Luteolin: A promising multifunctional natural flavonoid for human diseases.

Natural products are closely associated with human health. Luteolin (LUT), a flavonoid polyphenolic compound, is widely found in fruits, vegetables, flowers, and herbs. It is noteworthy that LUT exhibits a variety of beneficial pharmacological properties and holds significant potential for clinical applications, particularly in antitumor, anti-convulsion, diabetes control, anti-inflammatory, neuroprotection, anti-oxidation, anti-cardiovascular, and other aspects. The potential mechanism of action has been partially elucidated, including the mediation of NF-κB, toll-like receptor, MAPK, Wnt/ß-catenin, PI3K/Akt, AMPK/mTOR, and Nrf-2, among others. The review that aimed to comprehensively consolidate essential information on natural sources, pharmacological effects, therapeutic and preventive potential, as well as potential mechanisms of LUT. The objective is to establish a theoretical basis for the continued development and application of LUT.

Polyacetylenes from Saposhnikovia divaricata and their anticancer activity.

Nine polyacetylenes, including five new compounds named sadivaethynes E-I (1-5), were isolated from the roots of Saposhnikovia divaricata. Structural elucidation of compounds 1-5 was established by extensive spectroscopic analysis, quantum chemical calculations and DP4+ probability analysis. Among them, the absolute configuration of compound 1-2, 4-5 was unambiguous determined by ECD. Also, all compounds were evaluated for cytotoxicity against two human cancer cell lines (A549, HEPG2) in vitro, compound 9 showed moderate inhibitory effect with an IC50 value of 11.66 µM against HEPG2.

Seven new triterpenoids from the roots of Adenophora tetraphylla (Thub.) Fisch.

Seven new triterpenoids, named Adeterpenoids A-G (1-7) and eight known compounds (8-15), were isolated from 70% ethanol extract of the roots of Adenophora tetraphylla (Thub.) Fisch. The compounds from it were separated by column chromatography techniques such as silica gel, ODS, and preparative liquid chromatography. Their structures were clarified based on extensive spectral analysis (1D, 2D-NMR, HR-ESI-MS, IR, UV, and CD) and comparison with the literature. At the same time, all compounds were evaluated for their cytotoxic activity against the LN229 (human glioma cell line). The results showed that compounds 2, 5, 6, 13, and 14 had a significant inhibitory effect on LN229 cells.

Five new sesquiterpenoids isolated from Dictamnus dasycarpus Turcz.

Five new sesquiterpenoids, dictamtrinorguaianols E and F (1-2), and dictameudesmnosides F, G, and H (3-5), along with seven known sesquiterpenoids (6-12) were isolated from Dictamnus dasycarpus Turcz. The structures of all new compounds were characterized by spectroscopic methods, including UV, IR, HR-ESI-MS, and 1D and 2D NMR. The In-vitro anti-proliferative activities of all the compounds against two human cancer cell lines (SW982 and A549) were evaluated by CCK-8 assay. Compounds 1 and 4 showed medium anti-proliferative activity against SW982 cells, with IC50 values of 3.49 ± 0.10 and 6.42 ± 1.23 µM, respectively. Additionally, compounds 2, 7, and 8 exhibited medium anti-proliferative activity against A549 cells, with IC50 values ranging from 0.80 ± 0.05 to 6.60 ± 0.46 µM.

Syringa reticulata potently inhibits the activity of SARS-CoV-2 3CL protease.

The ongoing coronavirus infectious disease (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) still urgently requires effective treatments. The 3C-like (3CL) protease of SARS-CoV-2 is a highly conserved cysteine protease that plays an important role in the viral life cycle and host inflammation, providing an ideal target for developing broad-spectrum antiviral drugs. Herein, we describe the discovery of a large number of herbs mainly produced in Heilongjiang Province, China, that exhibited different inhibitory activities against SARS-CoV-2 3CL protease. We confirmed that Syringa reticulata, which is used for clinical treatment of chronic bronchitis and asthma, is a specific and potent inhibitor of 3CL protease. A 70 % ethanol extract of S. reticulata dose-dependently inhibited the cleavage activity of 3CL protease in a fluorescence resonance energy transfer assay with an IC50 value of 0.0018 mg/mL, but had minimal effect in pseudovirus-based cell entry and luciferase-based RNA-dependent RNA polymerase assays. These results suggest that S. reticulata will be a potential leading candidate for COVID-19 treatment.

Phenolic components from the fruits of Solanum xanthocarpum with anti-inflammatory activity.

Two new compounds (1 and 2), along with thirty-one known compounds (3-33) were isolated from the fruits of Solanum xanthocarpum. The structure of isolates was elucidated by analysis of spectroscopic data and the physicochemical methods. Meanwhile, the anti-inflammatory activity of isolates was determined using LPS-induced RAW 264.7 cells. The results of anti-inflammatory assays indicated that most isolated compounds (3, 4, 6, 8-14, 17-20, and 30) possessed significant nitric oxide (NO) production inhibition in lipopolysaccharide (LPS)-induced RAW 264.7 cells with IC50 values ranging from 14.33 to 48.55 µM.

Euchronin A-F isolated from the Arnebia euchroma (Royle) Johnst. and their anti-proliferative activities in vitro.

Six new naphthoquinones, euchronin A-F (1-6) and nine known naphthoquinones (7-15), were isolated from the roots of Arnebia euchroma (Royle) Johnst. The structures of the new compounds were confirmed by extensive spectroscopic analyses, including UV, IR, HR-ESI-MS, 1D and 2D NMR. In the present study, we estimated the anti-proliferative activities of these compounds with HaCaT cells. The results indicated that compounds 2 and 4 showed strong anti-proliferative activities at 25 µM, with relative viability at 38.83% and 68.44%, respectively.

Effects of Lianhuaqingwen Capsules in adults with mild-to-moderate coronavirus disease 2019: an international, multicenter, double-blind, randomized controlled trial.

BACKGROUND: In a randomized trial, Lianhuaqingwen (LHQW) capsule was effective for accelerating symptom recovery among patients with coronavirus disease 2019 (COVID-19). However, the lack of blinding and limited sample sizes decreased the level of clinical evidence. OBJECTIVES: To evaluate the efficacy and safety of LHQW capsule in adults with mild-to-moderate COVID-19. METHODS: We conducted a double-blind randomized controlled trial in adults with mild-to-moderate COVID-19 (17 sites from China, Thailand, Philippine and Vietnam). Patients received standard-of-care alone or plus LHQW capsules (4 capsules, thrice daily) for 14 days. The primary endpoint was the median time to sustained clinical improvement or resolution of nine major symptoms. RESULTS: The full-analysis set consisted of 410 patients in LHQW capsules and 405 in placebo group. LHQW significantly shortened the primary endpoint in the full-analysis set (4.0 vs. 6.7 days, hazards ratio: 1.63, 95% confidence interval: 1.39-1.90). LHQW capsules shortened the median time to sustained clinical improvement or resolution of stuffy or runny nose (2.8 vs. 3.7 days), sore throat (2.0 vs. 2.6 days), cough (3.2 vs. 4.9 days), feeling hot or feverish (1.0 vs. 1.3 days), low energy or tiredness (1.3 vs. 1.9 days), and myalgia (1.5 vs. 2.0 days). The duration to sustained clinical improvement or resolution of shortness of breath, headache, and chills or shivering did not differ significantly between the two groups. Safety was comparable between the two groups. No serious adverse events were reported. INTERPRETATION: LHQW capsules promote recovery of mild-to-moderate COVID-19 via accelerating symptom resolution and were well tolerated. Trial registration ChiCTR2200056727 .

Terpenoid compounds from the fruits of Solanum virginianum.

Eleven compounds were isolated and identified from ethanolic extracts of Solanum virginianum fruits, including two new compounds (1-2) and nine known compounds (3-11). Their structures were determined to be melongenaterpene C15-O-ß-D-glucopyranoside (1), (9Z)-3,7,11,15-tetramethyl -hexadeca-1,6,10-triene-3,5,14,15-tetraol-5-O-ß-D-glucopyranoside (2), actini-dioionoside A (3), byzantionoside B (4), citroside A (5), 7Z-roseoside (6), matenoside A (7), megastigmane (8), dihydrophaseic acid 3'-O-ß-D-glucopyranoside (9), taraxerol (10), and huzhangoside C (11). In this paper, NMR spectroscopy was used to study the structures of the compounds, comparing their data with those in the literature. In addition, the potential anti-inflammatory activity of the compounds was also evaluated using the RAW264.7 cell inflammation model induced by lipopolysaccharide (LPS). The terpenoids showed no significant anti-inflammatory activity.

Targeting Alpha-Ketoglutarate Disruption Overcomes Immunoevasion and Improves PD-1 Blockade Immunotherapy in Renal Cell Carcinoma.

The Warburg effect-related metabolic dysfunction of the tricarboxylic acid (TCA) cycle has emerged as a hallmark of various solid tumors, particularly renal cell carcinoma (RCC). RCC is characterized by high immune infiltration and thus recommended for immunotherapeutic interventions at an advanced stage in clinical guidelines. Nevertheless, limited benefits of immunotherapy have prompted investigations into underlying mechanisms, leading to the proposal of metabolic dysregulation-induced immunoevasion as a crucial contributor. In this study, a significant decrease is found in the abundance of alpha-ketoglutarate (αKG), a crucial intermediate metabolite in the TCA cycle, which is correlated with higher grades and a worse prognosis in clinical RCC samples. Elevated levels of αKG promote major histocompatibility complex-I (MHC-I) antigen processing and presentation, as well as the expression of ß2-microglobulin (B2M). While αKG modulates broad-spectrum demethylation activities of histone, the transcriptional upregulation of B2M is dependent on the demethylation of H3K4me1 in its promoter region. Furthermore, the combination of αKG supplementation and PD-1 blockade leads to improved therapeutic efficacy and prolongs survival in murine models when compared to monotherapy. Overall, the findings elucidate the mechanisms of immune evasion in anti-tumor immunotherapies and suggest a potential combinatorial treatment strategy in RCC.

Ginsenoside Rh2: A shining and potential natural product in the treatment of human nonmalignant and malignant diseases in the near future.

BACKGROUND: Ginseng is well-known as one of the most valuable and commonly used Chinese medicines not only in ancient China but also worldwide including East, Russia, Southeast Asia, North America and some Western European countries. Ginsenosides, as one of the main high active components of Ginseng, have various pharmacological activities, such as anti-inflammatory, antianaphylaxis, anti-depression, and anticancer activities. Ginsenoside Rh2 (Rh2), one of the major bioactive ginsenosides in Panax ginseng, also exhibits versatile pharmacological activities, such as increasing non-specific resistance and specific immune response, improving cardiac function and fibrosis, anti-inflammatory effects and antitumor effects, which may serve as an excellent medicinal potential. PURPOSE: As one of hundreds of ginsenosides being identified from ginseng, Rh2 exerts a markedly pharmacological effect on various diseases without severe toxicity, it has attracted many researchers 'attention. Although Rh2 plays important roles in some animal models and cell lines to simulate human diseases, its underlying molecular mechanisms have yet to be determined. During the past ten years, nearly 450 studies on Rh2 in the treatment of complex disease have been reported, however, up to now, no comprehensive reviews about the roles of Rh2 in animal models and cellular lines of human nonmalignant and malignant diseases have been conducted. METHOD: We searched articles on ginsenoside-related diseases from December 2010 to February 2023 in peer-reviewed and nonclinical databases, which include Web of Science, Scopus, PubMed, China national knowledge internet and Medline, and using the following keywords: Ginsenoside Rh2, Human diseases, Cancer, Mechanisms, Chinese herbal medicine, Natural products and Signaling pathway. RESULTS: Therefore, in this review, we make a comprehensive summary on the roles of Rh2 and support the potential mechanisms of Rh2 according to the disease classification, including nonmalignant disease such as ulcerative colitis, neuropathic pain, Asthma, myocardial injury, depression and malignant disease such as breast cancer, colorectal cancer, hepatocellular carcinoma and gastric cancer. Finally, the combination therapy of Rh2 and other medications in human diseases are summarized, apart from that, there are other problems such as the bioavailability of oral administration Rh2 to be overcome in following research. CONCLUSION: These findings provide strong evidence that Ginsenoside Rh2 plays important roles in the treatment of nonmalignant and malignant diseases.

Fu's Subcutaneous Needling for Knee Osteoarthritis Pain.

Fu's subcutaneous needling (FSN) is a new acupuncture and dry needling technique based on traditional Chinese medicine. It rapidly produces long-lasting effects in soft tissue injuries, particularly in painful musculoskeletal conditions, by providing stimulation primarily in the subcutaneous area. Osteoarthritis (OA) is the most common joint disease in adults worldwide and is often accompanied by a painful syndrome of structural changes in the peripheral joints of the knee. However, the etiology of OA pain is not fully understood, though myofascial trigger points (MTrPs) are commonly found in the lower limb muscles (so-called "tightened muscles") of patients with knee OA. FSN has been used in many fields for the treatment of acute pain problems and can relieve muscle contraction from MTrPs, thereby improving the local circulation. This study recruited patients with pain from knee OA into an FSN group or a transcutaneous electrical nerve stimulation (TENS) group with three treatment sessions and a follow-up over the course of 2 weeks. The results showed that FSN was effective in treating soft tissue pain around the knee with OA. This study aimed to establish and visualize three key technical indicators during FSN therapy, including the FSN needle insertion point and layer; the frequency and duration of the swaying movement; and the manipulation of the reperfusion approach. These findings have great potential for future applications in myofascial pain treatment, especially for pain management. Following this protocol could enhance FSN skills.

UHPLC-Orbitrap-Fusion-TMS-Based Metabolomics Study of Phenylpropionamides in the Seed of Cannabis sativa L. against Alzheimer's Disease.

Phenylpropionamides in the seed of Cannabis sativa L. (PHS) have a protective effect on neuroinflammation and antioxidant activity. In this study, the UHPLC-Orbitrap-fusion-TMS-based metabolomics approach was used to analyze the serum samples and identify potential biomarkers in Streptozotocin (STZ) induced Alzheimer's disease (AD) rats. The results revealed that primary bile acid biosynthesis and taurine and hypotaurine metabolism were significantly correlated with STZ-induced AD rats. In addition, the key enzymes in these two pathways were verified at the protein level. The levels of cysteine dioxygenase type I (CDO1), cysteine sulfinic acid decarboxylase (CSAD), cysteamine (2-aminoethanethiol) dioxygenase (ADO), 7α-hydroxylase (CYP7A1), and sterol 12α-hydroxylase (CYP8B1) were the key enzymes affecting the two pathways in AD rats compared with the control group (CON). Furthermore, after a high-dose group of phenylpropionamides in the seed of Cannabis sativa L. (PHS-H) was administrated, the levels of CDO1, CSAD, CYP7A1, and CYP8B1 were all callback. These findings demonstrate for the first time that the anti-AD effect of PHS is associated with the regulation of primary bile acid biosynthesis and taurine and hypotaurine metabolism in STZ-induced AD rats.

New chromones from the roots of Saposhnikovia divaricata (Turcz.) Schischk with anti-inflammatory activity.

Fifteen new chromones, sadivamones A-E (1-5), cimifugin monoacetate (6), sadivamones F-N (7-15), together with fifteen known chromones (16-30), were isolated from the ethyl acetate portions of 70% ethanol extract of Saposhnikovia divaricata (Turcz.) Schischk roots. The structures of the isolates were determined using 1D/2D NMR data and electron circular dichroism (ECD) calculations. Meanwhile, LPS induced RAW264.7 inflammatory cell model was used to determine the potential anti-inflammatory activity of all the isolated compounds in vitro. The results showed that compounds 2, 8, 12-13, 18, 20-22, 24, and 27 significantly inhibited the production of lipopolysaccharide (LPS)-induced NO in macrophages. To determine the signaling pathways involved in the suppression of NO production by compounds 8, 12 and 13, we investigated ERK and c-Jun N-terminal protein kinase (JNK) expression by western blot analysis. Further mechanistic studies demonstrated that compounds 12 and 13 inhibited the phosphorylation of ERK and the activation of ERK and JNK signaling in RAW264.7 cells via MAPK signaling pathways. Taken together, compounds 12 and 13 may be valuable candidates for the treatment of inflammatory diseases.

ntrC Contributes to Nitrogen Utilization, Stress Tolerance, and Virulence in Acidovorax citrulli.

Bacterial fruit blotch (BFB), caused by Acidovorax citrulli, severely damages watermelon, melon, and other cucurbit crops worldwide. Nitrogen, one of the most important limiting elements in the environment, is necessary for the growth and reproduction of bacteria. As a nitrogen-regulating gene, ntrC plays an important role in maintaining bacterial nitrogen utilization and biological nitrogen fixation. However, the role of ntrC has not been determined for A. citrulli. In this study, we constructed a ntrC deletion mutant and a corresponding complementary strain in the background of the A. citrulli wild-type strain, Aac5. Through phenotype assays and qRT-PCR analysis, we investigated the role of ntrC in A. citrulli in nitrogen utilization, stress tolerance, and virulence against watermelon seedlings. Our results showed that the A. citrulli Aac5 ntrC deletion mutant lost the ability to utilize nitrate. The ntrC mutant strain also exhibited significantly decreased virulence, in vitro growth, in vivo colonization ability, swimming motility, and twitching motility. In contrast, it displayed significantly enhanced biofilm formation and tolerance to stress induced by oxygen, high salt, and copper ions. The qRT-PCR results showed that the nitrate utilization gene nasS; the Type III secretion system-related genes hrpE, hrpX, and hrcJ; and the pili-related gene pilA were significantly downregulated in the ntrC deletion mutant. The nitrate utilization gene nasT, and the flagellum-related genes flhD, flhC, fliA, and fliC were significantly upregulated in the ntrC deletion mutant. The expression levels of ntrC gene in the MMX-q and XVM2 media were significantly higher than in the KB medium. These results suggest that the ntrC gene plays a pivotal role in the nitrogen utilization, stress tolerance, and virulence of A. citrulli.

Phenylpropanoids from Solanum capsicoides and their anti-inflammatory activity.

Two new phenylpropanoids, 4-O-(1''-O-cis-caffeoyl)-ß-glucopyran osyl-1-allyl-3-methoxy-benzene (1), 4'-O-(1''-O-cis-caffeoyl)-ß-glucopyranosyl-hydroxymegastigm-4-en-3-one (2), together with nine known compounds were obtained from the leaves of Solanum capsicoides. Their structures were elucidated based on spectroscopic methods, and comparing spectral data with those in literature. Meanwhile, their anti-inflammatory activities were evaluated on (LPS)-induced RAW 246.7 cells, and 1, 9, and 10 showed better inhibitory effects with IC50 values of 17.19 ± 1.12, 18.15 ± 0.47, and 19.8 ± 0.95 µM, respectively.

Exploring the common mechanism of Yindan Xinnaotong soft capsule in the treatment of stroke and coronary heart disease through HIF1α-MMP9-mediated HIF1α signaling pathway / 药学学报

Coronary heart disease (CHD) and stroke are the most well-known cardiovascular diseases, which share many common pathological basis. Yindan Xinnaotong soft capsule (YDXNT) is a commonly used Chinese patent medicine in the treatment of stroke and CHD. However, its action of mechanism of co-treatment for stroke and CHD is still unclear. The aim of this study was to explore the common mechanism of YDXNT in co-treatment of CHD and stroke using network pharmacology, experimental verification and molecular docking. An integrated literature mining and databases of IPA, ETCM, HERB, Swiss Target Prediction, OMIM and GeneCards were used to screen and predict active ingredients and potential targets of YDXNT in co-treatment of CHD and stroke. The protein-protein interaction network, GO analysis and pathway analysis were analyzed by IPA software. The effect of YDXNT on core targets was verified by immunofluorescence. UPLC-QTOF/MS and molecular docking were used to screen and predict the main active constituents of YDXNT and their interactions with core targets. A total of 151 potential targets are predicted for YDXNT in co-treatment of CHD and stroke. Hypoxia-inducible factor-1α (HIF1α)-matrix metalloproteinase-9 (MMP9)-mediated HIF1α signaling pathway serves as one of the common mechanisms. YDXNT could reduce the increase of mitochondrial fluorescence intensity and the protein expression of HIF1α and MMP9 in HL-1 and HA induced by oxygen and glucose deprivation/reperfusion (OGD/R) in a dose-dependent manner. Baicalin may be the material basis for treating stroke and CHD with YDXNT. In conclusion, the HIF1α signaling pathway is one of the common key mechanisms of YDXNT in the co-treatment of stroke and CHD. The study provides support and basis for the in-depth scientific connotation of the traditional Chinese medicine theory of "same treatment to different diseases".

Efficacy of Fu's Subcutaneous Needling in Treating Soft Tissue Pain of Knee Osteoarthritis: A Randomized Clinical Trial.

Purpose: Fu's subcutaneous needling (FSN) is a new acupuncture technique that produces a long-lasting effect in soft-tissue injuries. In patients with degenerative knee osteoarthritis (OA), myofascial trigger points (MTrPs) are common in the lower-limb muscles. In this randomized clinical trial, we evaluated the immediate, 1-week and 2-week effectiveness of FSN therapy in the treatment of degenerative knee OA. Patients and methods: We randomly divided 32 patients with knee OA into the FSN group (mean age: 65.73 ± 6.79 years) or the transcutaneous electrical nerve stimulation (TENS) group (mean age: 62.81 ± 5.72 years). The pressure pain threshold (PPT) and tissue hardness (TH) of the muscle and tendon attachment sites, knee range of motion, and physical ability (average walking speed) were measured. The subjective pain intensity index, Western Ontario and McMaster Universities OA Index (WOMAC), and Lequesne index were used to determine the efficacy of FSN on MTrP-induced soft-tissue pain compared with that of TENS. Results: A significantly greater improvement in pain qualities in the VAS (p < 0.05) was found in the FSN group. Moreover, in muscle and tendon qualities (including PPT and TH), a significant difference in the PPT of the quadriceps muscle (p < 0.05) was also observed among the immediate treatments in the FSN group. As for the functional index questionnaire assessment, the FSN group exhibited significant improvements among the immediate, 1-week and 2-week efficacies in terms of WOMAC (p < 0.05) and Lequesne index scores (p < 0.05). Conclusion: FSN was effective in treating soft-tissue pain in degenerative knee OA in terms of alleviating pain, strengthening walking ability, and improving overall functional performance. Pain relief was the primary benefit of FSN and a significant correlation between pain relief and knee joint mobility improvement was found. Trial registration: ClinicalTrials.gov Protocol Registration and Results System (registration number: NCT04356651).

Mantuoluosides A-H, new steroids isolated from the leaves of Datura stramonium L.

Eight new steroids, designated mantuoluosides A-H (1-8), were obtained from the enrichment of steroids of the Datura stramonium L. using HPD-BJQH macroporous resin. Their respective structures were elucidated based on spectroscopic methods and comparison data with literature. The anti-inflammatory activities of these compounds were evaluated on (LPS)-induced RAW264.7 cells with inhibition ratio. It was found that most isolates showed potential anti-inflammatory activity with varying degrees of inhibition rate in a concentration-dependent manner at non-cytotoxic concentrations.

Efficacy and Tolerability of Cranial Electrotherapy Stimulation in the Treatment of Anxiety: A Systemic Review and Meta-Analysis.

Objective: We aimed to investigate the efficacy and tolerability of cranial electrotherapy stimulation (CES) for patients with anxiety symptoms. Method: We searched the Pubmed, Cochrane Central Register of Controlled Trials (CENTRAL), Embase and Medline for randomized control trials (RCTs) from the time of inception until November 15, 2021, following Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. Data were pooled using a random-effects model. The primary outcomes were the mean change scores for anxiety symptoms. The secondary outcomes were the mean change scores for depressive symptoms. Results: Eleven RCTs were eligible (n = 794, mean age: 41.4, mean population of female: 64.8%). CES significantly reduced the anxiety symptoms compared to the control group [k = 11, n = 692, Hedge's g = -0.625, 95% confidence intervals (CIs) = -0.952 to -0.298, P < 0.001] with moderate effect size. The subgroup analysis showed that CES reduced both primary and secondary anxiety (primary anxiety, k =3, n = 288, Hedges' g = -1.218, 95% CIs = -1.418 to -0.968, P = 0.007; secondary anxiety, k = 8, n = 504, Hedges' g = -0.334, 95% CIs = -0.570 to -0.098, P = 0.006). After performing between group analysis, we found CES has significant better efficacy for patients with primary anxiety than those with secondary anxiety (P < 0.001). For secondary outcome, CES significantly reduced depressive symptoms in patients with anxiety disorders (k = 8, n = 552, Hedges' g = -0.648, 95% CIs = -1.062 to -0.234, P = 0.002). No severe side effects were reported and the most commonly reported adverse events were ear discomfort and ear pain. Conclusion: We found CES is effective in reducing anxiety symptoms with moderate effect size in patients with both primary and secondary anxiety. Furthermore, CES was well-tolerated and acceptable.Systematic Review Registration: PROSPERO, https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021267916.