Application of Retrospective Outcome Special Attention Nursing in the Continuous Nursing of Patients with Heart Failure During Vulnerable Period.

Objective: To assess the effectiveness and benefits of retrospective outcome special attention nursing in providing continuous care for patients with heart failure during a vulnerable period. Methods: 96 patients with heart failure discharged from the hospital between January 2021 and January 2022 were included in the study. Patients discharged from January 2021 to June 2021 (48 cases) formed the single group, while those from July 2021 to January 2022 (48 cases) constituted the combined group. The single group received standard continuous nursing, while the combined group underwent retrospective outcome special attention nursing intervention in addition to standard care. Following the interventions, cardiac function-related indicators, negative emotions, self-management ability, health behavior, quality of life, and readmission rates were compared between the two groups. Results: Following the intervention, the combined group exhibited significant improvements, including enhanced 6-minute walk test (6MWT) results (P < .05) and lower scores on the Hamilton Anxiety Rating Scale (HAMA) and Hamilton Depression Rating Scale (HAMD) (P < .05), indicating reduced anxiety and depression levels. The combined group also demonstrated superior self-management abilities, with higher scores in health behavior dimensions (nutrition, exercise, health responsibility, stress coping) and a higher overall self-management score (P < .05). However, the combined group had lower quality of life scores (P < .05). Notably, the combined group's readmission rate was significantly lower at 14.58% (7/48), compared to 33.33% (16/48) in the single group (P < .05). Conclusion: Retrospective outcome special attention nursing improves cardiac function, emotional regulation, self-management, health behaviors, quality of life, and reduces readmission rates in heart failure patients during vulnerable periods.

The markers and risk stratification model of intracranial aneurysm instability in a large Chinese cohort.

Intracranial aneurysm is the leading cause of nontraumatic subarachnoid hemorrhage. Evaluating the unstable (rupture and growth) risk of aneurysms is helpful to guild decision-making for unruptured intracranial aneurysms (UIA). This study aimed to develop a model for risk stratification of UIA instability. The UIA patients from two prospective, longitudinal multicenter Chinese cohorts recruited from January 2017 to January 2022 were set as the derivation cohort and validation cohort. The primary endpoint was UIA instability, comprising aneurysm rupture, growth, or morphology change, during a 2-year follow-up. Intracranial aneurysm samples and corresponding serums from 20 patients were also collected. Metabolomics and cytokine profiling analysis were performed on the derivation cohort (758 single-UIA patients harboring 676 stable UIAs and 82 unstable UIAs). Oleic acid (OA), arachidonic acid (AA), interleukin 1ß (IL-1ß), and tumor necrosis factor-α (TNF-α) were significantly dysregulated between stable and unstable UIAs. OA and AA exhibited the same dysregulated trends in serums and aneurysm tissues. The feature selection process demonstrated size ratio, irregular shape, OA, AA, IL-1ß, and TNF-α as features of UIA instability. A machine-learning stratification model (instability classifier) was constructed based on radiological features and biomarkers, with high accuracy to evaluate UIA instability risk (area under curve (AUC), 0.94). Within the validation cohort (492 single-UIA patients harboring 414 stable UIAs and 78 unstable UIAs), the instability classifier performed well to evaluate the risk of UIA instability (AUC, 0.89). Supplementation of OA and pharmacological inhibition of IL-1ß and TNF-α could prevent intracranial aneurysms from rupturing in rat models. This study revealed the markers of UIA instability and provided a risk stratification model, which may guide treatment decision-making for UIAs.

Sclareol attenuates liver fibrosis through SENP1-mediated VEGFR2 SUMOylation and inhibition of downstream STAT3 signaling.

Liver fibrosis is a key global health care burden. Sclareol, isolated from Salvia sclarea, possesses various biological activities. Its effect on liver fibrosis remains unknown. This study was proposed to evaluate the antifibrotic activity of sclareol (SCL) and explore its underlying mechanisms. Stimulated hepatic stellate cells served as an in vitro liver fibrosis model. The expression of fibrotic markers was assessed by western blot and real-time PCR. Two classical animal models, bile duct-ligated rats and carbon tetrachloride-treated mice, were utilized for the in vivo experiments. The liver function and fibrosis degree were determined by serum biochemical and histopathological analyses. VEGFR2 SUMOylation was analyzed using coimmunoprecipitation assay. Our results indicated that SCL treatment restricted the profibrotic propensity of activated HSCs. In fibrotic rodents, SCL administration alleviated hepatic injury and reduced collagen accumulation. Mechanistic studies indicated that SCL downregulated the protein level of SENP1 and enhanced VEGFR2 SUMOylation in LX-2 cells, which affected its intracellular trafficking. Blockade of the interaction between VEGFR2 and STAT3 was observed, resulting in the suppression of downstream STAT3 phosphorylation. Our findings demonstrated that SCL has therapeutic efficacy against liver fibrosis through mediating VEGFR2 SUMOylation, suggesting that SCL may be a potential candidate compound for its treatment.

Paeoniflorin-free subfraction of Paeonia lactiflora Pall. shows the potential of anti-hepatic fibrosis: an integrated analysis of network pharmacology and experimental validation.

ETHNOPHARMACOLOGICAL RELEVANCE: Hepatic fibrosis is a major consequence of liver disease. Radix Paeoniae Rubra (RPR), the dry root of Paeonia lactiflora Pall., has a long history of clinical application in traditional Chinese medicine (TCM) for the treatment of liver diseases. The researches of RPR active ingredients are mainly focused on paeoniflorin. However, the functional roles of other ingredients have not been clarified sufficiently in the treatment of hepatic fibrosis with RPR. AIM OF THE STUDY: This study was to figure out the anti-hepatic fibrosis potential and mechanisms of CS-4, one of the paeoniflorin-free subfraction of RPR. MATERIALS AND METHODS: With the guide of bioassay, CS-4, a subfraction of RPR showed in vitro inhibition of hepatic stellate cell activation, was obtained using multiple chromatographic techniques. Its ingredients were determined by UPLC-Q-TOF-MS/MS. Then, the target profiles of ingredients were obtained from the HERB database, and the disease targets were collected from the DisGeNET database. Through the network pharmacology method, a protein-protein interaction network of CS-4 against hepatic fibrosis was established to analyze and excavate the potential therapeutic targets. Combined with the KEGG analysis, a series of signaling pathways were obtained, thereby validated by western blot analysis. RESULTS: The paeoniflorin-free subfraction of RPR, CS-4, was obtained and showed the most potential anti-fibrotic effect in vitro. A total of 20 main ingredients were identified from CS-4 and considered as its active ingredients. From HERB and DisGeNET databases, 1460 potential targets of CS-4 and 1180 disease targets were obtained, respectively. The overlapped 79 targets were considered to exert the potential anti-fibrosis effect of CS-4, such as JAK2, MYC, SMAD3, and IFNG. The gene enrichment analysis revealed that classical TGF-ß/Smad signaling pathway and nonclassical TGF-ß/PI3K-AKT signaling pathway may be two of the main mechanisms of CS-4 against hepatic fibrosis, which supported by western blot analysis. CONCLUSION: In this study, a paeoniflorin-free subfraction with potential anti-hepatic fibrosis activity in vitro, CS-4, was obtained from RPR. Its multiple ingredients, multiple targets, and multiple mechanisms against hepatic fibrosis were explained by network pharmacology and verified by western blot analysis to further support the clinical applications of RPR.

Effectiveness of Laparoscopic Cholecystectomy in Patients with Gallbladder Stones with Chronic Cholecystitis.

Objective: To assess the effectiveness of laparoscopic cholecystectomy in patients with gallbladder stones and chronic cholecystitis. Methods: From July 2018 to January 2020, 90 patients with gallbladder stones and chronic cholecystitis assessed for eligibility were recruited and concurrently assigned (1 : 1) to receive either small-incision cholecystectomy (observation group) or laparoscopic cholecystectomy (experimental group). Outcome measures included operation time, intraoperative bleeding volume, postoperative hospital stay, c-reactive protein (CRP), interleukin (IL)-6, tumor necrosis factor-α (TNF-α), gastrin (GAS), vasoactive intestinal peptide (VIP), motilin (MOT), and adverse events. Results: Patients given laparoscopic cholecystectomy showed lower levels of operation-related indices versus those receiving small-incision cholecystectomy (P < 0.05). Laparoscopic cholecystectomy resulted in lower postoperative levels of CRP, IL-6, and TNF-α in the patients versus small-incision cholecystectomy (P < 0.05). Patients receiving laparoscopic cholecystectomy showed better GAS, VIP, and MOT levels than those receiving small-incision cholecystectomy (P < 0.05). The eligible patients after laparoscopic cholecystectomy had a significantly lower incidence of adverse events versus those after small-incision cholecystectomy (P < 0.05). Conclusion: Laparoscopic cholecystectomy effectively shortens the operative time and length of hospital stay in patients with gallbladder stones and chronic cholecystitis, reduces intraoperative bleeding, attenuates the inflammatory response, and enhances the gastrointestinal function, with less surgical trauma and high safety. Clinical trials are, however, required prior to promotion.

Multiple anti-non-alcoholic steatohepatitis (NASH) efficacies of isopropylidenyl anemosapogenin via farnesoid X receptor activation and TFEB-mediated autophagy.

BACKGROUND: Non-alcoholic steatohepatitis (NASH) can develop into cirrhosis, liver failure, or hepatocellular carcinoma without effective treatment. However, there are currently no drugs for NASH treatment, and the development of new therapeutics has remained a major challenge in NASH research. Advances in traditional Chinese medicine to treat liver disease inspired us to search for new NASH candidates from Chi-Shao, a widely used traditional Chinese medicine. PURPOSE: In this research, we aimed to clarify the anti-NASH effect and the underlying mechanism of isopropylidenyl anemosapogenin (IA, 1), which was a new lead compound isolated from Chi-Shao. STUDY DESIGN AND METHODS: Isopropylidenyl anemosapogenin (IA, 1) was first discovered by collagen type I α 1 promoter luciferase bioassay-guided isolation and then characterized by single crystal X-ray diffraction analysis and enriched by semi-synthesis. Using various molecular biology techniques, the multiple anti-NASH efficacies and mechanisms of IA were clarified based on in vitro LX-2 and Huh7 cell models, along with the in vivo choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD)-induced mouse model and bile duct ligation (BDL)-induced rat model. The UPLC-MS/MS method was used to assess the plasma concentration of IA. RESULTS: A new lead compound IA was isolated from the traditional Chinese medicine Chi-Shao, which showed significant anti-liver fibrosis activity in TGF-ß1-treated LX-2 cells and anti-liver steatosis activity in oleic acid-treated Huh7 cells. Furthermore, IA could significantly ameliorate in vivo CDAHFD-induced liver injury by activating the farnesoid X receptor pathway, including its targets Nr0b2, Abcb11, and Slc10a2. Simultaneously, IA activated the autophagy pathway by activating the TFEB factor, thereby promoting lipid degradation. Its liver-protective and anti-fibrosis activities were verified by the BDL-induced rat model. Finally, with an oral administration of 100 mg/kg, IA achieved the maximum plasma concentration of 1.23 ± 0.18 µg/ml at 2.67 ± 0.58 h. CONCLUSION: IA, an unreported lupine-type triterpenoid isolated from Chi-shao, can significantly alleviate liver injury and fibrosis via farnesoid X receptor activation and TFEB-mediated autophagy, which indicates that IA could serve as a novel therapeutic candidate against NASH.

Study on the mechanism of reducing biofilm toxicity and increasing antioxidant activity in vinegar processing phytomedicines containing pentacyclic triterpenoid saponins.

ETHNOPHARMACOLOGICAL RELEVANCE: Pentacyclic triterpenoid saponin (PTS) is a kind of particular chemicals with various pharmacological activities, as well as surface activity, mucosal irritation and hemolysis. PTS is closely related to the exertion of efficacy or adverse reactions in plant medicines rich in this component. For the better clinical application of natural resources, how to reduce toxicity and enhance curative efficacy is an important problem which needs to be solved at present. Till now, there has been few studies directly investigating the problem. AIM OF STUDY: Through comparison study of Radix Bupleuri (Chai hu) and Pulsatilla chinensis (Bai tou weng), which are typical traditional Chinese medicines containing PTS, explore the potential change rule of material basis and the mechanism of detoxification and synergistic effect of vinegar processing. MATERIALS AND METHODS: Composition change rule after vinegar processing was applied by UPLC-QTOF-MS/MS coupled with principal component analysis (PCA). Based on our previous research, this paper expounded the action mechanism from the perspective of reducing biofilm toxicity and increasing antioxidant activity. Direct toxicity reducing information was obtained at the cellular level including cellular morphology, MTT assays, western blots and RT-PCR in L02 cells with overload sphingomyelin (SM). The synergistic effect was investigated through histological examinations, mesenteric hemorheology, ELISA, flow cytometry and confocal microscopy. RESULTS: It was found that the structure of PTS take place a series of chemical reactions in the process of vinegar processing which enabled the more toxic components transformed into less toxic components and components with clear efficacy, so as to achieve the purpose of detoxification and synergistic effect. The results indicated that the mechanism of detoxification in vinegar processing was that vinegar processing could act on SM, cause less balance disturbance to sphingomyelin/ceramide (SM/Cer), inhibit apoptosis and then alleviate toxicity. In addition, the pharmacodynamic results showed that the vinegar processing could have an obvious synergistic effect through anti-oxidant stress. CONCLUSIONS: By changing the structures of the PTS, the SM/Cer disrupt was reduced and the antioxidant activity was enhanced, so as to decrease toxicity and increase efficiency in vinegar processing phytomedicines containing PTS.

Costunolide Loaded in pH-Responsive Mesoporous Silica Nanoparticles for Increased Stability and an Enhanced Anti-Fibrotic Effect.

Liver fibrosis remains a significant public health problem. However, few drugs have yet been validated. Costunolide (COS), as a monomeric component of the traditional Chinese medicinal herb Saussurea Lappa, has shown excellent anti-fibrotic efficacy. However, COS displays very poor aqueous solubility and poor stability in gastric juice, which greatly limits its application via an oral administration. To increase the stability, improve the dissolution rate and enhance the anti-liver fibrosis of COS, pH-responsive mesoporous silica nanoparticles (MSNs) were selected as a drug carrier. Methacrylic acid copolymer (MAC) as a pH-sensitive material was used to coat the surface of MSNs. The drug release behavior and anti-liver fibrosis effects of MSNs-COS-MAC were evaluated. The results showed that MSNs-COS-MAC prevented a release in the gastric fluid and enhanced the dissolution rate of COS in the intestinal juice. At half the dose of COS, MSNs-COS-MAC still effectively ameliorated parenchymal necrosis, bile duct proliferation and excessive collagen. MSNs-COS-MAC significantly repressed hepatic fibrogenesis by decreasing the expression of hepatic fibrogenic markers in LX-2 cells and liver tissue. These results suggest that MSNs-COS-MAC shows great promise for anti-liver fibrosis treatment.

Raw and wine processed Schisandra chinensis attenuate anxiety like behavior via modulating gut microbiota and lipid metabolism pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: In traditional Chinese medicine, the fruit of Schisandra chinensis (Turcz.) Baill (SC) is used to treat various nervous system diseases, such as dysphoria, anxiety, insomnia and many dreams. It is worthy to be noted that wine processed Schisandra chinensis (WSC) has been applied in clinic for thousands of years. AIM OF STUDY: This study aimed to investigate the possible mechanism and related metabolism of SC and WSC ameliorating anxiety behavior through modulating gut microbiota. MATERIALS AND METHODS: The ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-QTOF-MS) was used for the quality control of chemical components in SC and WSC. Chronic unpredictable stress procedure (CUSP)-induced anxiety rats were administrated with SC and WSC via gavage for five weeks. An untargeted UPLC/LTQ-Orbitrap MS metabolomic analysis of plasma was conducted to understand the effects of long-term intake of WSC and SC extracts on anxious rats. 16S rRNA microbial sequencing technology was applied to investigate gut microbiota structure. Expression of GPR81, TNF-α, S1PR2 as well as molecules in cAMP pathway was assayed by immunohistochemistry staining, RT-qPCR, or Western blot, respectively. RESULTS: 12 compounds were identified using UPLC-QTOF-MS technology, all of which are lignans. Results demonstrate that the amounts of 6-O-Benzoylgomisin O, Schisandrin, Gomisin D, Schizandrin A, Gomisin T, Schizandrin B, Schisandrin C were higher in wine-processed samples than in raw samples. Furthermore, both SC and WSC significantly ameliorated anxiety- and depression-like behavior and lipid metabolism dysfunction and attenuated hippocampal neuritis in anxiety rats. After WSC treatment, the structure and composition of gut microbiota in anxiety rats changed significantly, and gut microbiota derivatives lactate level was significantly lower in the plasma and feces. WSC treatment help restore gut microbial ecosystem dysbiosis and reverse the changes in Lachnospiraceae, Lactobacillus, Alloprevotella, and Bacteroidales in anxiety rat. In addition, the expression of liver GPR81 was decreased, and the molecules in cAMP pathway were increased in SC and WSC-treated anxiety rat. CONCLUSION: Raw and wine processed Schisandra chinensis treatment improved anxiety- and depression-like behavior through modulating gut microbiota derivatives in association with GPR81 receptor-mediated lipid metabolism pathway. And WSC has more exhibition than SC.

The anti-hepatic fibrosis effects of dihydrotanshinone I are mediated by disrupting the yes-associated protein and transcriptional enhancer factor D2 complex and stimulating autophagy.

BACKGROUND AND PURPOSE: Dihydrotanshinone I (DHI), a lipophilic component of traditional Chinese medicine Salvia miltiorrhiza Bunge, has various therapeutic effects. We investigated the anti-fibrotic effect of DHI and its underlying mechanisms in vitro and in vivo. EXPERIMENTAL APPROACH: Rats subjected to bile duct ligation (BDL) were treated with DHI (25 mg·kg-1 ·day-1 , i.p.) for 14 days. Serum biochemical and liver tissue morphological analyses were performed. The human hepatic stellate cell line LX-2 served as a liver fibrosis model in vitro. Liver fibrogenic genes, yes-associated protein (YAP) downstream genes and autophagy markers were examined using western blot and real-time PCR analyses. Similar analyses were done in rat primary hepatic stellate cells (pHSCs). Autophagy flux was assessed by immunofluorescence. KEY RESULTS: In BDL rats, DHI administration attenuated liver necrosis, bile duct proliferation and collagen accumulation and reduced the expression of genes associated with fibrogenesis, including Tgfb1, Mmp-2, Acta2 and Col1a1. DHI (1, 5, 10 µmol·L-1 ) time- and dose-dependently suppressed the protein level of COL1A1, TGFß1 and α-SMA in LX-2 cells and rat pHSCs. Furthermore, DHI blocked the nuclear translocation of YAP, which inhibited the YAP/TEAD2 interaction and its downstream fibrogenic genes, connective tissue growth factor, SOX4 and survivin. This stimulated autophagic flux and accelerated the degradation of liver collagen. CONCLUSIONS AND IMPLICATIONS: DHI exerts anti-fibrotic effects in BDL rats, LX-2 cells and rat pHSCs by inhibiting the YAP and TEAD2 complex and stimulating autophagy. These findings indicate that DHI may be a potential therapeutic for the treatment of liver fibrosis.

[Establishment and application of a high-throughput drug screening model based on COL1A1 promoter for anti-liver fibrosis].

For screening the potential drugs as anti-liver fibrosis candidates, we established a high- throughput drug screening cell model based on COL1A1 promoter. The activity of COL1A1 promoter and luciferase reporter gene can be elevated by TGF-ß1, and inhibited by candidate drugs. We constructed a recombined plasmid with COL1A1 promoter and luciferase reporter gene pGL4.17, the activity of COL1A1 promoter was reflected by fluorescence intensity. COL1A1 promoter activity was detected by Dual-Luciferase Reporter Assay System, it came that the relative luciferase activity of COL1A1 promoter was 15.98 times higher than that of control group induced by TGF-ß1, showing the recombined plasmid could be used in cell model. The recombined plasmid was transfected into human hepatic stellate cells LX2, detected the effect of potential drugs, and obtained a stable expression system through stable transfection and monoclonal cell culture. A sample which could reduce COL1A1 promoter activity signally by our cell model, decreased collagen I mRNA and protein expression detected by real-time RT-PCR and Western blotting. It indicates this novel cell model can be used in high-throughput drug screening of potential anti-liver fibrosis drugs.

Combination of retinoic acid and ursodeoxycholic acid attenuates liver injury in bile duct-ligated rats and human hepatic cells.

UNLABELLED: Cholestasis leads to liver cell death, fibrosis, cirrhosis, and eventually liver failure. Despite limited benefits, ursodeoxycholic acid (UDCA) is the only Food and Drug Administration-approved treatment for cholestatic disorders. Retinoic acid (RA) is a ligand for nuclear receptors that modulate bile salt homeostasis. RA also possesses immunomodulatory effects and is used to treat acute promyelocytic leukemia and inflammatory disorders such as psoriasis, acne, and rheumatoid arthritis. To test whether the supplementation of RA with UDCA is superior to UDCA alone for treating cholestasis, male Sprague-Dawley rats underwent common bile duct ligation (BDL) for 14 days and were treated with phosphate-buffered saline (PBS), UDCA, all-trans retinoic acid (atRA), or UDCA and atRA by gavage. Treatment with UDCA and atRA substantially improved animal growth rates, significantly reduced liver fibrosis and bile duct proliferation, and nearly eliminated liver necrosis after BDL. Reductions in the bile salt pool size and liver hydroxyproline content were also seen with treatment with atRA or atRA and UDCA versus PBS and UDCA. Furthermore, atRA and UDCA significantly reduced liver messenger RNA and/or protein expression of transforming growth factor ß1 (Tgf-ß1), collagen 1a1 (Col1A1), matrix metalloproteinase 2 (Mmp2), cytokeratin 19, α-smooth muscle actin (α-SMA), cytochrome P450 7A1 (Cyp7a1), tumor necrosis factor α, and interleukin-ß1. The molecular mechanisms of this treatment were also assessed in human hepatocytes, hepatic stellate cells, and LX-2 cells. atRA alone or in combination with UDCA greatly repressed CYP7A1 expression in human hepatocytes and significantly inhibited COL1A1, MMP2, and α-SMA expression and/or activity in primary human hepatic stellate cells and LX-2 cells. Furthermore, atRA reduced TGF-ß1-induced Smad2 phosphorylation in LX-2 cells. CONCLUSION: Our findings indicate that the addition of RA to UDCA reduces the bile salt pool size and liver fibrosis and might be an effective supplemental therapy with UDCA for cholestatic diseases.

Retinoic acid represses CYP7A1 expression in human hepatocytes and HepG2 cells by FXR/RXR-dependent and independent mechanisms.

Cholesterol 7alpha-hydroxylase (CYP7A1) plays a key role in maintaining lipid and bile salt homeostasis as it is the rate-limiting enzyme converting cholesterol to bile acids. Deficiency of CYP7A1 leads to hyperlipidemia in man and mouse. Hyperlipidemia is often seen in patients when treated with high-dose retinoic acid (RA), but the molecular mechanisms remain elusive. Our present study revealed that CYP7A1 mRNA expression is greatly repressed by RA in both human hepatocytes and HepG2 cells where increased fibroblast growth factor 19 (FGF19) and small heterodimer partner (SHP) expressions were also observed, suggesting farnesoid X receptor (FXR) and retinoid X receptor (RXR) were activated. Promoter reporter assays demonstrate that all-trans RA (atRA) specifically activated FXR/RXR. However, detailed molecular analyses indicate that this activation is through RXR, whose ligand is 9-cis RA. Knocking down of FXR or RXRalpha by small interference RNA (siRNA) in human hepatocytes increased CYP7A1 basal expression, but the repressive effect of atRA persisted, suggesting there are also FXR/RXR-independent mechanisms mediating atRA repression of CYP7A1 expression. Chromatin immunoprecipitation (ChIP) assay and cell transfection results indicate that PGC-1alpha plays a role in the FXR/RXR-independent mechanism. Our findings may provide a potential explanation for hyperlipidemic side effects observed in some patients treated with high-dose RA.