Based on the traditional Chinese medicine （TCM） theories of body fluid metabolism and turbid phlegm obstructing the orifices， and drawing on recent advances in cerebrospinal fluid-interstitial fluid （CSF-ISF） exchange， glymphatic clearance， and extracellular matrix （ECM） regulation， this article discusses the possible scientific connotation of "invisible phlegm" from the perspectives of pathogenesis， clinical manifestations， and therapeutic implications. Impaired brain fluid exchange may lead to reduced clearance， the retention of metabolic wastes and pathological proteins. Abnormal ECM remodeling may further disrupt molecular diffusion and local microenvironmental homeostasis， resulting in a pathological process characterized by slowed fluid movement， reduced clearance， and abnormal retention. This process bears a certain functional resemblance to the TCM pathogenesis of impaired distribution of body fluids， endogenous formation of turbid phlegm and obstruction of the brain orifices， and may also be associated with manifestations such as a clouded sensation in the head， cognitive abnormalities， and emotional disturbances. On this basis， the potential effects of certain phlegm-dissolving Chinese medicines in improving brain clearance function and extracellular microenvironmental homeostasis warrant further investigation. We therefore propose that， the "invisible phlegm" of TCM in brain tissue may manifest as a pathological retention state characterized by restricted fluid exchange， impaired clearance function， and extracellular microenvironmental imbalance. This perspective may provide a new avenue for investigating TCM treatment of neurological and psychiatric disorders from the perspective of phlegm.

Based on the traditional Chinese medicine （TCM） theories of body fluid metabolism and turbid phlegm obstructing the orifices， and drawing on recent advances in cerebrospinal fluid-interstitial fluid （CSF-ISF） exchange， glymphatic clearance， and extracellular matrix （ECM） regulation， this article discusses the possible scientific connotation of "invisible phlegm" from the perspectives of pathogenesis， clinical manifestations， and therapeutic implications. Impaired brain fluid exchange may lead to reduced clearance， the retention of metabolic wastes and pathological proteins. Abnormal ECM remodeling may further disrupt molecular diffusion and local microenvironmental homeostasis， resulting in a pathological process characterized by slowed fluid movement， reduced clearance， and abnormal retention. This process bears a certain functional resemblance to the TCM pathogenesis of impaired distribution of body fluids， endogenous formation of turbid phlegm and obstruction of the brain orifices， and may also be associated with manifestations such as a clouded sensation in the head， cognitive abnormalities， and emotional disturbances. On this basis， the potential effects of certain phlegm-dissolving Chinese medicines in improving brain clearance function and extracellular microenvironmental homeostasis warrant further investigation. We therefore propose that， the "invisible phlegm" of TCM in brain tissue may manifest as a pathological retention state characterized by restricted fluid exchange， impaired clearance function， and extracellular microenvironmental imbalance. This perspective may provide a new avenue for investigating TCM treatment of neurological and psychiatric disorders from the perspective of phlegm.

Metabolic dysfunction-associated fatty liver disease （MAFLD） is the most prevalent chronic liver disease worldwide， with a complex pathogenesis. Mitochondria play a pivotal role in this disease process， and studies have confirmed that mitochondrial dysfunction can exacerbate metabolic disorders and induce innate immune imbalance， while mitochondrial DNA （mtDNA） is the core molecule mediating these two pathological effects. After the abnormal release of mtDNA， it can be recognized by intracellular pattern recognition receptors， which in turn triggers innate immune responses and causes tissue damage， forming a pathological pathway of “mtDNA release-immune activation-tissue damage”. Currently， there is a lack of systematic reviews summarizing the mechanism of action of this pathway in different stages of MAFLD and the intervention strategies targeting this pathway. This article systematically reviews the core molecular mechanism of this pathway， its pathological role in the development and progression of MAFLD， and the current intervention strategies targeting this mechanism， in order to provide a theoretical basis for analyzing the pathogenesis of MAFLD and developing novel therapeutic strategies.

ObjectiveTo investigate the therapeutic effect of paeoniflorin on metabolic dysfunction-associated fatty liver disease （MASLD） combined with insulin resistance （IR）， and to elucidate its regulatory mechanisms on the Toll-like receptor 4 （TLR4）/nuclear transcription factor （NF）-κB-insulin receptor substrate 1 （IRS1） inflammation-insulin signaling axis. MethodsMASLD mouse model was established using a 60% high-fat diet. Mice were randomly assigned to a normal control group， a MASLD model group， and paeoniflorin groups （low dose： 25 mg·kg^-1·d^-1， medium dose： 50 mg·kg^-1·d^-1， high dose： 100 mg·kg^-1·d^-1）， receiving intragastric administration for consecutive 12 weeks. Concurrently， a palmitic acid/oleic acid （PA/OA）-induced lipid deposition model was established in HepG2 cells. Cell counting kit-8 （CCK-8） assay was performed to determine the optimal concentrations of PA/OA and paeoniflorin for intervention. Mice body weight， liver index， and serum levels of alanine aminotransferase （ALT）， aspartate aminotransferase （AST）， triglycerides （TG）， and total cholesterol （TC） were measured. Fasting blood glucose （FBG） and fasting insulin （FINS） levels were measured， and the homeostatic model assessment of insulin resistance （HOMA-IR） was calculated， while an oral glucose tolerance test （OGTT） was performed to evaluate glucose metabolism. Hematoxylin and eosin （HE） staining was used to observe pathological changes and inflammatory cell infiltration in liver tissue， and oil red O staining was used to evaluate lipid droplet deposition in liver tissue and HepG2 cells. Potential targets were screened using network pharmacology and molecular docking. Western blot analysis was performed to detect the expression of HSP90AA1， TLR4， p-NF-κB p65， p-IRS1， and p-Akt proteins in liver tissue and HepG2 cells. ResultsCompared with the normal control group， mice in the MASLD model group exhibited significantly increased body weight， liver index， and serum levels of ALT， AST， TG， and TC， as well as markedly elevated FBG， FINS， and HOMA-IR， and impaired glucose tolerance （P<0.01）. HE staining revealed marked hepatic steatosis and inflammatory cell infiltration， while oil red O staining showed a significant increase in lipid droplet deposition. Compared with the MASLD model group， after intervention with various doses of paeoniflorin， the increase in body weight and liver index was reduced， serum ALT， AST， TG， and TC levels decreased， and FBG， FINS， and HOMA-IR were significantly lowered， with glucose tolerance markedly improved （P<0.05， P<0.01）， showing a certain dose-dependent trend. HE and oil red O staining results showed a marked reduction in hepatic steatosis and lipid deposition. In vitro experiments demonstrated that， compared with the control group， PA/OA treatment significantly induced increased lipid deposition in HepG2 cells. Compared with the model group， paeoniflorin intervention significantly reduced intracellular lipid droplets， and lipid deposition showed a dose-dependent decreasing trend. Mechanism studies indicated that， compared with the normal control group， the MASLD model group exhibited significantly elevated expression of TLR4， HSP90AA1， and p-NF-κB p65， while p-IRS1 （Ser307） expression was elevated and p-Akt （Ser473） expression was reduced （P<0.01）. Compared with the model group， the expression of the aforementioned proteins was significantly reversed in all treatment groups following intervention （P<0.05， P<0.01）. ConclusionPaeoniflorin significantly alleviates lipid deposition and insulin resistance in MASLD mice. Its mechanism of action may involve targeting HSP90AA1， TLR4， and NF-κB1 to regulate the TLR4/NF-κB-IRS1 inflammation-insulin signaling axis. This regulation suppresses inflammatory responses and restores insulin signaling， thereby ameliorating abnormalities in glucose and lipid metabolism.

ObjectiveTo investigate the therapeutic effect of paeoniflorin on metabolic dysfunction-associated fatty liver disease （MASLD） combined with insulin resistance （IR）， and to elucidate its regulatory mechanisms on the Toll-like receptor 4 （TLR4）/nuclear transcription factor （NF）-κB-insulin receptor substrate 1 （IRS1） inflammation-insulin signaling axis. MethodsMASLD mouse model was established using a 60% high-fat diet. Mice were randomly assigned to a normal control group， a MASLD model group， and paeoniflorin groups （low dose： 25 mg·kg^-1·d^-1， medium dose： 50 mg·kg^-1·d^-1， high dose： 100 mg·kg^-1·d^-1）， receiving intragastric administration for consecutive 12 weeks. Concurrently， a palmitic acid/oleic acid （PA/OA）-induced lipid deposition model was established in HepG2 cells. Cell counting kit-8 （CCK-8） assay was performed to determine the optimal concentrations of PA/OA and paeoniflorin for intervention. Mice body weight， liver index， and serum levels of alanine aminotransferase （ALT）， aspartate aminotransferase （AST）， triglycerides （TG）， and total cholesterol （TC） were measured. Fasting blood glucose （FBG） and fasting insulin （FINS） levels were measured， and the homeostatic model assessment of insulin resistance （HOMA-IR） was calculated， while an oral glucose tolerance test （OGTT） was performed to evaluate glucose metabolism. Hematoxylin and eosin （HE） staining was used to observe pathological changes and inflammatory cell infiltration in liver tissue， and oil red O staining was used to evaluate lipid droplet deposition in liver tissue and HepG2 cells. Potential targets were screened using network pharmacology and molecular docking. Western blot analysis was performed to detect the expression of HSP90AA1， TLR4， p-NF-κB p65， p-IRS1， and p-Akt proteins in liver tissue and HepG2 cells. ResultsCompared with the normal control group， mice in the MASLD model group exhibited significantly increased body weight， liver index， and serum levels of ALT， AST， TG， and TC， as well as markedly elevated FBG， FINS， and HOMA-IR， and impaired glucose tolerance （P<0.01）. HE staining revealed marked hepatic steatosis and inflammatory cell infiltration， while oil red O staining showed a significant increase in lipid droplet deposition. Compared with the MASLD model group， after intervention with various doses of paeoniflorin， the increase in body weight and liver index was reduced， serum ALT， AST， TG， and TC levels decreased， and FBG， FINS， and HOMA-IR were significantly lowered， with glucose tolerance markedly improved （P<0.05， P<0.01）， showing a certain dose-dependent trend. HE and oil red O staining results showed a marked reduction in hepatic steatosis and lipid deposition. In vitro experiments demonstrated that， compared with the control group， PA/OA treatment significantly induced increased lipid deposition in HepG2 cells. Compared with the model group， paeoniflorin intervention significantly reduced intracellular lipid droplets， and lipid deposition showed a dose-dependent decreasing trend. Mechanism studies indicated that， compared with the normal control group， the MASLD model group exhibited significantly elevated expression of TLR4， HSP90AA1， and p-NF-κB p65， while p-IRS1 （Ser307） expression was elevated and p-Akt （Ser473） expression was reduced （P<0.01）. Compared with the model group， the expression of the aforementioned proteins was significantly reversed in all treatment groups following intervention （P<0.05， P<0.01）. ConclusionPaeoniflorin significantly alleviates lipid deposition and insulin resistance in MASLD mice. Its mechanism of action may involve targeting HSP90AA1， TLR4， and NF-κB1 to regulate the TLR4/NF-κB-IRS1 inflammation-insulin signaling axis. This regulation suppresses inflammatory responses and restores insulin signaling， thereby ameliorating abnormalities in glucose and lipid metabolism.

To evaluate long-term survival and clinical outcomes of patients with knee osteo-arthritis undergoing total knee arthroplasty (TKA) through long-term follow-up.

To analyze the occurrence of early complications after total hip arthroplasty (THA) in patients with systemic lupus erythematosus (SLE).

BACKGROUND: The optimal antidepressant dosages remain controversial. This study aimed to analyze the efficacy of antidepressants and characterize their dose-response relationships in the treatments of major depressive disorders (MDD). METHODS: We searched multiple databases, including the Embase, Cochrane Central Register of Controlled Trials, PubMed, and Web of Science, for the studies that were conducted between January 8, 2016, and April 30, 2023. The studies are double-blinded, randomized controlled trials (RCTs) involving the adults (≥18 years) with MDD. The primary outcomes were efficacy of antidepressant and the dose-response relationships. A frequentist network meta-analysis was conducted, treating participants with various dosages of the same antidepressant as a single therapy. We also implemented the model-based meta-analysis (MBMA) using a Bayesian method to explore the dose-response relationships. RESULTS: The network meta-analysis comprised 135,180 participants from 602 studies. All the antidepressants were more effective than the placebo; toludesvenlafaxine had the highest odds ratio (OR) of 4.52 (95% confidence interval [CI]: 2.65-7.72), and reboxetine had the lowest OR of 1.34 (95%CI: 1.14-1.57). Moreover, amitriptyline, clomipramine, and reboxetine showed a linear increase in effect size from low to high doses. The effect size of toludesvenlafaxine increased significantly up to 80 mg/day and subsequently maintained the maximal dose up to 160 mg/day while the predictive curves of nefazodone were fairly flat in different dosages. CONCLUSIONS: Although most antidepressants were more efficacious than placebo in treating MDD, no consistent dose-response relationship between any antidepressants was observed. For most antidepressants, the maximum efficacy was achieved at lower or middle prescribed doses, rather than at the upper limit. REGISTRATION No. CRD42023427480; https://www.crd.york.ac.uk/prospero/display_record.php?
Humans ; Antidepressive Agents/therapeutic use* ; Depressive Disorder, Major/drug therapy* ; Dose-Response Relationship, Drug ; Randomized Controlled Trials as Topic

[This corrects the article DOI: 10.1016/j.apsb.2021.07.024.].

Neuropathic pain is frequently comorbidity with cognitive deficits. Neuralized1 (Neurl1)-mediated ubiquitination of CPEB3 in the hippocampus is critical in learning and memory. However, the role of Neurl1 in the cognitive impairment in neuropathic pain remains elusive. Herein, we found that lumbar 5 spinal nerve ligation (SNL) in male rat-induced neuropathic pain was followed by learning and memory deficits and LTP impairment in the hippocampus. The Neurl1 expression in the hippocampal CA1 was decreased after SNL. And this decrease paralleled the reduction of ubiquitinated-CPEB3 level and reduced production of GluA1 and GluA2. Overexpression of Neurl1 in the CA1 rescued cognitive deficits and LTP impairment, and reversed the reduction of ubiquitinated-CPEB3 level and the decrease of GluA1 and GluA2 production following SNL. Specific knockdown of Neurl1 or CPEB3 in bilateral hippocampal CA1 in naïve rats resulted in cognitive deficits and impairment of synaptic plasticity. The rescued cognitive function and synaptic plasticity by the treatment of overexpression of Neurl1 before SNL were counteracted by the knockdown of CPEB3 in the CA1. Collectively, the above results suggest that the downregulation of Neurl1 through reducing CPEB3 ubiquitination and, in turn, repressing GluA1 and GluA2 production and mediating synaptic plasticity impairment in hippocampal CA1 leads to the genesis of cognitive deficits in neuropathic pain.
Animals ; Male ; Neuralgia/metabolism* ; Rats ; Down-Regulation/physiology* ; Ubiquitination/physiology* ; Neuronal Plasticity/physiology* ; Rats, Sprague-Dawley ; CA1 Region, Hippocampal/metabolism* ; Cognitive Dysfunction/metabolism* ; RNA-Binding Proteins/metabolism* ; Receptors, AMPA/metabolism*