Antifibrotic Effects Research Articles

Mechanistic Study of Purple Sweet Potato Anthocyanins: Multifaceted Anti-Fibrotic Effects and Targeting of PDGFRβ in Liver Fibrosis.

The purple sweet potato anthocyanins (PSPA) are known for their diverse health benefits, yet their hepatoprotective effects and the mechanisms by which they combat liver fibrosis have not been thoroughly investigated. This study aimed to elucidate these effects by employing a carbon tetrachloride (CCl4)-induced mouse model of liver fibrosis. We conducted a comprehensive analysis of the effects of PSPA on liver injury, oxidative stress, inflammation, and fibrosis-related signaling pathways. Our results demonstrate that PSPA can mitigate liver damage in mice, regulate key antioxidant enzymes such as catalase and SOD, and reduce oxidative stress as indicated by lowered MDA levels. PSPA also decrease the expression of inflammatory proteins, including CD3, CD4, CD45, IL-1β, TNF-α, and IL-17A, and reduce the accumulation of fibrotic markers like type I and III collagens and α-SMA. Additionally, PSPA have demonstrated the ability to inhibit key fibrogenic signaling proteins, including TGFβR2, p-Smad2, p-Smad3, p-PDGFRβ, p-AKT, p-ERK1/2, p-JNK1/2, and p-p38. Furthermore, we identified two potent monomers, PSPA-1 and PSPA-2, which directly target the PDGFRβ, a key player in fibrosis. The mechanism of action involves the inhibition of PDGF-B binding to PDGFRβ, thus disrupting the PDGF-B/PDGFRβ signaling pathway. These findings suggest that the hepatoprotective and antifibrotic effects of PSPA are due to their multifunctional bioactivities and the presence of specific active components that can effectively target fibrogenic protein.

Enhancing cancer therapy: advanced nanovehicle delivery systems for oridonin

Oridonin (ORI), an ent-kaurane diterpenoid derived from Rabdosia rubescens (Hemsl.) H.Hara, serves as the primary bioactive component of this plant. It demonstrates a broad spectrum of therapeutic activities, including moderate to potent anticancer properties, alongside anti-inflammatory, antibacterial, antifibrotic, immunomodulatory, and neuromodulatory effects, thus influencing diverse biological processes. However, its clinical potential is significantly constrained by poor aqueous solubility and limited bioavailability. In alignment with the approach of developing drug candidates from natural compounds, various strategies, such as structural modification and nanocarrier systems, have been employed to address these challenges. This review provides an overview of ORI-based nano-delivery systems, emphasizing their potential to improve the clinical applicability of oridonin in oncology. Although some progress has been made in advancing ORI nano-delivery research, it remains insufficient for clinical implementation, necessitating further investigation.

Protective effect of UDCA against IL-11- induced cardiac fibrosis is mediated by TGR5 signalling

IntroductionCardiac fibrosis occurs in a wide range of cardiac diseases and is characterised by the transdifferentiation of cardiac fibroblasts into myofibroblasts these cells produce large quantities of extracellular matrix, resulting in myocardial scar. The profibrotic process is multi-factorial, meaning identification of effective treatments has been limited. The antifibrotic effect of the bile acid ursodeoxycholic acid (UDCA) is established in cases of liver fibrosis however its mechanism and role in cardiac fibrosis is less well understood.MethodsIn this study, we used cellular models of cardiac fibrosis and living myocardial slices to characterise the macroscopic and cellular responses of the myocardium to UDCA treatment. We complemented this approach by conducting RNA-seq on cardiac fibroblasts isolated from dilated cardiomyopathy patients. This allowed us to gain insights into the mechanism of action and explore whether the IL-11 and TGFβ/WWP2 profibrotic networks are influenced by UDCA. Finally, we used fibroblasts from a TGR5 KO mouse to confirm the mechanism of action.Results and discussionWe found that UDCA reduced myofibroblast markers in rat and human fibroblasts and in living myocardial slices, indicating its antifibrotic action. Furthermore, we demonstrated that the treatment of UDCA successfully reversed the profibrotic IL-11 and TGFβ/WWP2 gene networks. We also show that TGR5 is the most highly expressed UDCA receptor in cardiac fibroblasts. Utilising cells isolated from a TGR5 knock-out mouse, we identified that the antifibrotic effect of UDCA is attenuated in the KO fibroblasts. This study combines cellular studies with RNA-seq and state-of-the-art living myocardial slices to offer new perspectives on cardiac fibrosis. Our data confirm that TGR5 agonists, such as UDCA, offer a unique pathway of action for the treatment of cardiac fibrosis. Medicines for cardiac fibrosis have been slow to clinic and have the potential to be used in the treatment of multiple cardiac diseases. UDCA is well tolerated in the treatment of other diseases, indicating it is an excellent candidate for further in-human trials.

Efficacy of Oroxylin A in ameliorating renal fibrosis with emphasis on Sirt1 activation and TGF-β/Smad3 pathway modulation

IntroductionRenal fibrosis poses a serious threat to human health. At present, there are few types of traditional Chinese medicine used to treat this disease, and Oroxylin A (OA), as a natural product with multiple biological activities, is expected to be used for the treatment of renal fibrosis.MethodsThe tolerance of osteoarthritis and its impact on renal fibrosis were studied through ADMET, Lipinski’s filter, establishment of a unilateral ureteral obstruction (UUO) model, and molecular docking.ResultsOA has good drug tolerance. Compared with the sham group, UUO mice that did not receive OA treatment showed severe tubular dilation and atrophy, extracellular matrix (ECM) deposition, and inflammatory cell infiltration in their kidneys, while OA-treated mice showed significant improvement in these symptoms. OA treatment remarkably restrained the accumulation of fibronectin and α-SMA. Moreover, OA treatment remarkably decreased the abnormal upregulation of inflammatory factors (IL-1β, IL-6, and TNF-α) in the obstructed kidney of UUO mice. Sirtuin1 (Sirt1) expression was markedly diminished in the kidneys of UUO mice and TGF-β1-induced HK-2 cells, whereas this reduction was largely reversed after OA treatment. The results support that OA exerts antifibrotic effects partly through the promotion of the activity of Sirt1. In in vitro results, OA treatment markedly inhibited the activation of Smad3 in UUO mice, thereby ameliorating renal fibrosis. OA could form hydrogen bonds with key the amino acid ASN226 in Sirt1, thereby activating Sirt1, which might also be the reason why OA could resist renal fibrosis.DiscussionOur study indicated that OA might exert anti-renal fibrosis effects through the activation of Sirt1 and the suppression of the TGF-β/Smad3 signaling pathway.

Fucoxanthin Enhances the Antifibrotic Potential of Placenta-derived Mesenchymal Stem Cells in a CCl4-induced Mouse Model of Liver.

The effectiveness of fucoxanthin (Fx) in liver diseases has been reported due to its anti-inflammatory and antifibrotic effects. Mesenchymal stem cells (MSCs)-based therapy has also been proposed as a promising strategy for liver fibrosis treatment. Recent studies have shown that the co-administration of MSCs and drugs demonstrates a pronounced effect on liver fibrosis. This study aimed to determine the therapeutic potential of placenta-derived MSCs (PD-MSCs) in combination with Fx to treat liver fibrosis and evaluate their impact on the main links of liver fibrosis pathogenesis. After PD-MSCs isolation and identification, outbred ICR/CD1 mice were divided into five groups: Control group, CCl4 group (CCl4), Fx group (CCl4+Fx), PD-MSCs group (CCl4+MSCs) and cotreatment group (CCl4+MSCs+Fx). Biochemical histopathological investigations were performed. Semiquantitative analysis of the alpha-smooth muscle actin (α-SMA+), matrix metalloproteinases (MMP-9+, MMP-13+), tissue inhibitor of matrix metalloproteinases-1 (TIMP-1+) areas, and the number of positive cells in them were studied by immunohistochemical staining. Transforming growth factor-beta (TGF-β), hepatic growth factor (HGF), procollagen-1 (COL1α1) in liver homogenate and proinflammatory cytokines in blood serum were determined using an enzyme immunoassay. Compared to the single treatment with PD-MSCs or Fx, their combined administration significantly reduced liver enzyme activity, the severity of liver fibrosis, the proinflammatory cytokine levels, TGF-β level, α-SMA+, TIMP-1+ areas and the number of positive cells in them, and increased HGF level, MMP-13+, and MMP-9+ areas. Fx enhanced the therapeutic potential of PD-MSCs in CCl4-induced liver fibrosis, but more investigations are necessary to understand the mutual impact of PD-MSCs and Fx.

Deubiquitinase inhibitor bAP-15 suppresses renal epithelial to mesenchymal transition via inhibition of p300 stability

Renal fibrosis is an irreversible disease that is common in patients with chronic kidney disease. Elevated levels of the histone acetyltransferase p300 have been reported in various fibrotic diseases, including renal fibrosis, suggesting that p300 may be a promising therapeutic target. To investigate the specific deubiquitinase (DUB) involved in the regulation of p300 protein stability in renal epithelial cells, we tested 13 DUB inhibitors using a kidney tubular epithelial cell line. We found that the p300-specific DUB inhibitor, bAP-15 reduces p300 protein stability by targeting ubiquitin-specific protease 14 (USP14) and ubiquitin C-terminal hydrolase L5 (UCHL5). The mRNA levels of USP14 and UCHL5 were increased in patients with chronic kidney disease, and increased protein levels of USP14 and UCHL5 during fibrosis progression were validated using a mouse renal fibrosis model. Both USP14 and UCHL5 interacted with p300 in kidney tubular epithelial cells, with increased binding affinity in response to TGF-β. Moreover, bAP-15-induced p300 degradation inhibited epithelial-to-mesenchymal transition and reduced the expression of pro-fibrotic target genes. Our findings demonstrate an anti-fibrotic effect of bAP-15 through the regulation of p300 stability and suggest that bAP-15 may be a potential therapeutic agent for renal fibrosis.

Melatonin ameliorates age-related sarcopenia by inhibiting fibrogenic conversion of satellite cell

The fibrogenic conversion of satellite cells contributes to the atrophy and fibrosis of skeletal muscle, playing a significant role in the pathogenesis of age-related sarcopenia. Melatonin, a hormone secreted by the pineal gland, exhibits anti-aging and anti-fibrotic effects in various conditions. However, the effect of melatonin on satellite cell fate and age-related sarcopenia remains under-explored. Here, we report that melatonin treatment mitigated the loss of muscle mass and strength in aged mice, replenished the satellite cell pool and curtailed muscle fibrosis. When primary SCs were cultured in vitro and subjected to aging induction via d-galactose, they exhibited a diminished myogenic potential and a conversion from myogenic to fibrogenic lineage. Notably, melatonin treatment effectively restored the myogenic potential and inhibited this lineage conversion. Furthermore, melatonin attenuated the expression of the fibrogenic cytokine, transforming growth factor-β1, and reduced the phosphorylation of its downstream targets Smad2/3 both in vivo and in vitro. In summary, our findings show melatonin's capacity to counteract muscle decline and inhibit fibrogenic conversion in aging SCs and highlight its potential therapeutic value for age-related sarcopenia.Graphical

Targeting CCL5 Attenuates Fibrosis via Activation of PI3k/Akt Signaling Axis After Glaucoma Filtration Surgery

Purpose Glaucoma filtration surgery (GFS) stands as a paramount clinical intervention for glaucoma. Nonetheless, the prevalent cause of GFS failure is filtration bleb scarring, and the role of inflammation and immune response in contributing to fibrosis remains elusive. Methods The study employed 30 female Sprague-Dawley rats (8 weeks old, 200-250 g) to assess the anti-scarring impact of the Chemokine (C-C motif) receptor 5 (CCR5)-Chemokine (C-C motif) ligand 5 (CCL5) antibody after GFS. Additionally, anti-fibrotic effects on HConFs were examined, creating an intra-operative inflammatory response using damaged-HConFs supernatant medium (DHSM). In vitro and in vivo validation aimed to elucidate the potential anti-fibrotic molecular mechanism of the CCR5-CCL5 antibody. Results The CCR5-CCL5 antibody effectively prolonged filtration bleb duration and enhanced the functionality of the filtered bleb. Improved postoperative intraocular pressure values (IOP) and morphological images were observed in the CCR5-CCL5 antibody-treated group. Histochemical staining and cellular experiments confirmed the antifibrotic function of the CCR5-CCL5 antibody. Notably, M2-type macrophage polarization was reduced in the CCR5-CCL5 antibody-treated model. CCL5-induced fibrosis in HConFs was mediated through the PI3K/Akt signaling pathway. Consistently, inhibition of PI3K/Akt significantly attenuated the profibrotic effects of CCR5-CCL5. Mechanistically, the CCL5 antibody exerts its antifibrotic effect by targeting CCR5 on HConFs, leading to the inhibition of the PI3K/Akt mechanism. Conclusions This study unveils that CCR5-CCL5 promotes fibrosis in GFS through inflammatory stimulation of HConFs and enhanced activation of the PI3K/Akt signaling pathway. The findings suggest that intraoperative CCR5-CCL5 antibody treatment could serve as a cost-effective therapeutic agent or a useful adjuvant in preventing ocular bleb scar formation.

Chemogenomic Screening in a Patient-Derived 3D Fatty Liver Disease Model Reveals the CHRM1-TRPM8 Axis as a Novel Module for Targeted Intervention.

Metabolic dysfunction-associated steatohepatitis (MASH) is a leading cause of chronic liver disease with few therapeutic options. To narrow the translational gap in the development of pharmacological MASH treatments, a 3D liver modelfrom primary human hepatocytes and non-parenchymal cells derived from patients with histologically confirmed MASH was established. The model closely mirrors disease-relevant endpoints, such as steatosis, inflammation and fibrosis, and multi-omics analyses show excellent alignment with biopsy data from 306 MASH patients and 77 controls. By combining high-content imaging with scalable biochemical assays and chemogenomic screening, multiple novel targets with anti-steatotic, anti-inflammatory, and anti-fibrotic effects are identified. Among these, activation of the muscarinic M1 receptor (CHRM1) and inhibition of the TRPM8 cation channel result in strong anti-fibrotic effects, which are confirmed using orthogonal genetic assays. Strikingly, using biosensors based on bioluminescence resonance energy transfer, a functional interaction along a novel MASH signaling axis in which CHRM1 inhibits TRPM8 via Gq/11 and phospholipase C-mediated depletion of phosphatidylinositol 4,5-bisphosphate can be demonstrated. Combined, this study presents the first patient-derived 3D MASH model, identifies a novel signaling module with anti-fibrotic effects, and highlights the potential of organotypic culture systems for phenotype-based chemogenomic drug target identification at scale.

The acidic microenvironment in the perisinusoidal space critically determines bile salt-induced activation of hepatic stellate cells

Cholestatic liver diseases, accompanied by the hepatic accumulation of bile salts, frequently lead to liver fibrosis, while underlying profibrogenic mechanisms remain incompletely understood. Here, we evaluated the role of extracellular pH (pHe) on bile salt entry and hepatic stellate cell (HSC) activation and proliferation. As modulators of intracellular pH (pHi), various proton pump inhibitors (PPI) were tested for their ability to prevent bile salt entry and HSC activation. Lastly, the PPI pantoprazole was employed in the 3,5-Diethoxycarbonyl-1,4-Dihydrocollidine (DDC)-diet model of cholestatic liver fibrosis. We found in vitro, that slightly acidic pHe (7.2–7.3) enhanced bile salt accumulation in HSC and was a prerequisite to bile salt-induced HSC activation. Pantoprazole in the DDC model exhibited antifibrotic effects. We conclude that bile salt-induced activation of HSC may depend on the slightly acidic microenvironment present in the perisinusoidal space and modulation of pHi in HSC may offer a novel pharmacological target in cholestatic disease.

Anti-fibrotic effects of lisinopril (ACE inhibitor) and fasudil (ROCK inhibitor) in combination for canine corneal fibrosis invitro.

Corneal fibrosis is a leading cause of blindness in mammalian species and may result in compromised performance in sports and daily functions. This study evaluated the safety and anti-fibrotic effects of the FDA-approved drugs, angiotensin-converting enzyme inhibitor (ACE-I) lisinopril and rho-kinase inhibitor (ROCK-I) fasudil, alone and in combination, on the canine cornea using an established invitro model. To test the safety and efficacy of lisinopril and fasudil, primary canine corneal fibroblasts (CCFs) generated from donor corneas of healthy dogs (n = 20) were used. A series of dose-dependent and time-dependent assays with lisinopril (1-50 μM) and fasudil (1-10 nM) were performed. qRT-PCR, immunofluorescence (IF) staining, cell viability assay, cell proliferation assay, LIVE/DEAD viability/cytotoxicity assay, TUNEL assay, and total cell count were performed. A 25-μM lisinopril and 3-nM fasudil dose were safe, nontoxic, and optimal for therapeutic evaluations invitro. Treatments of lisinopril or fasudil, alone or in-combination, to CCFs grown in the presence of TGF-β1 (5 ng/mL) showed inhibition of myofibroblast formation based on phase-contrast microscopy. The qRT-PCR and IF studies showed a significant decrease in expression of profibrotic markers, including α-smooth muscle actin (α-SMA; p < .0001), fibronectin (FN; p = .0002), tenascin C (TNC; p < .0001), Collagen I (Col-I; p < .0001), Collagen IIIA1 (Co-IIIA1; p < .0001), and Collagen IV (Co-lV; p < .0001). An ophthalmic formulation consisting of lisinopril and fasudil may offer a safe and effective method to treat canine corneal fibrosis. Additional studies evaluating safety and efficacy of this formulation invivo are warranted.

Osteopontin neutralization increases vitamin D receptors on NKT cells and ameliorates liver fibrosis by promoting their activity

Introduction and AimsVitamin D has an immunomodulatory property influencing the activity of NKT cells. We aimed to study the impact of osteopontin (OPN), a key driver of fibrosis, on NKT cells’ vitamin D receptor (VDR) and activity alterations.MethodsLiver fibrosis was induced in BALB/C mice with carbon-tetrachloride (CCl4) for 8 weeks with either vitamin D [100 ng/kg] or InVivoMAb anti-mouse OPN [100 μg/kg] 2X/week started at week-4 of CCl4. The liver injury profile of serum ALT, AST, and inflammatory cytokines were evaluated. Histopathological findings were assessed via H&amp;amp;E staining and Sirius-Red staining. Fibrotic genes of αSMA, CREBP, and collagen III were assessed using RT-PCR. Fast blood sugar, insulin, liver cholesterol, and triglyceride were evaluated. Liver tissue-resident (tr)-NKT cells were obtained for VDR expressions, molecular pathways of p-STAT1 and P-STAT-5, and activation markers of CD107a and NKp46 using flow cytometry.ResultsFollowing vitamin D treatment, H&amp;amp;E staining revealed reduced microvascular and macrovascular steatosis, while Sirius-Red staining showed less fibrosis accumulation in liver fibrosis mice than in untreated counterparts. Results were associated with a significant decrease in serum cytokines of IL-β/IL-6/IL-4/OPN/TNF-α and serum AST and ALT by 2-fold and 3-fold, respectively. Fibrotic markers showed an average 1.3-fold decrease in αSMA, CREB, and Col-III in liver fibrosis mice following vitamin D treatment. Quantitated liver cholesterol and triglycerides, serum insulin, and fasting blood sugar ameliorated their levels following vitamin D treatment in liver fibrosis mice. OPN-neutralizing antibody over-expressed VDR on trNKT cells and increased CD107a and NKp46 activities of 3.1 and 3.5 folds, respectively, associated with increasing in p-STAT1 and p-STAT5 phosphorylation. These results were accompanied with a decrease in hepatic-stellate-cell activation markers of αSMA, Col-III, and desmin.ConclusionVDR expressions affect trNKT cells activity and could modulate progressions of liver fibrosis. Using an OPN-neutralizing antibody exhibited an antifibrotic effect by alleviating the liver injury profile through NKT cells. It is also suggested as an immunomodulatory target of liver fibrosis.

Inhaled exogenous thymosin beta 4 suppresses bleomycin-induced pulmonary fibrosis in mice via TGF-β1 signalling pathway.

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and fibrotic interstitial lung disease. The two drugs indicated for IPF have limited efficacy and there is an urgent need to develop new drugs. Thymosin β4 (Tβ4) is a natural endogenous repair factor whose antifibrotic effects have been reported. This study aimed to evaluate the effect of exogenous recombinant human thymosin beta 4 (rhTβ4) on pulmonary fibrosis. Pulmonary fibrosis was induced in mice with bleomycin, and rhTβ4 was administrated by nebulization following three strategies: early dosing, mid-term dosing, and late dosing. The rhTβ4 efficacy was assessed by hydroxyproline, lung function, and lung histopathology. In vitro, the effects of rhTβ4 on fibroblast and lung epithelial cell phenotypes, as well as the TGF-β1 pathway, were evaluated. Aerosol administration of rhTβ4 could alleviate bleomycin-induced pulmonary fibrosis in mice at different stages of fibrosis. Studies conducted in vitro suggested that rhTβ4 could suppress lung fibroblasts from proliferating, migrating, and activation via regulating the TGF-β1 signalling pathway. In vitro, rhTβ4 also inhibited the epithelial-mesenchymal transition-like process of pulmonary epithelial cells. This study suggests that nebulized rhTβ4 is a potential treatment for IPF.

Gastrodin attenuates diabetic cardiomyopathy characterized by myocardial fibrosis by inhibiting the KLK8-PAR1 signaling axis

BackgroundDiabetic cardiomyopathy (DCM), characterized by myocardial fibrosis, is a major cause of mortality and morbidity in diabetic patients; the inhibition of cardiac fibrosis is a fundamental strategy for treating DCM. Gastrodin (GAS), a compound extracted from Gastrodia elata protects against DCM, but the molecular mechanism underlying its antifibrotic effect has not been elucidated.MethodsIn vivo, the effects of GAS were investigated using C57BL/6 mice with DCM, which was induced by administering a high-sugar, high-fat (HSF) diet and streptozotocin (STZ). We assessed the cardiac function in these mice and detected histopathological changes in their hearts and the degree of cardiac fibrosis. In vitro, neonatal rat cardiac fibroblasts (CFs) were transformed into myofibroblasts by exposing them to high glucose combined with high palmitic acid (HG-PA), and CFs were induced by pEX-1 (pGCMV/MCS/EGFP/Neo) plasmid-mediated overexpression of KLK8, which contains the rat KLK8 gene. The KLK8 siRNA was knocked down to study the effects of GAS on CF differentiation, collagen synthesis, and cell migration by specific mechanisms of action of GAS.ResultsGAS attenuated pathological changes in the hearts of DCM mice, rescued impaired cardiac function, and attenuated cardiac fibrosis. Additionally, the results of molecular docking analysis showed that GAS binds to kinin-releasing enzyme-related peptidase 8 (KLK8) to inhibit the increase in protease-activated receptor-1 (PAR-1), thus attenuating myocardial fibrosis. Specifically, GAS attenuated the transformation of neonatal rat CFs to myofibroblasts exposed to HG-PA. Overexpressing KLK8 promoted CF differentiation, collagen synthesis, and cell migration, and KLK8 siRNA attenuated HG-PA-induced CF differentiation, collagen synthesis, and cell migration. Further studies revealed that a PAR-1 antagonist, but not a PAR-2 antagonist, could attenuate CF differentiation, collagen synthesis, and cell migration. Additionally, GAS inhibited KLK8 upregulation and PAR1 activation, thus blocking the differentiation, collagen synthesis, and cell migration of HG-PA-exposed CFs and triggering TGF-β1/Smad3 signaling.ConclusionGAS alleviated pathological changes in the hearts of DCM model mice induced by an HSF diet combined with STZ. KLK8 mediated HG-PA-induced differentiation, collagen synthesis, and the migration of CFs. GAS attenuated the differentiation, collagen synthesis, and migration of CFs by inhibiting the KLK8-PAR1 signaling axis, a process in which TGF-β1 and Smad3 are involved.Graphical

Dual-Integrin-Targeted Supramolecular Peptide Nanoarchitectonics for Enhanced Hepatic Delivery and Antifibrotic Therapy.

The integration of integrin-binding peptides within self-assembling building blocks is crucial for the development of targeted nanoarchitectonics. However, such constructs typically incorporate only a single integrin-binding peptide, limiting their multifunctionality. Herein, a rationally designed self-assembling peptide with dual integrin-binding motifs for α5β1 and αvβ3 is presented. This peptide forms highly ordered nanofibers or nanoparticles (VH-NPs) with tailored secondary structures. In vitro and in vivo studies demonstrate that VH-NPs target activated hepatic stellate cells via dual-integrin interactions, enabling selective targeting to fibrotic livers and suppressing α5β1 and αvβ3. Notably, VH-NPs can encapsulate rhein through noncovalent interactions, resulting in peptide-rhein nanoarchitectonics that display augmented antifibrotic effects. These findings highlight the potential of self-assembling peptides that leverage multiple targets and therapeutic modules as a promising strategy for constructing multifunctional nanoarchitectonics.

Dachengqi decoction ameliorated liver injury in liver fibrosis mice by maintaining gut vascular barrier integrity

BackgroundSevere liver fibrosis may be accompanied by intestinal barrier damage, such as bacterial peritonitis, suggesting that the role of the gut-liver axis is nonnegligible. Dachengqi decoction (DCQD) was reported to improve bowel movements, but whether DCQD was effective for intestinal damage caused by liver fibrosis remained unclear. PurposeTo investigate the role of DCQD in liver fibrosis-related gut vascular barrier (GVB) damage in mice. Study DesignDCQD was verified to reduce the imbalance of the intestinal vascular barrier and restore intestinal homeostasis to prove that DCQD acts through the gut-liver axis. MethodsThree graded doses of DCQD were gavaged into the CCL4-induced mice for 12 weeks to evaluate the resistance to liver and intestinal damage. Immunoblotting and primary flow cytometry were used to assess organ damage; PV-1 to indicate gut vascular barrier damage; serum endotoxin, fecal SCFAs, and liver microbiota translocation to examine the gut-liver axis's crosstalk. Network pharmacology and RNA sequencing were used to analyze and verify the signaling pathway of DCQD. ResultsDCQD significantly ameliorated fibrosis and inflammatory response in the CCL4-induced mice, alleviated gut leakage, downregulated PV-1, relieved liver enterobacterial translocation, restored intestinal homeostasis, and reduced infiltration of myeloid cells in the lamina propria. Network pharmacology and RNA sequencing results indicated that DCQD exerted anti-fibrotic and anti-inflammatory effects in the liver through inhibition of the ESR1/NF-κB/TNFα pathway and maintained GVB homeostasis through the FUT2/Wnt/β-Catenin pathway. ConclusionsDCQD broke the closed-loop damage of the gut-liver axis to improve GVB injury in mice with liver fibrosis.

CXCL5 inhibition ameliorates acute kidney injury and prevents the progression from acute kidney injury to chronic kidney disease.

Acute kidney injury (AKI) increases the risk of chronic kidney disease (CKD). CXC motif chemokine ligand 5 (CXCL5) is up-regulated in kidney diseases. We aimed to investigate the direct effect of CXCL5 on the pathology of AKI. Serum and renal expression of CXCL5 were increased in animals with renal ischemia-reperfusion injury or unilateral ureteral obstruction. CXCL5-knockout mice exhibited reduced systemic oxidative stress and preserved renal function in the acute and chronic phases of AKI, as evidenced by reductions in serum BUN and creatinine levels, the urinary albumin-to-creatinine ratio, and the kidney-to-body weight ratio. CXCL5-knockout mice improved AKI-induced tubular injury and fibrosis, reduced renal macrophage infiltration, and reduced expression of NADPH oxidase and inflammatory and fibrotic proteins. CXCL5 activated p47 to up-regulate ROS generation and induce cellular damages through CXCR2. CXCL5 knockdown exerted antioxidative, anti-inflammatory, anti-fibrotic, and anti-apoptotic effects on hypoxia-reoxygenation-stimulated renal proximal tubular epithelial cells. Clinical data indicated elevated circulating and renal CXCL5 in CKD patients, and renal CXCL5 was correlated with increased renal fibrosis and decreased estimated glomerular filtration rate. Altogether, CXCL5 levels increased in experimental AKI and clinical CKD, and in vivo and in vitro CXCL5 inhibition may reduce acute tubular injury and prevent the subsequent progression from AKI to CKD.

The deleterious effects of CDK4/6 inhibition on renal recovery post-acute kidney injury

Acute kidney injury (AKI) is a common clinical problem, and patients who survive AKI have a high risk of chronic kidney disease (CKD). The acute protective effects of Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors in AKI have been examined, there is still relatively little known regarding the impact of acute CDK4/6 inhibition on the chronic sequence of AKI. Therefore, we utilized the CDK4/6 inhibitor Palbociclib to examine the long-term effects of CDK4/6 inhibition in a rodent model of ischemic AKI. Palbociclib (Palb) was administered during the acute stage or post the acute stage of AKI and mice were sacrificed 21 days post injury. We found that Palb could cause renal senescence and renal fibrosis. Furthermore, dasatinib (D) plus quercetin (Q) were used to eliminate senescent cells in ischemic AKI murine model and Palb was administered post the treatment of D + Q. We found that Palb could reverse the senolytic and antifibrotic effects induced by D + Q, which indicates that the profibrotic effect of Palb could be ascribed to its pro-senescent effects. Our results demonstrate that CDK4/6 inhibitors treatment might be deleterious on the chronic sequence of AKI.

Discovery of Selective PDE1 Inhibitors with Anti-pulmonary Fibrosis Effects by Targeting the Metal Pocket.

Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease with no ideal drugs. Our previous research demonstrated that phosphodiesterase 1 (PDE1) could be a promising target for the treatment of IPF. However, only a few selective PDE1 inhibitors are available, and the mechanism of recognition between inhibitors and the PDE1 protein is not fully understood. This study carried out a step-by-step optimization of a dihydropyrimidine hit Z94555858. By targeting the metal pocket of PDE1, a lead compound 3f was obtained, exhibiting an IC50 value of 11 nM against PDE1, moderate selectivity over other PDEs, and significant anti-fibrotic effects in bleomycin-induced pulmonary fibrosis rats. The structure-activity relationship study aided by molecular docking revealed that forming halogen bonds with water in the metal pocket greatly enhanced the PDE1 inhibition, providing a novel strategy for further rational design of PDE1 inhibitors.

Molecular Mechanism of Finerenone in Treating Diabetic Nephropathy Based on Bioinformatics

Background: Diabetic Nephropathy (DN) is the leading cause of the end-stage renal disease (ESRD). Finerenone (with the molecular formula C21H22N4O3) is an oral non-steroidal mineralocorticoid antagonist (ns-MRA) that is both highly potent and has strong selectivity for the MR. At present, it has been used to treat DN. However, the molecular mechanism of finerenone in the treatment of diabetic nephropathy remains unclear. Objective: In this study, we employed bioinformatics approaches to investigate the molecular mechanism of finerenone as a novel therapeutic agent for the treatment of DN. Methods: We examined a number of databases, including GEO, DisGeNET, Genecards, and OMIM, to find putative genes linked to DN. We then employed the PubChem database and PharmMapper service platform to identify targets of finerenone. Further analysis was conducted using the DAVID database for enrichment analysis and the STRING database for protein-protein interaction (PPI) networks. Molecular docking (MD) was performed using AutoDockTools software, and results were visualized using PyMOL software. Results: In total, we identified 82 drug-disease targets, primarily associated with lipid and atherosclerosis, diabetic cardiomyopathy, MAPK signaling pathway, and PI3K-Akt signaling pathway. Our PPI network analysis and docking studies demonstrated good binding ability of finerenone to specific targets such as AKT1, MMP-9, IGF1, EGFR, CASP3, PPARG, ESR1, MMP-2, and KDR. Conclusion: Finerenone has the potential to reduce the progression of DN through various pathways, including lipid and atherosclerosis, diabetic cardiomyopathy, MAPK signaling pathway, and PI3KAkt signaling pathway. Moreover, it could exert anti-inflammatory and antifibrotic effects on specific targets, such as AKT1, MMP-9, IGF1, EGFR, CASP3, PPARG, ESR1, MMP-2, and KDR.