhibit potent anti-inflammatory activities by inhibiting the production of nitric oxide (NO) in RAW264.7 cells with IC50 values of 21.5±1.1 and 32.6±1.16 µM, respectively.

Pain mediates the improvement of social functions of repeated intravenous ketamine in patients with unipolar and bipolar depression.

OBJECTIVE: Previous research has shown that ketamine can improve social functions. In addition, evidence also suggests that ketamine can alleviate pain. Herein, we propose that ketamine-induced improvements in pain and depression are partially mediated by a reduction in pain. We aimed to determine whether improvements in pain-mediated changes in psychological function were associated with ketamine treatment. METHOD: This trial included unipolar or bipolar patients (n = 103) who received 6 intravenous infusions (0.5 mg/kg) of ketamine over 2 weeks. The severity of current depressive symptoms and social function were evaluated by the Montgomery-Åsberg Depression Scale (MADRS), Self-Rating Depression Scale (SDS) and Global Assessment Function (GAF), respectively, at baseline and on day 13 and day 26. At the same time points, the three dimensions of pain, including the sensory index, affective index and present pain intensity (PPI), were measured by the Simple McGill Pain Scale (SF-MPQ). RESULTS: The mixed model results showed that ketamine plays an important role in improving the psychosocial functioning of patients. There was a significant decrease from baseline to the day 13 and day 26, indicating that the pain index of the patient improved significantly. Mediation analysis showed that for SDS score (coef = -5.171, 95 % CI[-6.317, -4.025]) and GAF score (coef = 1.021, 95 % CI[0.848, 1.194]), the overall effect of ketamine was observable. The overall indirect and direct effects of ketamine on social functioning were significant (SDS: direct: coef = -1949 to -2114; total indirect: from 0.594 to 0.664; GAF: from 0.399 to 0.427; total indirect: coef = 0.593 to 0.664). The MADRS total score and emotional index were important mediators of the association between ketamine treatment and improvements in subjective and objective social functioning. CONCLUSION: Depressive symptom severity and the affective index of pain partially mediated improvements in social function after six repeated ketamine treatments among patients with bipolar or unipolar depressive disorder.

Discovery of Novel Bactericides from Aspergillus alabamensis and Their Antibacterial Activity against Fish Pathogens.

The emerging outbreak of bacterial diseases is a major challenge for the aquaculture industry. The development of new antibacterial agents from natural resources to curb fish bacterial diseases in aquaculture is becoming increasingly popular. In this study, eight new benzoic acid-containing alkaloids, asperalin A-F (1-6), asperalumazine A (7), and N-(3-acetamidopropyl)-3,4-dihydroxybenzamide (8), along with four known compounds (9-12) were isolated and identified from a seagrass-derived Aspergillus alabamensis. Their chemical structures were established on the basis of extensive spectroscopic analyses (including HRESIMS, 1D and 2D NMR spectroscopy), NMR computational methods, and electronic circular dichroism (ECD) calculations. Compounds 1-6 exhibited moderate or potent inhibitory activities against at least one fish pathogenic bacterium, among Edwardsiella ictalurid, Streptococcus iniae, and Streptococcus parauberis, and these compounds represent the first report of the coupling of dihydroquinolone alkaloids with benzoic acid derivatives. Compounds 3 and 4 showed strong activities against Staphylococcus aureus, S. iniae, and S. parauberis, with an MIC value of 10.1, 5.0, and 10.1 µM, respectively. Compound 5, an N-alkylated product of 4, exhibited the strongest inhibitory effects against S. iniae, with an MIC value of 2.2 µM. Notably, compound 6, as a new natural bactericide, showed moderate to potent inhibitory activity toward all strains tested, including one Gram-negative bacterium E. ictalurid (10.9 µM, MIC) and four Gram-positive bacteria S. iniae (43.6 µM, MIC), S. aureus (21.8 µM, MIC), S. parauberis (87.3 µM, MIC), and Bacillus subtilis (21.8 µM, MIC). Compound 7 represents the first example of a lumazine derivative directly coupled to a benzoic acid moiety by a hydroxymethyl group.

Ketamine-induced hippocampal functional connectivity alterations associated with clinical remission in major depression.

OBJECTIVE: Hippocampal functional connectivity (FC) alterations, which may happen following ketamine treatment, play a key role in major depression remission. This study aims to investigate the resting-state FC changes of the hippocampus associated with clinical remission after repeated ketamine infusions. METHODS: Forty-four major depressive patients received six intravenous ketamine (0.5 mg/kg) infusions in 12 days. The FC change of the hippocampus subregions following ketamine treatment was compared between remitters (MADRS score ≤ 10 post-treatment) and nonremitters. We also investigated whether baseline hippocampus FC predicted the antidepressant efficiency of ketamine using Receiver Operating Characteristic Curve analyses. RESULTS: Thirty-nine patients were included in the analysis. There were significant differences in change of left rostral hippocampus FC with the right angular gyrus (the key node of the default mode network, DMN), left inferior parietal cortex and the right superior parietal cortex (parts of the dorsal attention network, dAN) between remitters and nonremitters following ketamine treatment. Specifically, while the remitters showed significantly less negative hippocampus FC than the nonremitters at baseline, the FC significantly decreased in remitters but increased in nonremitters after ketamine injections. Moreover, baseline hippocampus FC with the above three regions predicted the antidepressant effect of ketamine, with the highest predictive strength identified in the hippocampus-right angular gyrus FC (Area-Under-Curve = 0.8179, p < 0.05). CONCLUSION: Ketamine treat depression by modulating the left rostral hippocampus resting-state FC with the DMN and dAN. The FC between the hippocampus and parts of the DMN and dAN may show promising potential in predicting remission after ketamine treatment in MDD.

The efficacy and safety of esketamine in the treatment of major depressive disorder with suicidal ideation: study protocol for a randomized controlled trial.

BACKGROUND: Major depressive disorder (MDD) is a high risk factor for suicide, with up to 20% of MDD patients attempting suicide during their lifetime. Current treatments for MDD are slow onset of action, low efficiency, and the inability to control suicidal behaviors quickly and effectively. Intravenous ketamine has been shown to have a rapid but transient antidepressant effect, but there is still lack evidence on the efficacy and safety of intravenous esketamine in reducing suicidal ideation and depressive symptoms in MDD patients with suicidal ideation. We designed a study to investigate the effect of short-term repeated intravenous infusion of esketamine three times in MDD patients with suicidal ideation. METHODS: This study features a randomized, double-blind, placebo-controlled trial (RCT) comparing short-term repeated intravenous infusions of esketamine with placebo as a supplement to conventional antidepressants with an intervention period of 6 days and one infusion every other day, followed by 4 weeks of follow-up. These methods support the examination of the efficacy, safety, tolerability, and mechanism of action of short-term repeated intravenous infusions of esketamine in MDD patients with suicidal ideation. DISCUSSION: This is the first RCT to explore the efficacy and safety of short-term repeated infusion of esketamine on suicidal ideation and depressive symptoms in MDD patients with suicidal ideation. If proven effective and tolerated, it will provide evidence for rapid and effective treatment of suicidal ideation and depressive symptoms in MDD individuals with suicidal ideation. TRIAL REGISTRATION: Chinese Clinical Trial Register, ChiCTR2000041232 . Registered 22 December 2020.

Sesquiterpenoids with Phytotoxic and Antifungal Activities from a Pathogenic Fungus Aspergillus alabamensis.

Five new carotane sesquiterpenoids (asperalacids A-E (1-5)), one new tricyclic sesquiterpenoid (4-hydroxy-5(6)-dihydroterrecyclic acid A (6)), and two known analogues (7-8) were obtained from a seagrass-derived fungus Aspergillus alabamensis, which was speculated to be a phytopathogenic fungus, isolated from the necrotic leaves of Enhalus acoroides. The structures of 1-6 were established by a combination of spectroscopic methods, including comprehensive NMR analysis, mass spectrometry, conformational analysis, NMR computational methods, and ECD calculations. Compound 4, with higher inhibitory activity on wheat (Triticum aestivum L.) root and shoot elongation than the positive control terbutryn, a broad-spectrum systemic herbicide, is a new natural plant growth inhibitor. Compound 5, belonging to the rare glycosylated sesquiterpenoid class, represents the first example of glycosylated carotane sesquiterpenoid whose sugar moiety was identified as α-d-glucose. Compounds 1-4 and 6 displayed weak to potent antimicrobial activity against the plant pathogenic fungi Fusarium oxysporum, Fusarium graminearum, and Penicillium italicum and the Gram-positive bacteria Bacillus subtilis and Staphylococcus aureus.

Association of Thyroid Hormone Levels with Microvascular Complications in Euthyroid Type 2 Diabetes Mellitus Patients.

Purpose: To examine the prevalence of different microvascular complications and investigate the association between thyroid hormones (THs) and these complications in euthyroid patients with type 2 diabetes mellitus (T2DM). Methods: A total of 248 T2DM patients were analyzed retrospectively for the study. All patients received a detailed and standard assessment to identify diabetic peripheral neuropathy (DPN), diabetic nephropathy (DN), and diabetic retinopathy (DR). Multivariate logistic regression was carried out to analyze the association between THs and diabetic microvascular complications. Results: The study found the prevalence of any microangiopathy to be 72.18% (n = 179). At the same time, the prevalence of DPN was 54.84% (n=136), while that of DN was 31.85% (n=79). Likewise, the prevalence of DR was 35.48% (n=88). The odds ratios (ORs) for free triiodothyronine (FT3) developing any microangiopathy, DPN, DN and DR were 0.200, 0.361, 0.310, and 0.588 (P<0.05), respectively. Also, the ORs for free thyroxine (FT4) developing any microangiopathy, DPN, DN and DR were 0.643, 0.800, 0.702 and 0.726 (P<0.05), respectively. Lastly, the ORs for thyroid-stimulating hormone (TSH) developing DPN was 1.57 (95% CI: 1.148-2.137, P=0.005). Conclusion: The study concludes that serum FT3 and FT4 levels are negatively associated with any microangiopathy, DPN, DN and DR in euthyroid patients with T2DM, independent of traditional risk factors. However, the TSH levels are positively associated with DPN. Future larger sample-size studies are needed to confirm the relationship between thyroid hormone levels and microvascular complications in euthyroid patients with T2DM.

Astragaloside IV Alleviates Renal Tubular Epithelial-Mesenchymal Transition via CX3CL1-RAF/MEK/ERK Signaling Pathway in Diabetic Kidney Disease.

Background: Epithelial-mesenchymal transition (EMT) plays an important role in interstitial matrix deposition and renal fibrosis in diabetic kidney disease (DKD). It has been verified that Astragaloside IV (AS-IV) is beneficial for ameliorating DKD. However, the underlying mechanisms of AS-IV on regulating EMT in DKD are yet to be established. Accumulated evidence has suggested that C-X3-C motif ligand 1 (CX3CL1) plays a significant role in the progression of EMT. Purpose: We aimed to investigate whether AS-IV could alleviate EMT by regulating CX3CL1 in DKD and reveal its underlying mechanisms. Methods: For the in vivo study, mice were divided into the following five groups (n=10): db/m+vehicle, db/db+vehicle, db/db+AS-IV-L (10mg/kg/d), db/db+AS-IV-M (20mg/kg/d), db/db+AS-IV-H (40mg/kg/d). After 12 weeks of treatment, the renal injuries were assessed based on the related parameters of urine, blood and histopathological examination. Immunohistochemistry and Western blotting were used to detect relative proteins levels. Then in HK-2 cells, the molecular mechanism of AS-IV attenuating the EMT in mice with DKD through the CX3CL1-RAF/MEK/ERK pathway was studied. Results: In the present study, we found that AS-IV reduced urinary protein levels and improved renal pathological damage in DKD mice. Moreover, AS-IV ameliorated the renal tubular EMT induced by hyperglycemia or high glucose (HG), and decreased the expression of CX3CL1 and inhibited the activation of the RAF/MEK/ERK pathway in vivo and in vitro. In HK-2 cells, downregulation of CX3CL1 suppressed the stimulation of the RAF/MEK/ERK pathway and EMT induced by HG. However, CX3CL1 overexpression eliminated the benefits of AS-IV on the RAF/MEK/ERK pathway and EMT. Conclusion: In summary, we indicated that AS-IV alleviates renal tubular EMT through the CX3CL1-RAF/MEK/ERK signaling pathway, indicating that CX3CL1 could be a potential therapeutic target of AS-IV in DKD.

Genome Mining of α-Pyrone Natural Products from Ascidian-Derived Fungus Amphichordafelina SYSU-MS7908.

Culturing ascidian-derived fungus Amphichorda felina SYSU-MS7908 under standard laboratory conditions mainly yielded meroterpenoid, and nonribosomal peptide-type natural products. We sequenced the genome of Amphichorda felina SYSU-MS7908 and found 56 biosynthetic gene clusters (BGCs) after bioinformatics analysis, suggesting that the majority of those BGCSs are silent. Here we report our genome mining effort on one cryptic BGC by heterologous expression in Aspergillus oryzae NSAR1, and the identification of two new α-pyrone derivatives, amphichopyrone A (1) and B (2), along with a known compound, udagawanone A (3). Anti-inflammatory activities were performed, and amphichopyrone A (1) and B (2) displayed potent anti-inflammatory activity by inhibiting nitric oxide (NO) production in RAW264.7 cells with IC50 values 18.09 ± 4.83 and 7.18 ± 0.93 µM, respectively.