In Silico Prediction of Quercetin Analogs for Targeting Death-Associated Protein Kinase 1 (DAPK1) Against Alzheimer's Disease.

Alzheimer's Disease (AD) is a progressive neurodegenerative disorder that greatly affects the health and life quality of the elderly population. Existing drugs mainly alleviate symptoms but fail to halt disease progression, underscoring the urgent need for the development of novel drugs. Based on the neuroprotective effects of flavonoid quercetin in AD, this study was designed to identify potential AD-related targets for quercetin and perform in silico prediction of promising analogs for the treatment of AD. Database mining suggested death-associated protein kinase 1 (DAPK1) as the most promising AD-related target for quercetin among seven protein candidates. To achieve better biological effects for the treatment of AD, we devised a series of quercetin analogs as ligands for DAPK1, and molecular docking analyses, absorption, distribution, metabolism, and excretion (ADME) predictions, as well as molecular dynamics (MD) simulations, were performed. The energy for drug-protein interaction was predicted and ranked. As a result, quercetin-A1a and quercetin-A1a1 out of 19 quercetin analogs exhibited the lowest interaction energy for binding to DAPK1 than quercetin, and they had similar dynamics performance with quercetin. In addition, quercetin-A1a and quercetin-A1a1 were predicted to have better water solubility. Thus, quercetin-A1a and quercetin-A1a1 could be promising agents for the treatment of AD. Our findings paved the way for further experimental studies and the development of novel drugs.

N, N-Dimethyltryptamine, a natural hallucinogen, ameliorates Alzheimer's disease by restoring neuronal Sigma-1 receptor-mediated endoplasmic reticulum-mitochondria crosstalk.

BACKGROUND: Aberrant neuronal Sigma-1 receptor (Sig-1r)-mediated endoplasmic reticulum (ER)- mitochondria signaling plays a key role in the neuronal cytopathology of Alzheimer's disease (AD). The natural psychedelic N, N-dimethyltryptamine (DMT) is a Sig-1r agonist that may have the anti-AD potential through protecting neuronal ER-mitochondrial interplay. METHODS: 3×TG-AD transgenic mice were administered with chronic DMT (2 mg/kg) for 3 weeks and then performed water maze test. The Aß accumulation in the mice brain were determined. The Sig-1r level upon DMT treatment was tested. The effect of DMT on the ER-mitochondrial contacts site and multiple mitochondria-associated membrane (MAM)-associated proteins were examined. The effect of DMT on calcium transport between ER and mitochondria and the mitochondrial function were also evaluated. RESULTS: chronic DMT (2 mg/kg) markedly alleviated cognitive impairment of 3×TG-AD mice. In parallel, it largely diminished Aß accumulation in the hippocampus and prefrontal cortex. DMT restored the decreased Sig-1r levels of 3×TG-AD transgenic mice. The hallucinogen reinstated the expression of multiple MAM-associated proteins in the brain of 3×TG-AD mice. DMT also prevented physical contact and calcium dynamic between the two organelles in in vitro and in vivo pathological circumstances. DMT modulated oxidative phosphorylation (OXPHOS) and ATP synthase in the in vitro model of AD. CONCLUSION: The anti-AD effects of DMT are associated with its protection of neuronal ER-mitochondria crosstalk via the activation of Sig-1r. DMT has the potential to serve as a novel preventive and therapeutic agent against AD.

Add-on astragalus in type 2 diabetes and chronic kidney disease: A multi-center, assessor-blind, randomized controlled trial.

BACKGROUND: Diabetes leads to chronic kidney disease (CKD) and kidney failure, requiring dialysis or transplantation. Astragalus, a common herbal medicine and US pharmacopeia-registered food ingredient, is shown kidney protective by retrospective and preclinical data but with limited long-term prospective clinical evidence. This trial aimed to assess the effectiveness of astragalus on kidney function decline in macroalbuminuric diabetic CKD patients. METHODS: This randomized, assessor-blind, standard care-controlled, multi-center clinical trial randomly assigned 118 patients with estimated glomerular filtration rate (eGFR) of 30-90 ml/min/1.73m2 and urinary albumin-to-creatinine ratio (UACR) of 300-5000 mg/g from 7 public outpatient clinics and the community in Hong Kong between July 2018 and April 2022 to add-on oral astragalus granules (15 gs of raw herbs daily equivalent) or to continue standard care alone as control for 48 weeks. Primary outcomes were the slope of change of eGFR (used for sample size calculation) and UACR of the intention-to-treat population. Secondary outcomes included endpoint blood pressures, biochemistry, biomarkers, concomitant drug change and adverse events. (ClinicalTrials.gov: NCT03535935) RESULTS: During the 48-week period, the estimated difference in the slope of eGFR decline was 4.6 ml/min/1.73m2 per year (95 %CI: 1.5 to 7.6, p = 0.003) slower with astragalus. For UACR, the estimated inter-group proportional difference in the slope of change was insignificant (1.14, 95 %CI: 0.85 to 1.52, p = 0.392). 117 adverse events from 31 astragalus-treated patients and 41 standard care-controlled patients were documented. The 48-week endpoint systolic blood pressure was 7.9 mmHg lower (95 %CI: -12.9 to -2.8, p = 0.003) in the astragalus-treated patients. 113 (96 %) and 107 (91 %) patients had post-randomization and endpoint primary outcome measures, respectively. CONCLUSION: In patients with type 2 diabetes, stage 2 to 3 CKD and macroalbuminuria, add-on astragalus for 48 weeks further stabilized kidney function on top of standard care.

Acupuncture for chemotherapy-associated insomnia in breast cancer patients: an assessor-participant blinded, randomized, sham-controlled trial.

BACKGROUND: Insomnia is a highly prevalent symptom occurred during and post-chemotherapy. Acupuncture may have beneficial effects in the management of chemotherapy-associated insomnia. This study was conducted to determine the efficacy and safety of acupuncture in improving chemotherapy-associated insomnia in breast cancer patients. METHODS: This assessor-participant blinded, randomized, sham-controlled trial was conducted from November 2019 to January 2022 (follow-up completed July 2022). Participants were referred by oncologists from two Hong Kong hospitals. Assessments and interventions were conducted at the outpatient clinic of School of Chinese Medicine, the University of Hong Kong. The 138 breast cancer patients with chemotherapy-associated insomnia were randomly assigned to receive either 15 sessions of active acupuncture regimen by combining needling into body acupoints and acupressure on auricular acupoints or sham acupuncture control (69 each) for 18 weeks, followed by 24 weeks of follow-up. The primary outcome was measured using Insomnia Severity Index (ISI). Secondary outcomes included the Pittsburgh Sleep Quality Index, Actiwatch and sleep diary for sleep parameters, depression and anxiety, fatigue and pain, and quality of life. RESULTS: There were 87.7% (121/138) participants who completed the primary endpoint (week-6). The active acupuncture regimen was not superior to the sham control in reducing ISI score from baseline to 6 weeks (mean difference: - 0.4, 95% CI - 1.8-1.1; P = 0.609), but produced short-term treatment and long-term follow-up better outcomes in improving sleep onset latency, total sleep time, sleep efficiency, anxiety, depression, and quality of life. Participants of the active acupuncture group had a pronouncedly higher cessation rate of sleeping medications than the sham control (56.5% vs. 14.3%, P = 0.011). All treatment-related adverse events were mild. No participants discontinued treatments due to adverse events. CONCLUSION: The active acupuncture regimen could be considered as an effective option for the management of chemotherapy-associated insomnia. It also could serve as a tapering approach to reduce and even replace the use of sleeping medications in breast cancer patients. Trial registration Clinicaltrials.gov : NCT04144309. Registered 30 October 2019.

Berberine ameliorates depression-like behaviors in mice via inhibiting NLRP3 inflammasome-mediated neuroinflammation and preventing neuroplasticity disruption.

OBJECTIVES: Neuroinflammation has been suggested that affects the processing of depression. There is renewed interest in berberine owing to its anti-inflammatory effects. Herein, we investigated whether berberine attenuate depressive-like behaviors via inhibiting NLRP3 inflammasome activation in mice model of depression. METHODS: Adult male C57BL/6N mice were administrated corticosterone (CORT, 20 mg/kg/day) for 35 days. Two doses (100 mg/kg/day and 200 mg/kg/day) of berberine were orally administrated from day 7 until day 35. Behavioral tests were performed to measure the depression-like behaviors alterations. Differentially expressed gene analysis was performed for RNA-sequencing data in the prefrontal cortex. NLRP3 inflammasome was measured by quantitative reverse transcription polymerase chain reaction, western blotting, and immunofluorescence labeling. The neuroplasticity and synaptic function were measured by immunofluorescence labeling, Golgi-Cox staining, transmission electron microscope, and whole-cell patch-clamp recordings. RESULTS: The results of behavioral tests demonstrated that berberine attenuated the depression-like behaviors induced by CORT. RNA-sequencing identified that NLRP3 was markedly upregulated after long-term CORT exposure. Berberine reversed the concentrations of peripheral and brain cytokines, NLRP3 inflammasome elicited by CORT in the prefrontal cortex and hippocampus were decreased by berberine. In addition, the lower frequency of neuronal excitation as well as the dendritic spine reduction were reversed by berberine treatment. Together, berberine increases hippocampal adult neurogenesis and synaptic plasticity induced by CORT. CONCLUSION: The anti-depressants effects of berberine were accompanied by reduced the neuroinflammatory response via inhibiting the activation of NLRP3 inflammasome and rescued the neuronal deterioration via suppression of impairments in synaptic plasticity and neurogenesis.

Transcutaneous electrical cranial-auricular acupoint stimulation versus escitalopram for mild-to-moderate depression: An assessor-blinded, randomized, non-inferiority trial.

AIM: Transcutaneous electrical cranial-auricular acupoint stimulation (TECAS) is a novel non-invasive therapy that stimulates acupoints innervated by the trigeminal and auricular vagus nerves. An assessor-blinded, randomized, non-inferiority trial was designed to compare the efficacy of TECAS and escitalopram in mild-to-moderate major depressive disorder. METHODS: 468 participants received two TECAS sessions per day at home (n = 233) or approximately 10-13 mg/day escitalopram (n = 235) for 8 weeks plus 4-week follow-up. The primary outcome was clinical response, defined as a baseline-to-endpoint ≥50% reduction in Montgomery-Åsberg Depression Rating Scale (MADRS) score. Secondary outcomes included remission rate, changes in the severity of depression, anxiety, sleep and life quality. RESULTS: The response rate was 66.4% on TECAS and 63.2% on escitalopram with a 3.2% difference (95% confidence interval [CI], -5.9% to 12.9%) in intention-to-treat analysis, and 68.5% versus 66.2% with a 2.3% difference (95% CI, -6.9% to 11.4%) in per-protocol analysis. The lower limit of 95% CI of the differences fell within the prespecified non-inferiority margin of -10% (P ≤ 0.004 for non-inferiority). Most secondary outcomes did not differ between the two groups. TECAS-treated participants who experienced psychological trauma displayed a markedly greater response than those without traumatic experience (81.3% vs 62.1%, P = 0.013). TECAS caused much fewer adverse events than escitalopram. CONCLUSIONS: TECAS was comparable to escitalopram in improving depression and related symptoms, with high acceptability, better safety profile, and particular efficacy in reducing trauma-associated depression. It could serve an effective portable therapy for mild-to-moderate depression.

Minocycline, a classic antibiotic, exerts psychotropic effects by normalizing microglial neuroinflammation-evoked tryptophan-kynurenine pathway dysregulation in chronically stressed male mice.

The dysregulation of tryptophan-kynurenine pathway (TKP) is extensively involved in the pathophysiology of Alzheimer's disease, depression, and neurodegenerative disorders. Minocycline, a classic antibiotic, may exert psychotropic effects associated with the modulation of TKP. In this study, we examined the effects of minocycline in improving behaviour and modulating TKP components in chronically stressed male mice. Following repeated treatment with 22.5 mg/kg and 45 mg/kg minocycline for 27 days, the stressed mice particularly with higher dose displayed significant improvement on cognitive impairment, depression- and anxiety-like behaviour. Minocycline suppressed stress-induced overexpression of pro-inflammatory cytokines and restored anti-inflammatory cytokines. Chronic stress dramatically suppressed blood and prefrontal cortical levels of the primary substrate tryptophan (TRP), the neuroprotective metabolite kynurenic acid (KYNA), and KYNA/KYN ratio, but increased the intermediate kynurenine (KYN), 3-hydroxykynurenine (3-HK), KYN/TRP ratio, and the neurotoxic metabolite quinolinic acid (QUIN). Minocycline partially or completely reversed changes in these components. Minocycline also inhibited stress-induced overexpression of QUIN-related enzymes, indoleamine 2, 3-dioxygenase 1(iDO-1), kynureninase (KYNU), kynurenine 3-monooxygenase (KMO), 3-hydroxyanthranilate 3,4-dioxygenase (3-HAO), but rescued the decreased expression of kynurenine aminotransferase (KAT) in brain regions. Behavioral improvements were correlated with multiple TKP metabolites and enzymes. These results suggest that the psychotropic effects of minocycline are mainly associated with the restoration of biodistribution of the primary substrate in the brain and normalization of neuroinflammation-evoked TKP dysregulation.

Hirudin alleviates acute ischemic stroke by inhibiting NLRP3 inflammasome-mediated neuroinflammation: In vivo and in vitro approaches.

Acute ischemic stroke is a severe condition that a vessel supplying blood to the brain is abruptly blocked mostly due to cerebral thrombosis and embolism. There is a dearth of the effective prevention and early intervention strategies. NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome-mediated neuroinflammation plays a crucial role in the pathophysiology of ischemic stroke. Hirudin is a secretion from the salivary glands of the leech Hirudo medicinalis and has a role in regulating inflammation. In this study, hirudin with a dose of 10-40 mg/kg was given to middle cerebral artery occlusion/reperfusion mice. Hirudin markedly constrained cerebral infarct area in a dose-dependent manner, and significantly improved locomotor disability at 40 mg/kg dose. Similar to MCC950, a selective NLRP3 inflammasome inhibitor, hirudin inhibited M1 polarization and promoted M2 polarization. It also strikingly suppressed the ischemia-induced overexpression of NLRP3 and its downstream components, caspase-1, apoptosis-associated speck-like protein (ASC), and interleukin-1ß (IL-1ß). Hirudin and MCC950 equivalently protected viability and death of BV-2 microglia cells against oxygen-glucose deprivation/reperfusion (OGD/R), an in vitro cell model of brain ischemia. Both agents had similar effects in normalizing the OGD/R-evoked aberrant microglial profiles and NLRP3 pathway dysregulation as observed in the mice. These results demonstrated anti-ischemic effects of hirudin and its association with the inhibition of microglial NLRP3 inflammasome-mediated neuroinflammation. Hirudin is a promising agent for the early intervention of acute ischemic stroke.

Transcutaneous Electrical Cranial-Auricular Acupoint Stimulation vs. Escitalopram for Patients With Mild-to-Moderate Depression (TECAS): Study Design for a Randomized Controlled, Non-inferiority Trial.

Background: Previous studies in animals and humans indicated that transcutaneous vagus nerve stimulation (tVNS) and transcutaneous electrical acupoint stimulation (TEAS) on trigeminal nerve-innervated forehead acupoints can relief the symptoms of depression. However, due to the limited investigations on these two interventions, more research are needed to confirm their efficacy in depression. To improve the efficacy of the single treatment, we combined two treatments and created a novel non-invasive stimulation, transcutaneous electrical cranial-auricular acupoint stimulation (TECAS). To assess the efficacy and safety of TECAS, we compare it with a selective serotonin reuptake inhibitor (SSRI), escitalopram, for the treatment of depression. Methods/Design: This is a multi-center, non-inferiority, randomized controlled trial that will involve 470 patients with mild to moderate depression. Patients will be randomly assigned to either the TECAS group or the escitalopram group in a 1:1 ratio. The TEAS group will receive two sessions of treatments per day for 8 consecutive weeks, and the escitalopram group will receive 8 weeks of oral escitalopram tablets prescribed by clinical psychiatrists as appropriate for their condition. The primary outcome is the clinical response as determined by Montgomery-Åsberg Depression Rating Scale (MADRS) scores at week 8, with -10% as the non-inferior margin. The secondary outcomes include the response rate determined by 17-item Hamilton Depression Rating Scale (HAMD-17), remission rate, changes from baseline in the scores on the MADRS, the HAMD-17, the Hamilton Anxiety Rating Scale (HAMA), the Pittsburgh Sleep Quality Index (PSQI), and the Short Form 36 Health Survey (SF-36). Discussion: This will be the first randomized controlled trial to compare the efficacy of TECAS with escitalopram for depression. If effective, this novel intervention could have significant clinical and research implications for patients with depression. Clinical Trial Registration: [ClinicalTrials.gov], identifier [NCT03909217].

Acupuncture for cancer-related insomnia: A systematic review and meta-analysis.

BACKGROUND: Cancer-related insomnia is a highly prevalent complaint in cancer patients. However, there is no meta-analytic synthesis explored the efficacy of acupuncture for cancer-related insomnia among cancer patients undergoing active cancer treatments. OBJECTIVE: This systematic review and meta-analysis were performed to explore the efficacy and safety of acupuncture for insomnia in people diagnosed with cancer. STUDY DESIGN: Systematic review and meta-analysis of existing randomized controlled trials on acupuncture in the treatment of cancer-related insomnia. METHODS: According to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) Statement, we identified and extracted the trials through November 2021 from ten databases and two trials record platforms (Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, PUBMED, Web of Science, PsycINFO, Allied and Complementary Medicine, Cumulative Index to Nursing and Allied Health Literature, China National Knowledge Infrastructure, Wanfang Digital Journals, ClinicalTrials, World Health Organization International Clinical Trials Registry Platform). The quality of the trials was assessed using Jadad score and Risk of Bias (2.0). A meta-analysis was synthesized using the random-effects model if the included studies were in high methodological quality. RESULTS: A total of 690 studies were identified, with 22 were included in the review, and 6 of them were included in the quantitative synthesis. Studies were highly heterogeneous in terms of participant characteristics and study methodologies. Most studies recruited patients diagnosed with a specific cancer type, and breast cancer patients were the subgroup most represented. The qualitative review of available evidence suggested a beneficial efficacy of acupuncture on sleep without serious adverse events in several studies (55%). The meta-analysis revealed that acupuncture produced a significant improvement in the total Pittsburgh Sleep Quality Index (PSQI) score relative to the wait-list control among breast cancer patients undergoing active cancer treatments (MD -1.92, 95% CI -3.25 to -0.59, p = 0.005). Similar improvement of real and sham acupuncture on PSQI score change post-intervention was found (MD: -0.68, 95% CI: -2.44 to 1.07, p = 0.44). Manual acupuncture had similar effective rate as compared to estazolam immediately post-intervention (RR: 0.94, 95% CI: 0.87 to 1.01, p = 0.09), and had significantly better effective rate than estazolam at 1-week post-intervention follow-up (RR: 1.25, 95% CI: 1.10 to 1.43, p = 0.0009). All reported acupuncture related adverse events were mild or moderate in severity. CONCLUSION: Acupuncture has great potential to be used to manage cancer-related insomnia for cancer patients or survivors. More studies with rigorous designs and larger sample size are warranted to verify the efficacy and safety of acupuncture for insomnia among people diagnosed with cancer, in particular among those with clinically significant insomnia. REGISTRATION: PROSPERO (ID: CRD42021285844).

Clinician guidelines for the treatment of psychiatric disorders with nutraceuticals and phytoceuticals: The World Federation of Societies of Biological Psychiatry (WFSBP) and Canadian Network for Mood and Anxiety Treatments (CANMAT) Taskforce.

OBJECTIVES: The therapeutic use of nutrient-based 'nutraceuticals' and plant-based 'phytoceuticals' for the treatment of mental disorders is common; however, despite recent research progress, there have not been any updated global clinical guidelines since 2015. To address this, the World Federation of Societies of Biological Psychiatry (WFSBP) and the Canadian Network for Mood and Anxiety Disorders (CANMAT) convened an international taskforce involving 31 leading academics and clinicians from 15 countries, between 2019 and 2021. These guidelines are aimed at providing a definitive evidence-informed approach to assist clinicians in making decisions around the use of such agents for major psychiatric disorders. We also provide detail on safety and tolerability, and clinical advice regarding prescription (e.g. indications, dosage), in addition to consideration for use in specialised populations. METHODS: The methodology was based on the WFSBP guidelines development process. Evidence was assessed based on the WFSBP grading of evidence (and was modified to focus on Grade A level evidence - meta-analysis or two or more RCTs - due to the breadth of data available across all nutraceuticals and phytoceuticals across major psychiatric disorders). The taskforce assessed both the 'level of evidence' (LoE) (i.e. meta-analyses or RCTs) and the assessment of the direction of the evidence, to determine whether the intervention was 'Recommended' (+++), 'Provisionally Recommended' (++), 'Weakly Recommended' (+), 'Not Currently Recommended' (+/-), or 'Not Recommended' (-) for a particular condition. Due to the number of clinical trials now available in the field, we firstly examined the data from our two meta-reviews of meta-analyses (nutraceuticals conducted in 2019, and phytoceuticals in 2020). We then performed a search of additional relevant RCTs and reported on both these data as the primary drivers supporting our clinical recommendations. Lower levels of evidence, including isolated RCTs, open label studies, case studies, preclinical research, and interventions with only traditional or anecdotal use, were not assessed. RESULTS: Amongst nutraceuticals with Grade A evidence, positive directionality and varying levels of support (recommended, provisionally recommended, or weakly recommended) was found for adjunctive omega-3 fatty acids (+++), vitamin D (+), adjunctive probiotics (++), adjunctive zinc (++), methylfolate (+), and adjunctive s-adenosyl methionine (SAMe) (+) in the treatment of unipolar depression. Monotherapy omega-3 (+/-), folic acid (-), vitamin C (-), tryptophan (+/-), creatine (+/-), inositol (-), magnesium (-), and n-acetyl cysteine (NAC) (+/-) and SAMe (+/-) were not supported for this use. In bipolar disorder, omega-3 had weak support for bipolar depression (+), while NAC was not currently recommended (+/-). NAC was weakly recommended (+) in the treatment of OCD-related disorders; however, no other nutraceutical had sufficient evidence in any anxiety-related disorder. Vitamin D (+), NAC (++), methylfolate (++) were recommended to varying degrees in the treatment of the negative symptoms in schizophrenia, while omega-3 fatty acids were not, although evidence suggests a role for prevention of transition to psychosis in high-risk youth, with potential pre-existing fatty acid deficiency. Micronutrients (+) and vitamin D (+) were weakly supported in the treatment of ADHD, while omega-3 (+/-) and omega-9 fatty acids (-), acetyl L carnitine (-), and zinc (+/-) were not supported. Phytoceuticals with supporting Grade A evidence and positive directionality included St John's wort (+++), saffron (++), curcumin (++), and lavender (+) in the treatment of unipolar depression, while rhodiola use was not supported for use in mood disorders. Ashwagandha (++), galphimia (+), and lavender (++) were modestly supported in the treatment of anxiety disorders, while kava (-) and chamomile (+/-) were not recommended for generalised anxiety disorder. Ginkgo was weakly supported in the adjunctive treatment of negative symptoms of schizophrenia (+), but not supported in the treatment of ADHD (+/-). With respect to safety and tolerability, all interventions were deemed to have varying acceptable levels of safety and tolerability for low-risk over-the-counter use in most circumstances. Quality and standardisation of phytoceuticals was also raised by the taskforce as a key limiting issue for firmer confidence in these agents. Finally, the taskforce noted that such use of nutraceuticals or phytoceuticals be primarily recommended (where supportive evidence exists) adjunctively within a standard medical/health professional care model, especially in cases of more severe mental illness. Some meta-analyses reviewed contained data from heterogenous studies involving poor methodology. Isolated RCTs and other data such as open label or case series were not included, and it is recognised that an absence of data does not imply lack of efficacy. CONCLUSIONS: Based on the current data and clinician input, a range of nutraceuticals and phytoceuticals were given either a supportive recommendation or a provisional recommendation across a range of various psychiatric disorders. However several had only a weak endorsement for potential use; for a few it was not possible to reach a clear recommendation direction, largely due to mixed study findings; while some other agents showed no obvious therapeutic benefit and were clearly not recommended for use. It is the intention of these guidelines to inform psychiatric/medical, and health professional practice globally.

Acupuncture for insomnia after ischemic stroke: an assessor-participant blinded, randomized controlled trial.

BACKGROUND: To date, there has been little focus on research into acupuncture for insomnia after ischemic stroke. Insomnia is one of the most common sequelae after ischemic stroke, and it is the most unrecognized modifiable risk factor. OBJECTIVE: To evaluate the efficacy and safety of acupuncture for insomnia after ischemic stroke. METHODS: In this assessor-participant blinded, randomized, controlled trial, 144 ischemic stroke patients with insomnia meeting Diagnostic and Statistical Manual of Mental Disorders (fifth edition, DSM-5) criteria were assigned to verum or sham acupuncture treatment (n = 72 per group) for three sessions per week over 4 weeks. The outcomes were the Insomnia Severity Index (ISI), Pittsburgh Sleep Quality Index (PSQI), stroke-specific quality of life (SSQoL), and Hospital Anxiety and Depression Scale (HADS) scores. Multiple objective sleep variables were recorded using actigraphy. Assessment was conducted at baseline, and thereafter once biweekly for the 4-week treatment and at 4 weeks of follow-up. RESULTS: The verum acupuncture group had significantly greater improvements than the sham acupuncture group in sleep quality from 2 weeks into treatment throughout the follow-up, indicated by ISI scores and actigraphic variable SE (sleep efficiency). This greater improvement was also observed in the PSQI after 4 weeks of treatment throughout follow-up, as well as actigraphic variable TST (total sleep time), SSQoL and HADS scores at the end of treatment, and SSQoL and depression scores at follow-up. There was no significant difference between groups in the actigraphic variable SA (sleep awakenings). Adverse events were mild in severity, and their incidence was not significantly different between the two groups. CONCLUSION: Acupuncture appears to be efficacious, in terms of improving insomnia, related quality of life, and affective symptoms, for patients with ischemic stroke. TRIAL REGISTRATION NUMBER: ChiCTR-IIC-16008382 (Chinese Clinical Trial Registry).

Serum NLRP3 Inflammasome and BDNF: Potential Biomarkers Differentiating Reactive and Endogenous Depression.

Background: The highly heterogeneous pathogenesis of depression and limited response to current antidepressants call for more objective evidence for depression subtypes. Reactive and endogenous depression are two etiologically distinct subtypes associated with different treatment responses. This study aims to explore the potential biomarkers that differentiate reactive and endogenous depressions. Methods: The clinical manifestations and biological indicators of 64 unmedicated mild-to-moderate depression patients (32 reactive depression patients and 32 endogenous depression patients) and 21 healthy subjects were observed. The 24-item Hamilton rating scale for depression (HAMD-24) was used to evaluate the severity of depression. Serum levels of depression-related biological indicators were measured by using the enzyme-linked immunosorbent assay. Results: The NLRP3 level of reactive depression was significantly lower than those of endogenous depression and healthy controls. There was a significant negative correlation between the BDNF level and the HAMD-24 total scores for patients with reactive depression. Conclusion: Our findings suggested the serum NLRP3 and BDNF levels could be potential biomarkers for detecting and evaluating the severity of reactive depression.

Self-administered acupressure for insomnia disorder: A randomized controlled trial.

BACKGROUND: Insomnia is a significant health problem in the community. Self-administered acupressure (SAA) may be an alternative strategy to alleviate insomnia. PURPOSE: This study is the first to investigate the effects of SAA delivered through a training course in alleviating insomnia disorder compared with sleep hygiene education (SHE). METHODS: A randomized controlled trial was conducted on 200 participants with insomnia disorder. The eligible participants were randomized into the SAA or SHE group. Both groups attended the allocated training courses (two sessions, 2 h each) and then were followed up at weeks 4 and 8. The primary outcome was the severity of insomnia symptoms and related daytime impairment as measured by the Insomnia Severity Index (ISI). Other measures included a 7-day sleep diary and actigraphy, Hospital Anxiety and Depression Scale (HADS), and Short-Form Six-Dimension (SF6D). RESULTS: The SAA group showed a significantly greater improvement in ISI score than the SHE group at week 4 (mean difference: -1.89 units, 95% CI: 0.85, 2.93; Cohen's d = 0.51, p < 0.001) and week 8 (mean difference: -2.89 units, 95% CI: 1.67, 4.11; d = 0.67, p < 0.001). In addition, the SAA group showed a greater reduction in the HADS anxiety score and HADS depression score and increase in SF6D at week 8. CONCLUSIONS: SAA taught in a short training course is a feasible and effective approach to improve sleep and related daytime impairment and mood problems in individuals with insomnia disorder.

Granatin B and punicalagin from Chinese herbal medicine pomegranate peels elicit reactive oxygen species-mediated apoptosis and cell cycle arrest in colorectal cancer cells.

BACKGROUND: Colorectal cancer ranks among the most common cancers. 5-Fluorouracil (5-FU) based first-line chemotherapy for colorectal cancer treatment often leads to chemoresistance and gastrointestinal mucositis. PURPOSE: This study aimed to find potential therapeutic agents from herbal medicine with anti-colorectal cancer and anti-mucositis activities. METHODS: Chinese medicine theory, network pharmacology analyses, and antioxidant activity coupled with liquid chromatography tandem mass spectrometry analyses were used to identify potential bioactive compounds. HT-29 human colorectal cancer cell culture and xenograft tumor models were employed to study anti-colorectal cancer efficacy. Lipopolysaccharide-induced RAW 264.7 and 5-FU treated Dark Agouti rats were used to evaluate anti-inflammatory and anti-mucositis activities. Histological staining, immunofluorescence imaging, western blots, and flow cytometric analyses were employed to explore the underlying mechanisms. RESULTS: Both Chinese medicine theory and network pharmacology analyses indicated pomegranate peels as a potential anti-colorectal cancer and anti-mucositis agent. Antioxidant activity coupled with liquid chromatography tandem mass spectrometry analyses revealed granatin B and punicalagin as the most potent antioxidant compounds in pomegranate peels. Granatin B and punicalagin demonstrated superior anti-colorectal cancer activities in both cell culture and xenograft tumor models. Granatin B and punicalagin also exhibited strong anti-inflammatory activities in lipopolysaccharide-induced RAW264.7 cells and anti-mucositis activities in 5-FU-treated rats. Mechanistic studies revealed that granatin B and punicalagin induced reactive oxygen species-mediated S-phase cell cycle arrest and apoptosis in HT-29 cells. Moreover, these compounds sensitized HT-29 cells to 5-FU-induced cell death and S-phase cell cycle arrest. CONCLUSION: We report that granatin B and punicalagin exhibit superior anti-colorectal cancer and anti-mucositis activities. To the best of our knowledge, these results are novel and suggest that utilizing phenols from herbal medicine, such as granatin B and punicalagin, to target reactive oxygen species may be an innovative therapy to treat colorectal cancer and intestinal mucositis.

Randomized double-blind trial comparing low dose and conventional dose of a modified traditional herbal formula Guizhi Fuling Wan in women with symptomatic uterine fibroids.

ETHNOPHARMACOLOGICAL RELEVANCE: The herbal formula Guizhi Fuling Wan is one common remedy for treating uterine fibroids (UFs) and the relevant symptoms in Traditional Chinese Medicine (TCM). Previous systematic reviews showed that Guizhi Fuling Formula appeared to have additional benefit based on mifepristone treatment in reducing volume of fibroids. AIM OF STUDY: To study the efficacy and safety of the conventional dose of a modified herbal formula Guizhi Fuling Wan in patients with symptomatic uterine fibroids in comparison with a sub-effective dose control. MATERIALS AND METHODS: This randomized double-blind, dosage-controlled trial was carried out in an outpatient clinic of traditional Chinese medicine in Hong Kong. Women with symptomatic uterine fibroids diagnosed according to the WHO International Classification of Diseases (ICD-10) were recruited and randomly assigned to one of two groups that received modified Guizhi Fuling Wan at either a low dose or the conventional dose on a daily basis for 16 weeks. This study was quality controlled by a data safety monitoring board. The primary outcome was the symptom severity as measured with the Uterine Fibroid Symptom-Quality of Life questionnaire. The secondary outcomes included quality of life, menstrual bleeding (measured on a pictorial blood loss assessment chart), pain severity (measured on the 6-point behavioral rating scale), change in Chinese medicine syndrome score, fibroid volume (measured by magnetic resonance imaging), hemoglobin level, and hormone levels. RESULTS: Seventy-eight women were recruited for this study. Between-groups comparison showed no significant difference at the endpoint for all outcomes except for the Chinese medicine syndrome score; however, at the endpoint, within-group comparison showed significant improvement in both groups relative to baseline in symptom severity, functional influence of pelvic pain, Chinese medicine syndrome score, and fibroid volume and uterus condition on magnetic resonance imaging (p < 0.05).The low-dose group yielded greater endpoint improvement in the Chinese medicine syndrome score than the conventional-dose group (p=0.024). No serious adverse events related to the intervention were noted. CONCLUSION: Both low-dose and conventional-dose preparations significantly ameliorated uterine fibroid-related symptoms and fibroid volume, although no significant difference was found between the low-dose and conventional-dose groups. The herbal formula GuizhiFuling Wan is safe in women with uterine fibroids.

Adiponectin regulates electroacupuncture-produced analgesic effects in association with a crosstalk between the peripheral circulation and the spinal cord.

Neurotransmitter-mediated acupuncture analgesia has been widely studied in nervous systems. It remains largely unclear if peripheral substances are involved the acupuncture analgesia. Adiponectin (APN), a circulating adipokine, shows analgesic effects. The study aimed to examine whether APN regulates analgesic effects of electroacupuncture (EA) in the complete Freund's adjuvant (CFA)-induced mouse model. APN wild type (WT) and knockout (KO) mouse were employed in the study. We found that EA attenuates the CFA-induced pain as demonstrated by the Hargreaves thermal test and the von Frey filament test. The deletion of APN significantly reduced the acupuncture analgesia in the CFA-treated APN KO mice while the intrathecal administration of APN mimicked the analgesic effects of EA. We further revealed that EA produced analgesic effects mainly via APN/AdipoR2-mediated AMPK pathway by the siRNA inhibitions of APN receptors (adipoR1/2) in the spinal cord. The immunofluorescence staining analysis showed that EA increased the APN accumulation in spinal cord through the blood circulation. In conclusion, the study indicates a novel mechanism that acupuncture produces analgesic effects at least partially via APN/AdipoR2-AMPK pathway in the spinal cord.

Adjunctive berberine reduces antipsychotic-associated weight gain and metabolic syndrome in patients with schizophrenia: a randomized controlled trial.

AIM: The aim of this study was to evaluate the efficacy and safety of berberine as an adjuvant in treating antipsychotic-associated weight gain and metabolic syndrome. METHODS: One hundred thirteen participants with schizophrenia spectrum disorders who had developed metabolic syndrome were recruited. They were randomly assigned to berberine (600 mg/d, n = 58) or placebo (n = 55) groups for 12 weeks. The primary outcome was the change from baseline to week 12 in net weight. Secondary outcomes included body mass index, waist circumference, serum glucose and lipid profiles, and the severity of psychotic symptoms. RESULTS: Compared with the placebo group, the berberine group showed a significantly greater reduction in weight gain at 9 weeks (mean difference [MD], -0.75; 95% CI, -1.42 to -0.07 [P = 0.031, d = 0.41]) and 12 weeks (MD, -1.08; 95% CI, -1.76 to -0.40 [P = 0.002, d = 0.59]). Patients who received berberine also showed statistically significant improvements in end point in body mass index (MD, -0.41; 95% CI, -0.65 to -0.17 [P = 0.001, d = 0.64]), total cholesterol (MD, -0.58; 95% CI, -0.74 to -0.41 [P < 0.001, d = 1.31]), low-density lipoprotein (MD, -0.52; 95% CI, -0.68 to -0.35 [P < 0.001, d = 1.19]), and glycated hemoglobin (MD, -0.09; 95% CI, -0.18 to 0 [P = 0.05, d = 0.37]). Berberine was well tolerated without serious adverse events and aggravation of psychotic symptoms compared with placebo. CONCLUSION: The findings suggest that berberine is effective in attenuating antipsychotic-associated weight gain and metabolic syndrome.

Chinese Medicine for Coronavirus Disease 2019 (COVID-19): A GRADE-Assessed Systematic Review and Meta-Analysis.

Coronavirus disease 2019 (COVID-19) has caused enormous public health and socioeconomic burden globally. This study aims to evaluate the efficacy and safety of Chinese medicine (CM) against COVID-19. Eleven databases were searched on April 30, 2021, and 52 studies were included. The RoB 2.0, ROBINS-I, and GRADE tools were employed to assess the risks and evidence grades. The findings with moderate certainty in GRADE showed that compared with routine treatment (RT), Lianhua Qingwen granules (LHQW) adjunctive to RT showed significantly improved efficacy rate (relative risk (RR) = 1.19, 95% confidence interval (CI): [1.09, 1.31]), febrile score (standard mean difference (SMD) = -1.21, 95% CI: [-1.43, -0.99]), and computerized tomography (CT) lung images (RR = 1.23, 95% CI: [1.10, 1.38]); Qingfei Paidu decoction (QFPD) plus RT significantly shortened the length of hospital stay (SMD = -1.83, 95% CI: [-2.18, -1.48]); Feiyan Yihao formula (FYYH) plus RT significantly improved the clinical efficacy rate (RR = 1.07, 95% CI: [1, 1.15]), febrile time (SMD = -0.02, 95% CI: [-0.23, 0.19]), and time to negative PCR test for COVID-19 (SMD = -0.72, 95% CI: [-0.94, -0.51]). Adjunctive effects of CM with lower certainty of evidence were found, including the improvements of symptoms, laboratory findings, and mortality. No or mild adverse events were observed in most of the studies. In conclusion, the current evidence indicates that CM formulae, particularly LHQW, QFPD, and FYYH, have adjunctive effects on the standard treatment of COVID-19.

Multidimensional single-cell analysis of human peripheral blood reveals characteristic features of the immune system landscape in aging and frailty.

Frailty is an intermediate status of the human aging process, associated with decompensated homeostasis and death. The immune phenotype of frailty and its underlying cellular and molecular processes remain poorly understood. We profiled 114,467 immune cells from cord blood, young adults and healthy and frail old adults using single-cell RNA and TCR sequencing. Here we show an age-dependent accumulation of transcriptome heterogeneity and variability in immune cells. Characteristic transcription factors were identified in given cell types of specific age groups. Trajectory analysis revealed cells from non-frail and frail old adults often fall into distinct paths. Numerous TCR clonotypes were shared among T-cell subtypes in old adults, indicating differential pluripotency and resilience capabilities of aged T cells. A frailty-specific monocyte subset was identified with exclusively high expression of long noncoding RNAs NEAT1 and MALAT1. Our study discovers human frailty-specific immune cell characteristics based on the comprehensive dimensions in the immune landscape of aging and frailty.