Integrated bioinformatics and multiomics reveal Liupao tea extract alleviating NAFLD via regulating hepatic lipid metabolism and gut microbiota.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) poses a significant global public health concern. Liupao tea (LPT) is a Chinese national geographical indication product renowned for its lipid-lowering properties. However, the precise mechanisms and active constituents contributing to the efficacy of LPT against NAFLD remain unclear. PURPOSE: This study aims to comprehensively explore the therapeutic potential of Liupao tea extract (LPTE) in alleviating NAFLD through an integrated strategy. METHODS: Initially, network pharmacology analysis was conducted based on LPTE chemical ingredient analysis, identifying core targets and key components. Potential active ingredients were validated through chemical standards based on LC-MS/MS. To confirm the pharmacological efficacy of LPTE in NAFLD, NAFLD mice models were employed. Alterations in hepatic lipid metabolism were comprehensively elucidated through integration of metabolomics, lipidomics, network pharmacology analysis, and real-time PCR analysis. To further explore the binding interactions between key components and core targets, molecular docking and microscale thermophoresis (MST) analysis were employed. Furthermore, to investigate LPTE administration effectiveness on gut microbiota in NAFLD mice, a comprehensive approach was employed. This included Metorigin analysis, 16S rRNA sequencing, molecular docking, and fecal microbiome transplantation (FMT). RESULTS: Study identified naringenin, quercetin, luteolin, and kaempferol as the potential active ingredients of LPTE. These compounds exhibited therapeutic potential for NAFLD by targeting key proteins such as PTGS2, CYP3A4, and ACHE, which are involved in the metabolic pathways of hepatic linoleic acid (LA) and glycerophospholipid (GP) metabolism. The therapeutic effectiveness of LPTE was observed to be comparable to that of simvastatin. Furthermore, LPTE exhibited notable efficacy in alleviating NAFLD by influencing alterations in gut microbiota composition (Proteobacteria phylum, Lactobacillus and Dubosiella genus) that perhaps impact LA and GP metabolic pathways. CONCLUSION: LPTE could be effective in preventing high-fat diet (HFD)-induced NAFLD by modulating hepatic lipid metabolism and gut microbiota. This study firstly integrated bioinformatics and multi-omics technologies to identify the potential active components and key microbiota associated with LPTE's effects, while also primally elucidating the action mechanisms of LPTE in alleviating NAFLD. The findings offer a conceptual basis for LPTE's potential transformation into an innovative pharmaceutical agent for NAFLD prevention.

Advances in contezolid: novel oxazolidinone antibacterial in Gram-positive treatment.

PURPOSE: The principal objective of this project was to review and thoroughly examine the chemical characteristics, pharmacological activity, and quantification methods associated with contezolid. METHODS: The article was based on published and ongoing preclinical and clinical studies on the application of contezolid. These studies included experiments on the physicochemical properties of contezolid, in vitro antimicrobial research, in vivo antimicrobial research, and clinical trials in various phases. There were no date restrictions on these studies. RESULTS: In June 2021, contezolid was approved for treating complicated skin and soft tissue infections. The structural modification of contezolid has resulted in better efficacy compared to linezolid. It inhibits bacterial growth by preventing the production of the functional 70S initiation complex required to translate bacterial proteins. The current evidence has indicated a substantial decline in myelosuppression and monoamine oxidase inhibition without impairing its antibacterial properties. Contezolid was found to have a more significant safety profile and to be metabolised by flavin monooxygenase 5, reducing the risk of harmful effects due to drug-drug interactions. Adjusting doses is unnecessary for patients with mild to moderate renal or hepatic insufficiency. CONCLUSION: As an oral oxazolidinone antimicrobial agent, contezolid is effective against multi-drug resistant Gram-positive bacteria. The introduction of contezolid provided a new clinical option.

UHPLC-HRMS-based Multiomics to Explore the Potential Mechanisms and Biomarkers for Colorectal Cancer.

BACKGROUND: Understanding the metabolic changes in colorectal cancer (CRC) and exploring potential diagnostic biomarkers is crucial for elucidating its pathogenesis and reducing mortality. Cancer cells are typically derived from cancer tissues and can be easily obtained and cultured. Systematic studies on CRC cells at different stages are still lacking. Additionally, there is a need to validate our previous findings from human serum. METHODS: Ultrahigh-performance liquid chromatography tandem high-resolution mass spectrometry (UHPLC-HRMS)-based metabolomics and lipidomics were employed to comprehensively measure metabolites and lipids in CRC cells at four different stages and serum samples from normal control (NR) and CRC subjects. Univariate and multivariate statistical analyses were applied to select the differential metabolites and lipids between groups. Biomarkers with good diagnostic efficacy for CRC that existed in both cells and serum were screened by the receiver operating characteristic curve (ROC) analysis. Furthermore, potential biomarkers were validated using metabolite standards. RESULTS: Metabolite and lipid profiles differed significantly among CRC cells at stages A, B, C, and D. Dysregulation of glycerophospholipid (GPL), fatty acid (FA), and amino acid (AA) metabolism played a crucial role in the CRC progression, particularly GPL metabolism dominated by phosphatidylcholine (PC). A total of 46 differential metabolites and 29 differential lipids common to the four stages of CRC cells were discovered. Eight metabolites showed the same trends in CRC cells and serum from CRC patients compared to the control groups. Among them, palmitoylcarnitine and sphingosine could serve as potential biomarkers with the values of area under the curve (AUC) more than 0.80 in the serum and cells. Their panel exhibited excellent performance in discriminating CRC cells at different stages from normal cells (AUC = 1.00). CONCLUSIONS: To our knowledge, this is the first research to attempt to validate the results of metabolism studies of serum from CRC patients using cell models. The metabolic disorders of PC, FA, and AA were closely related to the tumorigenesis of CRC, with PC being the more critical factor. The panel composed of palmitoylcarnitine and sphingosine may act as a potential biomarker for the diagnosis of CRC, aiding in its prevention.

Aerobic Exercise Attenuates Pressure Overload-Induced Myocardial Remodeling and Myocardial Inflammation via Upregulating miR-574-3p in Mice.

BACKGROUND: Exercise training can promote cardiac rehabilitation, thereby reducing cardiovascular disease mortality and hospitalization rates. MicroRNAs (miRs) are closely related to heart disease, among which miR-574-3p plays an important role in myocardial remodeling, but its role in exercise-mediated cardioprotection is still unclear. METHODS: A mouse myocardial hypertrophy model was established by transverse aortic coarctation, and a 4-week swimming exercise training was performed 1 week after the operation. After swimming training, echocardiography was used to evaluate cardiac function in mice, and histopathologic staining was used to detect cardiac hypertrophy, myocardial fibrosis, and cardiac inflammation. Quantitative real-time polymerase chain reaction was used to detect the expression levels of miR-574-3p and cardiac hypertrophy markers. Western blotting detected the IL-6 (interleukin-6)/JAK/STAT inflammatory signaling pathway. RESULTS: Echocardiography and histochemical staining found that aerobic exercise significantly improved pressure overload-induced myocardial hypertrophy (n=6), myocardial interstitial fibrosis (n=6), and cardiac inflammation (n=6). Quantitative real-time polymerase chain reaction detection showed that aerobic exercise upregulated the expression level of miR-574-3p (n=6). After specific knockdown of miR-574-3p in mouse hearts with adeno-associated virus 9 using cardiac troponin T promoter, we found that the protective effect of exercise training on the heart was significantly reversed. Echocardiography and histopathologic staining showed that inhibiting the expression of miR-574-3p could partially block the effects of aerobic exercise on cardiac function (n=6), cardiomyocyte cross-sectional area (n=6), and myocardial fibrosis (n=6). Western blotting and immunohistochemical staining showed that the inhibitory effects of aerobic exercise on the IL-6/JAK/STAT pathway and cardiac inflammation were partially abolished after miR-574-3p knockdown. Furthermore, we also found that miR-574-3p exerts cardioprotective effects in cardiomyocytes by targeting IL-6 (n=3). CONCLUSIONS: Aerobic exercise protects cardiac hypertrophy and inflammation induced by pressure overload by upregulating miR-574-3p and inhibiting the IL-6/JAK/STAT pathway.

Chapter 1: The Burden of Heart Failure.

Heart failure (HF) affects an estimated 6 million American adults, and the prevalence continues to increase, driven in part by the aging of the population and by increases in the prevalence of diabetes. In recent decades, improvements in the survival of patients with HF have resulted in a growing number of individuals living longer with HF. HF and its comorbidities are associated with substantial impairments in physical functioning, emotional well-being, and quality of life, and also with markedly increased rates of morbidity and mortality. As a result, the management of patients with HF has a substantial economic impact on the health care system, with most costs arising from hospitalization. Clinicians have an important role in helping to reduce the burden of HF through timely diagnosis of HF as well as increasing access to effective treatments to minimize symptoms, delay progression, and reduce hospital admissions. Prevention and early diagnosis of HF will play a fundamental role in efforts to reduce the large and growing burden of HF. Recent advances in pharmacotherapies for HF have the potential to radically change the management of HF, offering the possibility of improved survival and quality of life for patients.

Single-nucleus transcriptome sequencing reveals hepatic cell atlas in pigs.

BACKGROUND: As the largest substantive organ of animals, the liver plays an essential role in the physiological processes of digestive metabolism and immune defense. However, the cellular composition of the pig liver remains poorly understood. This investigation used single-nucleus RNA sequencing technology to identify cell types from liver tissues of pigs, providing a theoretical basis for further investigating liver cell types in pigs. RESULTS: The analysis revealed 13 cells clusters which were further identified 7 cell types including endothelial cells, T cells, hepatocytes, Kupffer cells, stellate cells, B cells, and cholangiocytes. The dominant cell types were endothelial cells, T cells and hepatocytes in the liver tissue of Dahe pigs and Dahe black pigs, which accounts for about 85.76% and 82.74%, respectively. The number of endothelial cells was higher in the liver tissue of Dahe pigs compared to Dahe black pigs, while the opposite tendency was observed for T cells. Moreover, functional enrichment analysis demonstrated that the differentially expressed genes in pig hepatic endothelial cells were significantly enriched in the protein processing in endoplasmic reticulum, MAPK signaling pathway, and FoxO signaling pathway. Functional enrichment analysis demonstrated that the differentially expressed genes in pig hepatic T cells were significantly enriched in the thyroid hormone signaling pathway, B cell receptor signaling pathway, and focal adhesion. Functional enrichment analysis demonstrated that the differentially expressed genes in pig hepatic hepatocytes were significantly enriched in the metabolic pathways. CONCLUSIONS: In summary, this study provides a comprehensive cell atlas of porcine hepatic tissue. The number, gene expression level and functional characteristics of each cell type in pig liver tissue varied between breeds.

High-performance cost efficient simultaneous wireless information and power transfers deploying jointly modulated amplifying programmable metasurface.

Programmable metasurfaces present significant capabilities in manipulating electromagnetic waves, making them a promising candidate for simultaneous wireless information and power transfer (SWIPT), which has the potential to enable sustainable wireless communication in complex electromagnetic environments. However, challenges remain in terms of maximum power transmission distance and stable phase manipulation with high-power scattered waves. Additionally, waveform limitations restrict average scattered power and rectifier conversion efficiency, affecting data transmission rates and energy transmission distance. Here we show an amplifying programmable metasurface (APM) and a joint modulation method to address these challenges. The APM mitigates the peak-to-average power ratio and improves maximum power, phase response stability, average output power, and rectifier conversion efficiency. Through experimental validation, we demonstrate the feasibility of the SWIPT system, showcasing simultaneous LED array powering and movie video transmission. This innovative SWIPT system holds promise for diverse applications, including 6 G wireless communications, IoT, implanted devices, and cognitive radio networks.

Loss of USP22 alleviates cardiac hypertrophy induced by pressure overload through HiF1-α-TAK1 signaling pathway.

Ubiquitin-specific protease 22 (USP22) is a member of the ubiquitin specific protease family (ubiquitin-specific protease, USPs), the largest subfamily of deubiquitinating enzymes, and plays an important role in the treatment of tumors. USP22 is also expressed in the heart. However, the role of USP22 in heart disease remains unclear. In this study, we found that USP22 was elevated in hypertrophic mouse hearts and in angiotensin II (Ang II)-induced cardiomyocytes. The inhibition of USP22 expression with adenovirus significantly rescued hypertrophic phenotype and cardiac dysfunction induced by pressure overloaded. Consistent with in vivo study, silencing by USP22 shRNA expression in vitro had similar results. Molecular analysis revealed that transforming growth factor-ß-activating protein 1 (TAK1)-(JNK1/2)/P38 signaling pathway and HIF-1α was activated in the Ang II-induced hypertrophic cardiomyocytes, whereas HIF-1α expression was decreased after the inhibition of USP22. Inhibition of HIF-1α expression reduces TAK1 expression. Co-immunoprecipitation and ubiquitination studies revealed the regulatory mechanism between USP22 and HIF1α.Under hypertrophic stress conditions, USP22 enhances the stability of HIF-1α through its deubiquitination activity, which further activates the TAK1-(JNK1/2)/P38 signaling pathway to lead to cardiac hypertrophy. Inhibition of HIF-1α expression further potentiates the in vivo pathological effects caused by USP22 deficiency. In summary, this study suggests that USP22, through HIF-1α-TAK1-(JNK1/2)/P38 signaling pathway, may be potential targets for inhibiting pathological cardiac hypertrophy induced by pressure overload.

Cell based dATP delivery as a therapy for chronic heart failure.

Transplanted human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) improve ventricular performance when delivered acutely post-myocardial infarction but are ineffective in chronic myocardial infarction/heart failure. 2'-deoxy-ATP (dATP) activates cardiac myosin and potently increases contractility. Here we engineered hPSC-CMs to overexpress ribonucleotide reductase, the enzyme controlling dATP production. In vivo, dATP-producing CMs formed new myocardium that transferred dATP to host cardiomyocytes via gap junctions, increasing their dATP levels. Strikingly, when transplanted into chronically infarcted hearts, dATP-producing grafts increased left ventricular function, whereas heart failure worsened with wild-type grafts or vehicle injections. dATP-donor cells recipients had greater voluntary exercise, improved cardiac metabolism, reduced pulmonary congestion and pathological cardiac hypertrophy, and improved survival. This combination of remuscularization plus enhanced host contractility offers a novel approach to treating the chronically failing heart.

Urinary miR-16-5p can be used as a potential marker of endocapillary hypercellularity in IgA nephropathy.

The most prevalent primary glomerulonephritis and leading cause of end-stage renal disease worldwide is IgA nephropathy (IgAN). More and more studies are describing urinary microRNA (miRNA) as a non-invasive marker for a variety of renal diseases. We screened candidate miRNAs based on data from three published IgAN urinary sediment miRNAs chips. In separate confirmation and validation cohorts, we included 174 IgAN patients, 100 patients with other nephropathies as disease controls (DC), and 97 normal controls (NC) for quantitative real-time PCR. A total of three candidate miRNAs, miR-16-5p, Let-7g-5p, miR-15a-5p were obtained. In both the confirmation and validation cohorts, these miRNAs levels were considerably higher in the IgAN than in NC, with miR-16-5p significantly higher than in DC. The area under the ROC curve for urinary miR-16-5p levels was 0.73. Correlation analysis suggested that miR-16-5p was positively correlated with endocapillary hypercellularity (r = 0.164 p = 0.031). When miR-16-5p was combined with eGFR, proteinuria and C4, the AUC value for predicting endocapillary hypercellularity was 0.726. By following the renal function of patients with IgAN, the levels of miR-16-5p were noticeably higher in the IgAN progressors than in the non- progressors (p = 0.036). Urinary sediment miR-16-5p can be used as noninvasive biomarkers for the assessment of endocapillary hypercellularity and diagnosis of IgA nephropathy. Furthermore, urinary miR-16-5p may be predictors of renal progression.

Synergistic prevention and reparative effects of sesquiterpene farnesol in a rabbit model of surgical resection-induced osteoarthritis.

Articular cartilage may regenerate poorly after injury or during aging. In vitro, farnesol can modulate extracellular matrix synthesis and restore chondrocyte phenotypes by increasing type II collagen (COL II) and glycosaminoglycan (GAG) production. Here, we evaluated farnesol's preventive and reparative effects against osteoarthritis (OA) in vivo. We induced OA in rabbits through resection of the lateral collateral ligament and meniscus. After 2 weeks, the affected limb was treated with 0.5 ml of 0.4 mM farnesol, hyaluronan (HA) nanoparticle-encapsulated 0.8 mM farnesol (Farn/HA), or HA nanoparticles intra-articularly. After 2 and 6 treatment weeks, synovial inflammatory cytokine levels were analyzed. We also removed the entire joint cartilage from lateral femoral condyles for histological investigation. The half-maximum inhibitory concentration of farnesol was 0.5 mM. Farn/HA had relatively low cytotoxicity showing cells remained viable after being treated with 1 mM a concentration Farn/HA. Untreated lateral condyle exhibited extensive wear. By contrast, 0.4 mM farnesol or 0.8 mM Farn/HA led to a relatively transparent and bright appearance. After 2 and 6 treatment weeks, farnesol, particularly 0.8 mM Farn/HA, reduced matrix metalloproteinase 1 and 13 levels considerably. Therefore, 0.8 mM Farn/HA, which enabled slow drug release, demonstrated the highest anti-inflammatory and OA preventive effects. After 6 treatment weeks, farnesol also promoted COL II and GAG synthesis and, thus, aided healing.

Cardiac-Specific Overexpression of Caveolin-1 in Rats With Ischemic Cardiomyopathy Improves Arrhythmogenicity and Cardiac Remodelling.

BACKGROUND: Ischemic cardiomyopathy (ICM) is associated with electrical and structural remodelling, leading to arrhythmias. Caveolin-1 (Cav1) is a membrane protein involved in the pathogenesis of ischemic injury. Cav1 deficiency has been associated with arrhythmogenicity. The current study aimed to determine how Cav1 overexpression inhibits arrhythmias and cardiac remodelling in ICM. METHODS: ICM was modelled using left anterior descending (LAD) artery ligation for 4 weeks. Cardiac-specific Cav1 overexpression in ICM on arrhythmias, excitation-contraction coupling, and cardiac remodelling were investigated using the intramyocardial injection of an adeno-associated virus serotype 9 (AAV-9) system, carrying a specific sequence expressing Cav1 (AAVCav1) under the cardiac troponin T (cTnT) promoter. RESULTS: Cav1 overexpression decreased susceptibility to arrhythmias by upregulating gap junction connexin 43 (CX43) and reducing spontaneous irregular proarrhythmogenic Ca2+ waves in ventricular cardiomyocytes. It also alleviated ischemic injury-induced contractility weakness by improving Ca2+ cycling through normalizing Ca2+-handling protein levels and improving Ca2+ homeostasis. Masson stain and immunoblotting revealed that the deposition of excessive fibrosis was attenuated by Cav1 overexpression, inhibiting the transforming growth factor-ß (TGF-ß)/Smad2 signalling pathway. Coimmunoprecipitation assays demonstrated that the interaction between Cav1 and cSrc modulated CX43 expression and Ca2+-handling protein levels. CONCLUSIONS: Cardiac-specific overexpression of Cav1 attenuated ventricular arrhythmia, improved Ca2+ cycling, and attenuated cardiac remodelling. These effects were attributed to modulation of CX43, normalized Ca2+-handling protein levels, improved Ca2+ homeostasis, and attenuated cardiac fibrosis.

Alterations in whole-brain dynamic functional stability during memory tasks under dexmedetomidine sedation.

Purpose: This study aimed to explore the neurological effects of dexmedetomidine-induced sedation on memory using functional stability, a whole-brain voxel-wise dynamic functional connectivity approach. Methods: A total of 16 participants (10 men) underwent auditory memory task-related fMRI in the awake state and under dexmedetomidine sedation. Explicit and implicit memory tests were conducted 4 h after ceasing dexmedetomidine administration. One-sample Wilcoxon signed rank test was applied to determine the formation of explicit and implicit memory in the two states. Functional stability was calculated and compared voxel-wise between the awake and sedated states. The association between functional stability and memory performance was also assessed. Results: In the awake baseline tests, explicit and implicit memory scores were significantly different from zero (p < 0.05). In the tests under sedation, explicit and implicit memory scores were not significantly different from zero. Compared to that at wakeful baseline, functional stability during light sedation was reduced in the medial prefrontal cortex, left angular gyrus, and right hippocampus (all clusters, p < 0.05, GRF-corrected), whereas the left superior temporal gyrus exhibited higher functional stability (cluster p < 0.05, GRF-corrected). No significant associations were observed between functional stability and memory test scores. Conclusions: The distribution and patterns of alterations in functional stability during sedation illustrate the modulation of functional architecture by dexmedetomidine from a dynamic perspective. Our findings provide novel insight into the dynamic brain functional networks underlying consciousness and memory in humans.

Plasma levels of interleukin-8 and response to paroxetine in patients with major depressive disorder.

OBJECTIVES: Immune dysregulation plays a key role in major depressive disorder (MDD). However, little is known about the complicated involvement of various interleukins in MDD. This study was performed to investigate the correlation between plasma interleukin-8 (IL-8) levels and treatment outcome of paroxetine (a selective serotonin reuptake inhibitor) in patients with MDD. METHODS: A total of 115 hospitalized patients (36 males and 79 females), aged from 18 to 72 years, were enrolled. Plasma levels of IL-8 were measured before treatment initiation (baseline) and at 8 weeks after oral paroxetine treatment. Efficacy of paroxetine was evaluated by use of the Hamilton Depression Rating Scale (HAMD-17). Baseline IL-8 levels were compared between responders and non-responders to paroxetine treatment. RESULTS: Plasma IL-8 levels decreased significantly after an 8-week antidepressant treatment in responders, in association with a dramatic decrease in HAMD-17 scores. In non-responders, plasma IL-8 levels did not change significantly at 8 weeks after antidepressant treatment. Baseline plasma IL-8 levels were found to be significantly lower in responders than in non-responders, showing a correlation between IL-8 and antidepressant response to paroxetine. CONCLUSIONS: These results indicate that plasma IL-8 levels were related to treatment outcome of paroxetine, and therefore suggest that IL-8 could be a promising predicator of treatment response in individual patients with MDD.

Differentiation Capacity of Human Urine-Derived Stem Cells to Retain Telomerase Activity.

Telomerase activity is essential for the self-renewal and potential of embryonic, induced pluripotent, and cancer stem cells, as well as a few somatic stem cells, such as human urine-derived stem cells (USCs). However, it remains unclear how telomerase activity affects the regeneration potential of somatic stem cells. The objective of this study was to determine the regenerative significance of telomerase activity, particularly to retain cell surface marker expression, multipotent differentiation capability, chromosomal stability, and in vivo tumorigenic transformation, in each clonal population of human primary USCs. In total, 117 USC specimens from 10 healthy male adults (25-57 years of age) were obtained. Polymerase chain reaction amplification of a telomeric repeat was used to detect USCs with positive telomerase activity (USCsTA+). A total of 80 USCsTA+ (70.2%) were identified from 117 USC clones, but they were not detected in the paired normal bladder smooth muscle cell and bone marrow stromal cell specimens. In the 20-40 years age group, approximately 75% of USC clones displayed positive telomerase activity, whereas in the 50 years age group, 59.2% of the USC clones expressed positive telomerase activity. USCsTA+ extended to passage 16, underwent 62.0 ± 4.8 population doublings, produced more cells, and were superior for osteogenic, myogenic, and uroepithelial differentiation compared to USCsTA-. Importantly, USCs displayed normal chromosome and no oncological transformation after being implanted in vivo. Overall, as a safe cell source, telomerase-positive USCs have a robust regenerative potential in cell proliferation and multipotent differentiation capacity.

Restoration of the Phenotype of Dedifferentiated Rabbit Chondrocytes by Sesquiterpene Farnesol.

Osteoarthritis (OA) is a joint disorder characterized by the progressive degeneration of articular cartilage. The phenotype and metabolism behavior of chondrocytes plays crucial roles in maintaining articular cartilage function. Chondrocytes dedifferentiate and lose their cartilage phenotype after successive subcultures or inflammation and synthesize collagen I and X (COL I and COL X). Farnesol, a sesquiterpene compound, has an anti-inflammatory effect and promotes collagen synthesis. However, its potent restoration effects on differentiated chondrocytes have seldom been evaluated. The presented study investigated farnesol's effect on phenotype restoration by examining collagen and glycosaminoglycan (GAG) synthesis from dedifferentiated chondrocytes. The results indicated that chondrocytes gradually dedifferentiated through cellular morphology change, reduced expressions of COL II and SOX9, increased the expression of COL X and diminished GAG synthesis during four passages of subcultures. Pure farnesol and hyaluronan-encapsulated farnesol nanoparticles promote COL II synthesis. GAG synthesis significantly increased 2.5-fold after a farnesol treatment of dedifferentiated chondrocytes, indicating the restoration of chondrocyte functions. In addition, farnesol drastically increased the synthesis of COL II (2.5-fold) and GAG (15-fold) on interleukin-1ß-induced dedifferentiated chondrocytes. A significant reduction of COL I, COL X and proinflammatory cytokine prostaglandin E2 was observed. In summary, farnesol may serve as a therapeutic agent in OA treatment.

Transplantation of 3D adipose-derived stem cell/hepatocyte spheroids alleviates chronic hepatic damage in a rat model of thioacetamide-induced liver cirrhosis.

Cirrhosis refers to irreversible liver damage where healthy tissue is replaced by scar tissue, resulting in impaired liver function. There is no cure and current treatments only prevent further liver damage; thus, novel therapeutic options are urgently needed. Here, we report a new approach that enables the formation of self-assembled 3D spheroids of adipose-derived stem cells (ADSCs) and murine hepatocytes (AML12) via reconstituted collagen fibers. Compared with the spheroids formed in the commercially available EZSHERE dish, the collagen fiber-based ADSC/hepatocyte spheroids offer a notable benefit in structure formation and paracrine factor secretion. To test the regenerative capability of the collagen fiber-based 3D ADSC/hepatocyte spheroids, a rat model of thioacetamide (TAA)-induced liver cirrhosis was employed. The transplantation of the collagen fiber-based 3D ADSC/hepatocyte spheroids show an improvement in liver function and ameliorates pathological liver cirrhosis in TAA-treated rats. In summary, our data show collagen fiber-based self-assembled 3D ADSC/hepatocyte spheroids to possess the excellent regenerative capacity in response to TAA-induced liver injury, promising an alternative therapeutic strategy for liver cirrhosis.

Dapagliflozin attenuates pressure overload-induced myocardial remodeling in mice via activating SIRT1 and inhibiting endoplasmic reticulum stress.

Endoplasmic reticulum stress-mediated apoptosis plays a vital role in the occurrence and development of heart failure. Dapagliflozin (DAPA), a new type of sodium-glucose cotransporter 2 (SGLT2) inhibitor, is an oral hypoglycemic drug that reduces glucose reabsorption by the kidneys and increases glucose excretion in the urine. Studies have shown that DAPA may have the potential to treat heart failure in addition to controlling blood sugar. This study explored the effect of DAPA on endoplasmic reticulum stress-related apoptosis caused by heart failure. In vitro, we found that DAPA inhibited the expression of cleaved caspase 3, Bax, C/EBP homologous protein (CHOP), and glucose-regulated protein78 (GRP78) and upregulated the cardiomyoprotective protein Bcl-2 in angiotensin II (Ang II)-treated cardiomyocytes. In addition, DAPA promoted the expression of silent information regulator factor 2-related enzyme 1 (SIRT1) and suppressed the expression of activating transcription factor 4 (ATF4) and the ratios p-PERK/PERK and p-eIF2α/eIF2α. Notably, the therapeutic effect of DAPA was weakened by pretreatment with the SIRT1 inhibitor EX527 (10 µM). Simultaneous administration of DAPA inhibited the Ang II-induced transformation of fibroblasts into myofibroblasts and inhibited fibroblast migration. In summary, our present findings first indicate that DAPA could inhibit the PERK-eIF2α-CHOP axis of the ER stress response through the activation of SIRT1 in Ang II-treated cardiomyocytes and ameliorate heart failure development in vivo.

Therapeutic Efficacy of Sesquiterpene Farnesol in Treatment of Cutibacterium acnes-Induced Dermal Disorders.

Acne vulgaris is a highly prevalent skin disorder requiring treatment and management by dermatologists. Antibiotics such as clindamycin are commonly used to treat acne vulgaris. However, from both medical and public health perspectives, the development of alternative remedies has become essential due to the increase in antibiotic resistance. Topical therapy is useful as a single or combined treatment for mild and moderate acne and is often employed as maintenance therapy. Thus, the current study investigated the anti-inflammatory, antibacterial, and restorative effects of sesquiterpene farnesol on acne vulgaris induced by Cutibacterium acnes (C. acnes) in vitro and in a rat model. The minimum inhibitory concentration (MIC) of farnesol against C. acnes was 0.14 mM, and the IC50 of 24 h exposure to farnesol in HaCaT keratinocytes was approximately 1.4 mM. Moreover, 0.8 mM farnesol exhibited the strongest effects in terms of the alleviation of inflammatory responses and abscesses and necrotic tissue repair in C.acnes-induced acne lesions; 0.4 mM farnesol and clindamycin gel also exerted similar actions after a two-time treatment. By contrast, nearly doubling the tissue repair scores, 0.4 mM farnesol displayed great anti-inflammatory and the strongest reparative actions after a four-time treatment, followed by 0.8 mM farnesol and a commercial gel. Approximately 2-10-fold decreases in interleukin (IL)-1ß, IL-6, and tumor necrosis factor (TNF)-α, found by Western blot analysis, were predominantly consistent with the histopathological findings and tissue repair scores. The basal hydroxypropyl methylcellulose (HPMC) gel did not exert anti-inflammatory or reparative effects on rat acne lesions. Our results suggest that the topical application of a gel containing farnesol is a promising alternative remedy for acne vulgaris.