Comparative efficacy of acupuncture point stimulation treatments for dialysis patients with uremic pruritus: a systematic review and network meta-analysis.

Background: Uremic pruritus (UP) is a common complication of chronic kidney disease that causes sleep disturbances and increases all-cause mortality. Currently, the first-line medications for UP exhibit inadequate pruritus control with adverse effects. Various acupuncture point stimulation treatments (APSTs) have been shown to be effective as adjuvant therapies in UP, and a network meta-analysis can offer relative efficacy estimates for treatments for which head-to-head studies have not been performed. Methods: We conducted a random-effects network meta-analysis on a consistency model to compare the different APSTs for UP. The primary outcomes were the mean visual analog scale (VAS) score and effectiveness rate (ER). Results: The network meta-analysis retrieved 27 randomized controlled trials involving 1969 patients. Compared with conventional treatment alone, combination treatment with acupuncture (mean difference, -2.63; 95% confidence interval, -3.71 to -1.55) was the most effective intervention in decreasing VAS scores, followed by acupoint injection and massage (mean difference, -2.04; 95% confidence interval, -3.96 to -0.12). In terms of the ER, conventional treatment with acupuncture and hemoperfusion (risk ratio, 14.87; 95% confidence interval, 2.18 to 101.53) was superior to other therapeutic combinations. Considering the VAS score and ER, combination treatment with acupoint injection and massage showed benefits in treating UP. Conclusion: Our network meta-analysis provided relative efficacy data for choosing the optimal adjuvant treatment for UP. Combined treatment with acupuncture was more effective than conventional treatment only and was the most promising intervention for treating UP.Systematic review registration: PROSPERO (CRD42023425739: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42023425739).

An Apriori algorithm-based association rule analysis to identify acupoint combinations for treating uremic pruritus.

Objective: Uremic pruritus (UP) is a prevalent and troublesome condition affecting individuals with end-stage renal failure, which results in intense pruritus, depression, as well as poor quality of sleep, significantly impacting their quality of life. According to previous studies, acupuncture and acupoint stimulation have been shown to provide additional benefits in treating UP in dialysis patients. In addition, using acupoints combination may yield superior effectiveness compared to utilizing a singular acupoint. To investigate the potential correlations between acupoint combinations, an association-rule analysis was employed. Materials and Methods: Apriori algorithms stand out as highly potent techniques for identifying associations in databases; this study utilized an association rule mining to examine the association rules of key acupoint groupings that could be employed for treating UP. Results: The analysis utilized information derived from the meta-analysis encompassing 40 randomized controlled trials that used acupuncture to treat UP. In total, 64 acupoints were analyzed, and 71 association rules were found. The following acupoint combinations: Auricular shenmen (TF4), Quchi (LI11), and Geshu (BL17); Auricular heart (Extra14), Sanyinjiao (SP6), and Auricular lung (CO14); and Auricular heart (Extra14), Xuehai (SP10), and Auricular lung (CO14) showed the strongest associations. Conclusion: Acupoints involving Auricular shenmen (TF4), Quchi (LI11), Geshu (BL17), Auricular heart (Extra14), Sanyinjiao (SP6), Auricular lung (CO14), and Xuehai (SP10) can be regarded as the core combination of acupuncture points for managing UP.

AMPK activation modulates IL-36-induced inflammatory responses by regulating IκBζ expression in the skin.

BACKGROUND AND PURPOSE: The interleukin (IL)-36 pathway is a critical player in the pathogenesis of pustular psoriasis. However, therapies targeting this pathway are limited or unaffordable (e.g. the anti-IL-36 receptor antibody). AMP-activated protein kinase (AMPK), a regulator of cellular energy and metabolism, is known to participate in inflammatory diseases. However, its role in IL-36-induced skin inflammation remains unclear. Therefore, we sought to investigate the role of AMPK signals in regulating IL-36-induced responses in the skin. EXPERIMENTAL APPROACH: IL-36-stimulated primary normal human epidermal keratinocytes (NHEKs) and IL-36-injected (intradermally) BALB/c mice served as the cell and animal models, respectively. Additionally, 5-aminoimidazole-4-carboxamide riboside (AICAR) and A769662 served as AMPK activators. KEY RESULTS: AICAR and A769662 significantly suppressed the IL-36-induced IL-8 (CXCL8) and CCL20 production from NHEKs. IL-36-induced IκBζ protein expression was prominently reduced and IKK/IκBα phosphorylation was attenuated by AICAR and A769662. Conversely, AMPKα knockdown increased IκBζ protein expression and IKK/IκBα phosphorylation in IL-36-treated NHEKs. Furthermore, AICAR and A769662 enhanced IL-36-induced-IκBζ protein degradation via the proteasome-dependent but not the lysosome-dependent pathway. Pretreatment of NHEKs with IL-36 slightly suppressed the AICAR- and A769662-triggered phosphorylation of AMPK and acetyl-CoA carboxylase. In the mouse model, topical application of AICAR significantly reduced ear swelling, redness, epidermal thickening, neutrophil infiltration and inflammatory and antimicrobial peptide gene expression. CONCLUSION AND IMPLICATIONS: AMPK activation suppresses IL-36-induced IL-8 and CCL20 release by regulating IκBζ expression in keratinocytes and reduces IL-36-induced skin inflammation in mice, suggesting that AMPK activation is a potential strategy for treating patients with IL-36-mediated inflammatory skin disorders.

Comparative efficacy of Chinese herbal medicines for dialysis patients with uremic pruritus: A systematic review and network meta-analysis.

Introduction: Uremic pruritus is common in dialysis patients and reduces their quality of life. Chinese herbal medicine has been effective in patients with this condition. Methods: We conducted a random-effects network meta-analysis to compare the efficacies of different Chinese herbal medicine treatments for uremic pruritus. Outcome measures including the overall effective rates, visual analog scale scores, C-reactive protein levels, and adverse drug reactions were analyzed. Results: The network meta-analysis retrieved 25 randomized controlled trials. Compared with conventional treatments alone, combination treatments with Xiao-Yang-Ke-Li was the most effective intervention in decreasing visual analog scale scores (mean difference -2.98, 95% mean difference -5.05 to -0.91) and levels of C-reactive protein (mean difference -5.01, 95% mean difference -7.27 to -2.75). Conventional treatment combined with Si-Wu Tang was superior to other therapeutic combinations when overall effective rates were determined. The best visual analog scale scores and overall effective rates were achieved by adjunctive treatment with the Touxie-Jiedu-Zhiyang decoction followed by uremic clearance granules; these treatments were the most beneficial for uremic pruritis. Conclusion: Our network meta-analysis provided the relative efficacies of different adjunctive Chinese herbal formulas. Adjunctive treatment with the Touxie-Jiedu-Zhiyang decoction was the best treatment for improving overall effective rates and reducing visual analog scores of uremic pruritus in dialysis patients. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=357656; Identifier: CRD42022357656.

Efficacy of acupoint stimulation as a treatment for uremic pruritus: A systematic review and meta-analysis.

Background: Uremic pruritus causes sleep disturbances, poor quality of life, and increased morbidity in patients with chronic kidney disease. Acupuncture has been shown to improve uremic pruritus. There is limited evidence of the efficacy of traditional Chinese therapies. We conducted a systematic review and meta-analysis to evaluate the efficacy of acupoint stimulation therapy in patients with uremic pruritus. Methods: A systematic search of seven databases (up to Sep 2022) was conducted for randomized controlled trials that evaluated the clinical efficacy of acupuncture, acupressure, auricular acupressure, acupoint injection, acupoint thermal therapy, acupoint sticking therapy, or transcutaneous electrical acupoint stimulation in the treatment of patients with uremic pruritus. Two reviewers selected eligible articles for inclusion in the meta-analysis and evaluated the risk of bias via Cochrane Collaboration. The results of pruritus assessments and uremic pruritus-related laboratory parameters were analyzed. Results: Forty trials published between 2002 and 2022, including a total of 2,735 participants, were identified for inclusion in the meta-analysis. The effective rates for acupuncture, auricular acupressure, and the combination of acupoint injection and acupoint massage were significantly greater in patients with uremic pruritus compared to the control group. The levels of serum BUN, PTH, and histamine levels were significantly lower vs. control group. Conclusions: Acupuncture, auricular acupressure, and the combination of acupoint injection and acupoint massage seem to be effective in improving uremic pruritus in patients with chronic kidney disease. However, further investigation of these potential treatments is now warranted in larger patient populations and over a longer time frame. Systematic review registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022354585, identifier: PROSPERO CRD42022354585.

Omega-3 fatty acids for uremic pruritus: A meta-analysis of randomized controlled trials.

Uremic pruritus (UP) is common in the late stages of chronic kidney disease. Currently, there is a lack of effective treatment for UP. Limited evidence exists on the therapeutic effect of omega-3 fatty acid (O3FA). The aim of this study was to evaluate the efficacy of O3FA supplements in UP patients. We evaluated the efficacy of O3FA supplements in patients with UP through a systematic review and a meta-analysis of randomized control trials retrieved from PubMed, Embase, Cochrane Library, CINAHL, and ClinicalTrials.gov databases. The included studies were summarized and assessed for the risk of bias, and pruritus assessment results were analyzed. To compared with a controlled group, five articles including 164 participants published between 2012 and 2019 using different pruritus scales reported that patients taking O3FA supplement exhibited no significant decrease in the pruritus score (standardized mean difference [SMD] =1.34, 95% confidence interval [CI] = -2.70-0.01, P = 0.05), but three articles using same pruritus scale significant decrease Duo pruritus score (SMD = -0.85, 95% CI = -1.39 to -0.30, P < 0.05). O3FA supplement could be an appealing complementary therapy for UP patients. More rigorously designed studies are needed before recommending the O3FA supplement.

Clinical Efficacy and Safety of Chinese Herbal Medicine in the Treatment of Uremic Pruritus: A Meta-Analysis of Randomized Controlled Trials.

Uremic pruritus is a disturbing and refractory symptom in patients with advanced chronic kidney disease. Chinese herbal medicine has been reported to alleviate uremic pruritus. To investigate the effects of Chinese herbal medicine, we conducted a systematic review and meta-analysis on patients with uremic pruritus. We searched databases (prior to 3 May 2022) for randomized controlled trials on the effects of Chinese herbal medicine in treating uremic pruritus. Our meta-analysis included 3311 patients from 50 randomized controlled trials. In patients with uremic pruritus, adjunctive Chinese herbal medicine significantly improved overall effectiveness (risk ratio 1.29, 95% CI 1.23 to 1.35), quality of life, renal function, reduced pruritus score, and inflammatory biomarkers compared to control groups with hemodialysis alone or with anti-pruritic treatments. Chinese herbal medicine treatment showed a time-dependent tendency in improving the visual analog scale of dialysis patients. Compared to control groups, no significantly higher risk of adverse events in patients taking Chinese herbal medicine (risk ratio 0.60, 95% CI 0.22 to 1.63). Chinese herbal medicine appears to be effective and safe in complementing the treatment of patients with uremic pruritus.

Thioredoxin-interacting protein regulates keratinocyte differentiation: Implication of its role in psoriasis.

Thioredoxin-interacting protein (TXNIP), also known as Vitamin-D upregulated protein-1 (VDUP-1), interacts with thioredoxin to regulate redox responses and participates in diverse disorders including metabolic, cardiovascular, inflammatory and malignant diseases. Psoriasis is characterized by chronic skin inflammation and an aberrant pattern of keratinocyte differentiation. Clinically, psoriasis is associated with various cardiometabolic comorbidities but studies on TXNIP's biological role in skin disorders are limited. In this study, we investigated TXNIP expression in psoriasis and its regulation in normal human epidermal keratinocytes (NHEKs), and then explored how TXNIP regulated skin keratinocyte differentiation to determine its role in psoriasis pathogenesis. Our immunohistochemical study demonstrated extensive TXNIP expression in the upper and lower epidermis of psoriasis compared to predominant TXNIP expression in the basal layer of normal skin. 1, 25-dihydroxyvitamin D3  suppressed but TGF-α and EGF enhanced TXNIP expression in NHEKs. An inducer of keratinocyte differentiation, phorbol 12-myristate 13-acetate (PMA), also diminished TXNIP expression, which was reversed by PKC-δ knockdown. TXNIP knockdown reduced PMA-induced involucrin and transglutaminse-1 expression, and increased p63 expression in NHEKs but did not significantly affect cell proliferation. H2 O2 -induced ROS production and EGFR phosphorylation decreased in NHEKs with TXNIP knockdown. Furthermore, PMA-induced PKC-δ phosphorylation, TGF-α, and EGF-triggered EGFR phosphorylation were attenuated by TXNIP knockdown. Our results unraveled the regulation and function of TXNIP expression in skin keratinocytes and the cross-regulation between TXNIP and EGFR signaling. These findings imply a role of TXNIP in psoriasis and provide insight into the possible impact of TXNIP regulators on the skin or psoriasis.

Spleen tyrosine kinase regulates keratinocyte inflammasome activation and skin inflammation induced by UVB irradiation.

UVB can induce inflammatory responses contributing to diverse skin damage. UVB-triggered inflammasome activation of human keratinocytes underlies UVB-induced skin sunburn reaction. Pleiotropic functions of spleen tyrosine kinase (Syk) have rendered it as a potential therapeutic target. In immunocytes, Syk modulates immunoreceptor signaling and NLRP3 inflammasome activation. In skin, Syk mediates EGFR signaling, regulates keratinocyte differentiation and is involved in inflammatory disorders. However, roles of Syk in UVB-induced inflammasome activation in keratinocytes remain elusive. We investigated roles of keratinocyte Syk in UVB-triggered photo-responses. Primary normal human epidermal keratinocytes (NHEKs) isolated from skin were used. Syk knockdown or Syk inhibitor R406 was applied to investigate functions of keratinocyte Syk in UVB photobiology. The possible in vivo role of Syk was evaluated by checking UVB-induced skin damage in R406-treated mice. UVB was able to induce Syk phosphorylation in NHEKs that could be regulated by reactive oxygen species (ROS) generation and EGFR. Syk knockdown or Syk inhibitor (R406) treatment reduced UVB-triggered apoptosis-associated speck-like protein containing a caspase-recruitment domain (ASC) crosslinking, procaspase-1 cleavage, active IL-1ß formation, and gasdermin D activation, indicating roles of Syk in UVB-triggered inflammasome activation in keratinocytes. UVB-induced production of IL-8, TNF-α, ROS, and phosphorylation of JNK and p38 were attenuated after Syk knockdown or inhibition. R406 ameliorated UVB-induced mouse skin damage, including erythema and transepidermal water loss (TEWL). Thus, Syk participated in UVB-induced inflammasome activation and inflammatory response in vitro and in vivo, suggesting potential photo-protective effects of Syk inhibition in UVB-induced skin inflammation.

Clinical Efficacy and Safety of Sodium Thiosulfate in the Treatment of Uremic Pruritus: A Meta-Analysis of Randomized Controlled Trials.

Uremic pruritus is a distressful complication of chronic kidney disease and results in impaired quality of life and higher mortality rates. Intravenous sodium thiosulfate has been reported to alleviate pruritus in hemodialysis patients. We performed a systematic review and meta-analysis to estimate the efficacy of intravenous sodium thiosulfate in patients with uremic pruritus. A systematic search of electronic databases up to June 2021 was conducted for randomized controlled trials that evaluated the clinical effects of sodium thiosulfate in the management of patients with uremic pruritus. Two reviewers selected eligible articles and evaluated the risk of bias; the results of pruritus assessment and uremic pruritus-related laboratory parameters in selected studies were analyzed. There are four trials published between 2018 and 2021, which include 222 participants. The sodium thiosulfate group displayed significant decrease in the pruritus score (standardized mean difference = -3.52, 95% confidence interval = -5.63 to -1.41, p = 0.001), without a significant increase in the adverse effects (risk ratio = 2.44, 95% confidence interval = 0.37 to 15.99, p = 0.35) compared to the control group. Administration of sodium thiosulfate is found to be a safe and efficacious complementary therapy in improving uremic pruritus in patients with chronic kidney disease.

Effects of Uremic Clearance Granules in Uremic Pruritus: A Meta-Analysis.

Uremic pruritus is common among patients with advanced or end-stage renal disease, with an incidence of >40% among patients on dialysis. Uremic clearance granules (UCGs) are effective in managing uremic pruritus and delay the progression of chronic kidney disease. We conducted a systematic review and a meta-analysis to evaluate the efficacy of UCG in patients with uremic pruritus. Several electronic databases were searched systematically from their inceptions until 19 July 2021. Randomized control trials evaluating the efficacy of UCG in patients with uremic pruritus were selected. Eleven trials including 894 participants were published between 2011 and 2021. Patients administered UCGs had a significantly decreased visual analog scale score (mean difference [MD], -2.02; 95% confidence interval [CI], -2.17 to -1.88), serum levels of hsCRP (MD, -2.07 mg/dL; 95% CI, -2.89 to -1.25; p < 0.00001), TNF-α (MD, -15.23 mg/L; 95% CI, -20.00 to -10.47; p < 0.00001]), ß2-MG (MD, -10.18 mg/L; 95% CI, -15.43 to -4.93; p < 0.00001), and IL-6 (MD, -6.13 mg/L; 95% CI, -7.42 to -4.84; p < 0.00001). In addition, UCGs significantly reduced serum levels of creatinine, BUN, PTH, iPTH, phosphorus, and the overall effectiveness rate. UCGs could be an attractive complementary therapy for patients with uremic pruritus.

An Apriori Algorithm-Based Association Rule Analysis to Identify Acupoint Combinations for Treating Diabetic Gastroparesis.

We explored the potential association rules within acupoints in treating diabetic gastroparesis (DGP) using Apriori algorithm complemented with another partition-based algorithm, a frequent pattern growth algorithm. Apriori algorithm is a data mining-based analysis that is widely applied in various fields, such as business and medicine, to mine frequent patterns in datasets. To search for effective acupoint combinations in the treatment of DGP, we implemented Apriori algorithm to investigate the association rules of acupoints among 17 randomized controlled trials (RCTs). The acupoints were extracted from the 17 included RCTs. In total, 29 distinct acupoints were observed in the RCTs. The top 10 frequently selected acupoints were CV12, ST36, PC6, ST25, BL21, BL20, BL23, SP6, BL18, and ST21. The frequency pattern of acupoints achieved by using a frequent pattern growth algorithm also confirms the result. The results showed that the most associated rules were {BL23, BL18} ≥ {SP6}, {BL20, BL18} ≥ {PC6}, {PC6, BL18} ≥ {BL20}, and {SP6, BL18} ≥ {BL23} in the database. Acupoints, including BL23, BL18, SP6, BL20, and PC6, can be deemed as core elements of acupoint combinations for treating DGP.

Galectin-3 regulates UVB-induced inflammation in skin.

BACKGROUND: Galectin-3 is widely expressed in many immunocytes and epithelial cells including skin keratinocytes. Galectin-3 can regulate immunological or inflammatory processes and plays a proinflammatory role in some disease models. Galectin-3 has a role in disorders related to ultraviolet (UV) photodamage such as apoptosis, skin squamous cell carcinoma and basal cell carcinoma. However, the evidence of galectin-3 in UVB-induced skin inflammation is still limited and the underlying molecular mechanism remains elusive. OBJECTIVE: We aimed to investigate the effects of galectin-3 in human epidermal keratinocytes and in mice after UVB irradiation. METHODS: Primary human epidermal keratinocytes with galectin-3 knockdown were used as the in vitro model. ELISA, QPCR, and western blotting were applied to evaluate the released cytokine, mRNA and protein expression. Histologic analysis, measurement of erythema and transepidermal water loss (TEWL) were applied to evaluate UVB-induced skin damage in galectin-3 knockout mice. RESULTS: In UVB-irradiated human keratinocytes, galectin-3 knockdown downregulated the UVB-induced ASC crosslinking, cleavage of caspase-1, and formation of active IL-1ß. Galectin-3 knockdown also decreased UVB-induced production of reactive oxygen species, p38 phosphorylation, and COX2 expression in human keratinocytes. After four days of UVB irradiation, galectin-3 knockout mice showed reduced gross erythema, histologic features of tissue inflammation, quantified levels of erythema and TEWL compared to wild type mice. The skin tissue lysate also showed less expression of active IL-1ß and COX2 in galectin-3 knockout mice. CONCLUSION: Galectin-3 may play a positive regulatory role in UVB-induced skin inflammation.

Stromal cell-derived factor-1alpha (SDF-1alpha/CXCL12)-enhanced angiogenesis of human basal cell carcinoma cells involves ERK1/2-NF-kappaB/interleukin-6 pathway.

Stromal cell-derived factor 1alpha (SDF-1alpha) (CXCL12) has been observed to enhance tumor angiogenesis. However, the comprehensive role of SDF-1alpha (CXCL12)-CXCR4 interaction, exerted during angiogenesis, has not been well understood. We have previously demonstrated that human basal cell carcinoma (BCC) tissues and a BCC cell line (BCC-1/KMC) had significant expression of CXCR4, whose level was higher in invasive than in the non-invasive BCC types. Here, we observed that human BCC tissues with high expression levels of CXCR4 had higher vascularity. Further, among the 71 BCCs diagnosed between the years 2004-2005, BCCs with high CXCR4 expression had concomitantly higher microvessel density, as compared with those with low CXCR4 expression (P < 0.001). We found that SDF-1alpha induced angiogenic activity in human BCC cells, both in vitro and in vivo. SDF-1alpha significantly upregulated several angiogenesis-associated genes such as interferon-alpha-inducible protein 27, interleukin (IL)-6, bone morphogenetic protein (BMP)-6, SOCS2 and cyclooxygenase 2 (COX)-2 in human BCC cells. Among them, IL-6 was the earliest and highest upregulated gene whose induction was observed within 6 h of the commencement of SDF-1alpha-CXCR4 interaction. The mechanisms behind the SDF-1alpha-induced time and dose-dependent upregulation of messenger RNA expression and protein secretion of IL-6 were investigated. The transcriptional regulation of IL-6 by SDF-1alpha was mediated by phosphorylation of extracellular signal-related kinase 1/2 and activation of the nuclear factor-kappaB complex. The identification of the angiogenic profiles induced through SDF-1alpha-CXCR4 interactions in human BCC cells may contribute further insights into the mechanisms involved in the angiogenic potential of SDF-1alpha (CXCL12).