Search

Recent studies indicate mammalian target of rapamycin (mTOR) may play an important role in PCa progression and drug resistance. Here, we investigated the effects of a novel mTORC1/C2 dual inhibitor, AZD2014, on naive and docetaxel (Doc)‐pre‐treated castration‐resistant PCa (CRPC) cells and explored its therapeutic potential in CRPCs. In the current study, AZD2014 has a greater inhibitory effect against 4EBP1 and AKT phosphorylation than rapamycin in CRPC cells and prevented the feedback activation of AKT signalling. Importantly, AZD2014 suppressed CRPC cell growth in vitro by suppressing proliferation, apoptosis, cell cycle arrest at G1 phase and autophagy to a greater extent than rapamycin. Moreover, AZD2014 was more efficacious than rapamycin in inhibiting migration, invasion and EMT progression in Doc‐sensitive and Doc‐resistant CRPC cells. Overall, AZD2014 showed significant antitumour effects. Thereby, the current study highlights a reliable theoretical basis for the clinical application of AZD2014 in both Doc‐sensitive and Doc‐resistant CRPCs.

Introduction: Prostatic stromal tumor of uncertain malignant potential (STUMP) is a rare disease that may coexist with prostate stromal sarcoma (PSS). We aimed to analyze the histological and clinical features of STUMP. Methods: Twenty-three patients diagnosed with STUMP from 2008 to 2019 were included. Clinicopathological and follow-up information was collected. In the subgroup analysis, we divided the patients into a pure STUMP group (N = 18) and a mixed STUMP (STUMP coexisting with PSS) group (N = 5). Student’s t test was used to compare the 2 groups. Results: Patients had a mean age of 55.5 ± 19.4 years and an average follow-up time of 42.3 months. The mean prostate volume was 109.2 ± 73.5 cm3, and the mean prostate-specific antigen was 8.03 ± 10.5 ng/mL. In the subgroup analysis, 16.7% (2/12) of pure STUMP patients had disease progression, while 100% (3/3) of mixed STUMP patients suffered from recurrence. Compared with the pure STUMP group, the mixed STUMP group was younger (37.2 vs. 60.6 years, p = 0.013) and had lower expression of estrogen receptor and progesterone receptor (p = 0.004 and p < 0.001, respectively). Conclusion: STUMP is a rare disease with a relatively good prognosis. However, there is still a possibility of disease progression or coexistence with stromal sarcoma. Timely diagnosis and regular monitoring may be helpful in improving treatment outcomes.

Mitochondrial dysfunction is a hallmark of cancer cells and targeting cancer mitochondria has emerged as a promising anti-cancer therapy. Previously, we repurposed chlorambucil by conjugating it to a mitochondrial targeting triphenylphosphonium (TPP) group to design Mito-Chlor, a novel agent that acts on mitochondria DNA (mtDNA). Herein, we show that Mito-Chlor, but not chlorambucil, inhibits the nascent transcription of mtDNA. Clustering analysis of transcriptomic profile of our Bru-seq database led to the identification of another mitochondrial transcription inhibitor SQD1, which inhibits the proliferation of MIA PaCa-2 cells with an IC(50) of 1.3 μM. Interestingly, Mito-Chlor reduces expression of mitochondrial proteins, interferes with mitochondria membrane potential, and impairs oxidative phosphorylation while SQD1 does not. Both compounds increased cellular and mitochondrial reactive oxygen species and stimulated similar signaling pathways in response to oxidative stress. As mitochondrial transcription inhibitors and redox modulators, SQD1 and Mito-Chlor are promising for the treatment of pancreatic cancer by blocking mitochondrial function.

This study aimed at identifying antioxidant and anti-inflammatory peptides derived from the in vitro gastrointestinal digestion of germinated and heated (microwave and boiling) foxtail millet. The protein digest fraction containing low-molecular-weight peptides (

Background Many studies have reported the prognostic significance of the bone scan index (BSI) for metastatic castration-resistant prostate cancer (mCRPC); however, these reports are controversial. This study investigated the BSI in mCRPC and its relationship with prognosis. Methods The PubMed, Cochrane, and Embase databases were searched systematically for relevant articles published before September 1, 2019. Hazard ratios (HRs) were used to investigate the prognostic value. Results This study finally identified 9 eligible studies. The results suggested that high baseline BSI predicted poor OS (HR = 1.331, 95% CI: 1.081–1.640) and that elevated ΔBSI also predicted poor OS (HR = 1.220, 95% CI: 1.015–1.467). The subgroup analysis stratified by ethnicity showed that the baseline BSI and ΔBSI predicted poor OS in the Asian population but not in the Caucasian population. We also performed a subgroup analysis based on the different cut-off values of baseline BSI. The subgroup of ≤1 showed a significant association with OS in mCRPC patients. Conclusion Our study demonstrated that high baseline BSI and elevated ΔBSI predicted poor OS in patients with mCRPC. Hence, the BSI can serve as a prognostic indicator for mCRPC patients and may therefore guide clinical treatment in the future.

Anti-epidermal growth factor receptor (EGFR) therapy–associated cutaneous toxicity is a syndrome characterized by papulopustular rash, local inflammation, folliculitis and microbial infection, resulting in a decrease in quality of life and dose interruption. However, no effective clinical intervention is available for this adverse effect. Here, we report the atrophy of dermal white adipose tissue (dWAT), a highly plastic adipose tissue with various skin-specific functions, correlates with rash occurrence and exacerbation in a murine model of EGFR inhibitor-induced rash. The reduction in dWAT is due to the inhibition of adipogenic differentiation by defects in peroxisome proliferator-activated receptor γ (PPARγ) signaling, and increased lipolysis by the induced expression of the lipolytic cytokine IL6. The activation of PPARγ by rosiglitazone maintains adipogenic differentiation and represses the transcription of IL6, eventually improving skin functions and ameliorating the severity of rash without altering the antitumor effects. Thus, activation of PPARγ represents a promising approach to ameliorate cutaneous toxicity in patients with cancer who receive anti-EGFR therapy.Graphical abstract

Excessive apoptosis of chondrocytes and degradation of the extracellular matrix (ECM) contribute to the typical pathological characteristics of osteoarthritis (OA). Various studies have reported that tetramethylpyrazine (TMP) protects against multiple disorders by inhibiting inflammation and oxidative stress. The present study investigated the effects of TMP on chondrocytes and evaluated the associated mechanisms. To determine the effect of TMP on OA and the underlying mechanisms, chondrocytes were incubated with TMP and IL‑1β or thapsigargin (TG) Western blotting assays were performed to examine the expression levels of endoplasmic reticulum (ER) stress proteins, and TUNEL staining, fluorescence immunostaining and reverse transcription‑quantitative PCR were used to determine the apoptosis levels, and catabolic and inflammatory factors. It was found that TMP protected chondrocytes by suppressing IL‑1β‑induced expression of glucose‑regulated protein 78 (GRP78) and CHOP (an apoptotic protein). TMP regulated the TG‑mediated upregulated expression of GRP78 and CHOP in the chondrocytes of rats, as well as markedly suppressed levels of ER stress‑triggered inflammatory cytokines (TNF‑α and IL‑6). Furthermore, TMP modulated TG‑induced changes in ECM catabolic metabolism in rat chondrocytes. Collectively, TMP alleviated ER‑stress‑activated apoptosis and related inflammation in chondrocytes, indicating that it has therapeutic potential for the treatment of OA.

BackgroundIncreasing researches have been reported that epigenetic alterations play critical roles in ESCC development. However, the role of the histone demethylase KDM4D in ESCC tumorigenesis is poorly investigated. This study aims to discover the underlying mechanisms between KDM4D and ESCC progression.MethodsCCK-8 assays, clone formation assay and soft-agar assays were performed to assess cell proliferation. Transwell assay was utilized to assess cell migration efficiency, while sphere formation assay was used to evaluate the cell self-renewal ability. Bioinformatic analysis was conducted to identify prognostic factors and predict the potential E3 ubiquitin ligases. In vitro ubiquitination assay was conducted to confirm the regulations between SYVN1 and HMGB1. The mRNA levels or protein levels of genes were detected by real-time PCR and western blot analysis. In vivo tumor xenograft models were used to determine whether the HMGB1 inhibition affected the malignant features of ESCC cells.ResultEpigenome screening and low-throughput validations highlighted that KDM4D is a tumor suppressor in ESCC. KDM4D expressed lowly in tumors that predicts poor prognosis. KDM4D deficiency significantly enhanced tumor growth, migration and stemness. Mechanistically, KDM4D transcriptionally activates SYVN1 expressions via H3K9me3 demethylation at the promoter region, thereby triggering the ubiquitin-dependent degradation of HMGB1. Low KDM4D depended on accumulated HMGB1 to drive ESCC progression and aggressiveness. Targeting HMGB1 (Glycyrrhizin) could remarkably suppress ESCC tumor growth in vitro and in vivo, especially in KDM4D-deficient cells.ConclusionsWe systematically identified KDM4D/SYVN1/HMGB1 axis in ESCC progression, proving novel biomarkers and potential therapeutic targets.

Neuroinflammation following spinal cord injury usually aggravates spinal cord damage. Many inflammatory cytokines are key players in neuroinflammation. Owing largely to the multiplicity of cytokine targets and the complexity of cytokine interactions, it is insufficient to suppress spinal cord damage progression by regulating only one or a few cytokines. Herein, we propose a two-pronged strategy to simultaneously capture the released cytokines and inhibit the synthesis of new ones in a broad-spectrum manner. To achieve this strategy, we designed a core/shell-structured microcomposite, which was composed of a methylprednisolone-incorporated polymer inner core and a biocompatible polydopamine outer shell. Thanks to the inherent adhesive nature of polydopamine, the obtained microcomposite (MP-PLGA@PDA) efficiently neutralized the excessive cytokines in a broad-spectrum manner within 1 day after spinal cord injury. Meanwhile, the controlled release of immunosuppressive methylprednisolone reduced the secretion of new inflammatory cytokines. Benefiting from its efficient and broad-spectrum capability in reducing the level of cytokines, this core/shell-structured microcomposite suppressed the recruitment of macrophages and protected the injured spinal cord, leading to an improved recovery of motor function. Overall, the designed microcomposite successfully achieved the two-pronged strategy in cytokine neutralization, providing an alternative approach to inhibit neuroinflammation in the injured spinal cord.

Background: This article presents a rare case of skull metastasis of primary hepatocellular carcinoma that manifests the isolated progressive enlargement of the head mass as the first symptom. Case presentation:A 65-year-old female patient presented an isolated painless mass in the head, which grew rapidly over the last month. Head CT revealed a 6.4 cm×5.6cm osteolytic destruction in the right parietal bone. MRI further revealed that the occupation was significantly enhanced in the T1 reinforced phase. The patient underwent total surgical resection. Postoperative pathology confirmed that the head mass was the skull metastasis from hepatocellular carcinoma (HCC). Conclusion: The case of skull metastasis from primary hepatocellular carcinoma is rare, and HCC patient with intracranial metastasis tends to have a rather poor prognosis. Surgical excision of the metastatic mass and radiotherapy can improve the life quality and prolong the survival time of the patient.

An effect of Cl− concentration on the stress corrosion cracking (SCC) behavior of 13Cr stainless steel was investigated by employing electrochemical measurements and the slow strain rate tensile tests. These tests were conducted in various solutions with different concentrations of NaCl at 90 °C under 3 MPa CO2 with 3 MPa N2. The results indicate that the passive film of the specimen formed in the 10% NaCl solution has the best protective effect on the matrix. The SCC susceptibility does not increase with increasing the chloride ion concentration, the lowest SCC susceptibility occurs when the NaCl concentration is 10%, and the specimens show higher SCC susceptibility in the 5% NaCl and 20% NaCl solutions.

Background Benign prostatic hyperplasia (BPH) is the most common urological disease in elderly men, but the underlying pathophysiological mechanisms are complex and not fully understood. Phosphodiesterase type 5 inhibitors (PDE5-Is) used to treat BPH could upregulate the cyclic guanosine monophosphate (cGMP)-dependent protein kinase G (PKG) signaling, which was shown to blunt inflammation in the prostate. Our previous findings indicate that CD8+ T cells promote the proliferation of BPH epithelial cells (BECs) in low androgen conditions through secretion of CCL5; however, the role of the cGMP/PKG pathway in the process is unclear. Methods Paraffin-embedded tissues were used for expression quantity of CD8+ T cells, CCL5, cyclin D1, and PDE5 protein by immunohistology in prostate specimens which were/were not treated with finasteride 5 mg daily for at least 6 months before surgery. BPH-1 cells were cocultured with or without CD8 + T cells or PDE5-Is in low androgen conditions for 4 days. The conditioned media, BPH-1 cells, and CD8 + T cells were harvested for the subsequent experiments. The quantitative polymerase chain reaction was used for assaying the level of messenger RNA expression of CCL5. CCL5 in the conditioned media was detected by the enzyme-linked immunosorbent assay. The effect of PDE5-Is on cocultured BPH-1/CD8 + T-cell proliferation was detected by the cell counting kit-8. A high-fat diet (HFD)-induced prostatic hyperplasia rat model was used to investigate the effect of cGMP/PKG activation in CD8 + T cells in vivo. Results CD8+ T-cell infiltration into human BPH tissues was positively correlated with the expression of CCL5, cyclin D1, and PDE5, whereas in an HFD-induced prostatic hyperplasia rat model, the activation of the cGMP/PKG signaling by a PDE5-I could suppress the CD8 + T-cell infiltration and the CCL5 and cyclin D1 expression. Furthermore, the activation of the cGMP/PKG pathway inhibited CCL5 secretion by CD8 + T cells by downregulating nuclear factor-κB p65 phosphorylation, which reduced the growth of BPH-1 through CCL5/STAT5/CCND1 signaling. Conclusions Our results indicate that the upregulation of the cGMP/PKG/p65 signaling reduces CCL5 secretion in CD8 + T cells, which in turn decreases the proliferation of BECs in low androgen conditions, suggesting that the combination of 5α reductase inhibitors lowering androgen levels and PDE5-Is may be a novel, more effective treatment for BPH patients.

Background Chemotherapy with Docetaxel (Doc) is efficient in a subset of prostate cancer (PCa) cases; however, most patients ultimately develop resistance to Docetaxel. The tumor immune microenvironment and secreted cytokines play a substantial role in development of resistance to chemotherapy. Our previous study has demonstrated that CD4+ T cells in prostate tumor microenvironment contribute to PCa progression; meanwhile, we found increased CD4+ T‐cell infiltration in tumor area after Doc treatment; however, their effects on PCa chemosensitivity remain unclear. Here, we aim to explore the role and mechanisms of CD4+ T cells in PCa chemotherapy sensitivity. Methods CD4+ T‐cell infiltration in Doc‐treated paraffin‐embedded specimens from transurethral resection of prostate, radical prostatectomy, or bone metastasis was detected by immunohistochemistry. The castration‐resistant PCa cell lines—C4‐2 and CWR22RV1, and CD4+ T‐cell lines—HH and Molt‐3 were used in the coculture system. After coculture with the lymphocytes, PCa cell chemosensitivity was detected by cell counting kit‐8, terminal deoxynucleotidyl transferase dUTP nick‐end labeling assays, and Western blot analysis. Various cell cytokines were determined by cytokine arrays and reverse‐transcription polymerase chain reaction. The recombinant human C‐C motif chemokine ligand 5 (CCL5) was added to PCa cells for further confirming its effects and anti‐CCL5 antibody was used for neutralization. S3I‐201, a signal transducer and activator of transcription 3 (STAT3) inhibitor, was added to the coculture system to detect STAT3 role in chemosensitivity. Tumor xenografts in nude mice were used for confirming effects of CD4+ T cells in vivo study. Results We found more infiltrated CD4+ T cells in human PCa lesions than in the adjacent noncancerous tissues after Doc treatment. In vitro cell line study confirmed that CD4+ T cells increase the PCa Doc resistance. Quantative polymerase chain reaction and cytokine arrays indicated that after coculture with PCa, CD4+ T cells could secrete large amounts of CCL5. Moreover, CCL5 stimulation enhanced PCa resistance to Doc, and anti‐CCL5 antibody could partly reverse this process. We found that CD4+ T cells could activate P‐STAT3 signaling via secreting CCL5 and adding a STAT3 inhibitor can reverse the chemoresistance. In vivo mouse model with xenografted 22RV1 cells and CD4+ T cells also confirmed the in vitro results. Conclusions Together, our results indicate that infiltrating CD4+ T cells could promote PCa chemotherapy resistance via modulation of the CCL5/STAT3 signaling pathway.

Background Postoperative ileus is a frequent complication after surgery, especially abdominal surgery. Of the factors, sympathetic excitation is the primary factor for postoperative ileus. Sympathetic activation is always increased by the stress of surgery and postoperative pain. It was reported that dexmedetomidine (DEX) lessens pain and inhibits the sympathetic nerve by acting on the locus coeruleus. Therefore we designed our study to observe whether DEX promotes bowel movements in patients after laparoscopic nephrectomy.MethodsOne hundred and twenty patients undergoing laparoscopic nephrectomy were assigned into three groups, group C (normal saline infusion), group D1 (DEX 0.02 µg/kg/h), and group D2 (DEX 0.04 µg/kg/h). The primary outcome was to record the times of first flatus, defecation and eating after surgery. The secondary outcome was postoperative pain accessd by the numerical rating scale (NRS), concerning adverse effects, as well as the duration of the postoperative hospital stay.ResultsThe times of first flatus, defecation and eating in groups D1 and D2 were shorter than those in group C (P0.05).ConclusionDEX in 0.04 µg/kg/h postoperative infusion facilitates bowel movements in patients undergoing laparoscopic nephrectomy.Trial registrationThis trial was registered in a Chinese Clinical Trial Registry (ChiCTR) center on December 23, 2015. The registered number was ChiCTR-IPR-15007628.

Many G-protein-coupled receptor (GPCR) agonists have been studied for transactivating epidermal growth factor receptor (EGFR) signaling through extracellular or intracellular pathways. Accumulated evidence has confirmed that GPCR transactivation participates in various diseases. However, the clinical application of GPCR transactivation has not been explored, and more translational studies are needed to develop therapies to target GPCR-mediated EGFR transactivation. In cancer patients treated with EGFR inhibitors (EGFRi), especially afatinib, a unique acneiform rash is frequently developed. In this study, we first established the connection between GPCR transactivation and EGFRi-induced skin disease. We examined the ability of three different GPCR agonists to reverse signaling inhibition and ameliorate rash induced by EGFRi. The activation of different agonists follows unique time and kinase patterns. Rats treated with EGFRi show a similar skin phenotype, with rash occurring in the clinic; correspondingly, treatment with GPCR agonists reduced keratinocyte apoptosis, growth retardation and infiltration of inflammatory cytokines by transactivation. This phenomenon demonstrates that EGFR inhibition in keratinocytes regulates key factors associated with rash. Our findings indicate that maintaining EGFR signaling by GPCR agonists might provide a possible therapy for EGFR inhibitor-induced skin toxicities. Our study provides the first example of the translational application of GPCR transactivation in treating diseases.

There is a need for accurate and rapid detection of renal cancer in clinic. Here, we integrated photoacoustic tomography (PAT) with ultrasound imaging in a single system, which achieved tissue imaging depth about 3 mm and imaging speed about 3.5 cm2/min. We used the wavelength at 1197 nm to map lipid distribution in normal renal tissues and clear cell renal cell carcinoma (ccRCC) tissues collected from 19 patients undergone nephrectomy. Our results indicated that the photoacoustic signal from lipids was significantly higher in ccRCC tissues than that in normal tissues. Moreover, based on the quantification of lipid area ratio, we were able to differentiate normal and ccRCC with 100 % sensitivity, 80 % specificity, and area under receiver operating characteristic curve of 0.95. Our findings demonstrate that multimodal PAT can differentiate normal and ccRCC by integrating the morphologic information from ultrasound and lipid amount information from vibrational PAT.

Inflammation and proinflammatory cytokines have been implicated in the progression of benign prostatic hyperplasia (BPH). Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine. Our previous study found that MIF is highly expressed in BPH epithelium. It has been reported that there is a correlation between MIF and clinical BPH progression. However, whether MIF has an effect on BPH epithelial cells is not clear. The aim of this study was to explore whether MIF has a role in BPH. Our results showed that immunohistochemistry (IHC) showed that MIF is highly expressed in the epithelium and that MIF and PCNA expression levels are higher in BPH samples than in control. CCK8 and flow cytometry assays showed that recombinant human MIF (rMIF) promoted the proliferation of BPH-1 and PWR-1E cells, while ISO-1 partially reversed this effect on proliferation. JC-1 assays showed that rMIF inhibited the apoptosis of BPH-1 and PWR-1E cells, and ISO-1 could partially reverse this inhibition. Moreover, western blotting indicated that rMIF downregulated P53 and upregulated COX-2. Furthermore, MIF-induced proliferation could be inhibited by celecoxib in the CCK8 and flow cytometry assay. MIF-inhibited apoptosis could be partially reversed by celecoxib in the JC-1 assay. Western blotting showed that celecoxib could partially reverse MIF-induced COX-2 upregulation and P53 downregulation. Together, MIF is highly expressed in BPH epithelium. In vitro, MIF promoted BPH epithelial cell growth by regulating COX-2 and P53 signaling. Targeting MIF may provide a new option for the improved treatment of BPH in the future., Summary: This study found high levels of MIF expression in BPH epithelium. MIF promoted BPH epithelial cell growth and participated in the progression of BPH by regulating COX-2 and P53 signaling

Background The distribution characteristics of inflammatory cells in hyperplastic prostatic tissue and its influences on disease development remain unknown. We aimed to explore the infiltration characteristics of different inflammatory cells in histological structures of benign prostatic hyperplasia (BPH) in combination with clinical data. Methods The present study included 76 cases of BPH patients underwent transurethral resection of prostate (TURP). Hematoxylin-eosin staining was performed to identify the degree of general inflammation in prostatic tissues. The infiltration of T-lymphocytes (CD3), B-lymphocytes (CD20), and macrophages (CD68) were recorded by immunohistochemistry. Results The present study included 76 BPH patients with the mean age of 69.5 years old (range, 49-83 years) and the mean prostate volume of 91.9 mL (range, 24-218 mL). Periglandular inflammation was the most common pattern, being presented in 94.7% (72/76) patients, followed by stromal inflammation (67/76, 88.2%) and glandular inflammation (57/76, 75.0%). However, the stroma presented the highest rate of severe inflammation (14.6%). And the grades of glandular inflammation and stromal inflammation were independently correlated with prostate volume. T-lymphocytes, B-lymphocytes and macrophages had different infiltrated patterns in histological structures of prostate. And stromal hyperplasia dominated BPH was only significantly correlated with the T-lymphocytes infiltration condition (P=0.001). Meanwhile, overweight patients had more severe glandular inflammation in the prostate (P=0.010). The grade of glandular inflammation could independently increase prostate-specific antigen (PSA). Conclusions We characterized infiltrated patterns of different inflammatory cells in histological structures of hyperplasic prostatic tissues from surgically treated BPH specimens. The role of inflammation in BPH development was highlighted by its correlation with the prostate volume, metabolism and PSA level.

Redox modulators have been developed as an attractive approach to treat cancer. Herein, we report the synthesis, identification, and biological evaluation of a quinazolinedione reactive oxygen species (ROS) inducer, QD394, with significant cytotoxicity in pancreatic cancer cells. QD394 shows a transcriptomic profile remarkably similar to napabucasin, a cancer stemness inhibitor. Both small molecules inhibit STAT3 phosphorylation, increase cellular ROS, and decrease the GSH/GSSG ratio. Moreover, QD394 causes an iron- and ROS-dependent, GPX4 mediated cell death, suggesting ferroptosis as a major mechanism. Importantly, QD394 decreases the expression of LRPPRC and PNPT1, two proteins involved in mitochondrial RNA catabolic processes and both negatively correlated with the overall survival of pancreatic cancer patients. Pharmacokinetics-guided lead optimization resulted in the derivative QD394-Me, which showed improved plasma stability and reduced toxicity in mice compared to QD394. Overall, QD394 and QD394-Me represent novel ROS-inducing drug-like compounds warranting further development for the treatment of pancreatic cancer.

INTRODUCTION AND OBJECTIVE:The mammalian target of rapamycin (mTOR) is a vital effect factor in regulating cell growth, survival and autophagy via direct interaction with mTORC1 (mTOR complex 1) an...

BackgroundErector spinae plane (ESP) block has been reported to provide analgesia in spine surgery in case reports or case series, and there have been no controlled studies to date evaluating its efficacy. We aimed to exam the roles of ESP block in lumbar surgery in a single center randomized control trial by injecting local analgesic into the interfacial plane between the erector spinae muscles and the transverse process under ultrasound guidance.MethodsConsecutive elective lumbar surgery patients were randomized into either a control group (general anesthesia only, Group G, N=32) or a treatment group (general anesthesia plus ESP block, Group E, N=30). Several parameters including visual analog scale (VAS, primary outcome), perioperative anesthetics and analgesics usage, indexes of hemodynamics variation, return of bowel function and overall benefit of analgesia score (OBAS) were measured.ResultsSignificant differences in VAS scores over time were found between the two matched groups (P = 0.010). Group E patients had significantly lower pain scores than Group G patients in the early postoperative period within the first 6 hr. Group G and Group E VAS scores peaked at 1 hr and 12 hr, respectively, and the peak pain score in Group G is significantly higher than that of Group E (P = 0.002). In addition, patients who received ESP block had lower perioperative analgesic and sedative medication requirements, improved satisfaction with pain management, more stable hemodynamics, and earlier bowel function return than those using general anesthesia alone.ConclusionPre-incision bilateral single injection ESP blocks provided effective analgesia perioperatively during lumbar laminoplasty, decreased perioperative anesthesia and analgesia requirement, and accelerated short-term recovery.

An underestimated biopsy Gleason score 3 + 3 can result in unfounded optimism amongst patients and cause physicians to miss the window for prostate cancer (PCa) cure. This study aims to evaluate the effectiveness of Prostate Imaging Reporting and Data System (PI-RADS) version 2 as well as periprostatic fat (PPF) measured on multiparametric magnetic resonance imaging (mp-MRI) at predicting pathological upgrading amongst patients with biopsy Gleason score 3 + 3 disease.A retrospective analysis of 56 patients with biopsy Gleason score 6 PCa who underwent prebiopsy mp-MRI and radical prostatectomy (RP) between November 2013 and March 2018 was conducted. Two radiologists performed PI-RADS v2 score evaluation and different fat measurements on mp-MRI. The associations amongst clinical information, PI-RADS v2 score, different fat parameters and pathologic findings were analyzed. A nomogram predicting upgrading was established based on the results of logistic regression analysis.A total of 38 (67.9%) patients were upgraded to Gleason ≥7 disease on RP specimens. Prostate-specific antigen density (PSAD) (p .001), positive core (p .001), single-core positivity (p = .039), PI-RADS score (p .001), front PPF area (p = .007) and front-to-total ratio (the ratio of front PPF area to total contour area) (p .001) were risk factors for upgrading. On multivariate analysis, Epstein criteria (p = .02), PI-RADS score3 (p = .024), and front-to-total ratio (p = .006) were independent risk factors for pathologic upgrading. The AUC value of the nomogram was 0.893 (95% CI, 0.787-0.999).The combination of PI-RADS v2 and periprostatic fat measured on mp-MRI can help predict pathologic upgrading amongst patients with biopsy Gleason score 3 + 3 PCa.

Inhibition of proteasome activity blocks the degradation of dysfunctional proteins and induces cancer cell death due to cellular stress. Thus, proteasome inhibitors represent an attractive class of anticancer agents, and bortezomib, carfilzomib and ixazomib have been FDA-approved to treat multiple myeloma. However, cancer cells acquire resistance to these inhibitors through point mutations in the proteasome catalytic subunit or induction of alternative compensatory mechanisms. In this study, we identified a quinolin-chlorobenzothioate, QCBT7, as a new proteasome inhibitor showing cytotoxicity in a panel of cancer cell lines. QCBT7 is a more stable derivative of quinoline-8-thiol that targets the regulatory subunit instead of the catalytic subunit of the proteasome. QCBT7 caused the accumulation of ubiquitylated proteins in the cancer cells, indicating its proteasome inhibitory activity. Additionally, QCBT7 increased the expression of a set of genes (PFKFB4, CHOP, HMOX1 and SLC7A11) at both nascent RNA and protein levels, similarly to the known proteasome inhibitors MG132 and ixazomib. Together, QCBT7 induces proteasome inhibition, hypoxic response, endoplasmic reticulum stress and glycolysis, finally leading to cell death. Importantly, we have identified PFKFB4 as a potential biomarker of proteasome inhibitors that can be used to monitor treatment response.

Protein folding in the endoplasmic reticulum is an oxidative process that relies on protein disulfide isomerase (PDI) and endoplasmic reticulum oxidase 1 (ERO1). Over 30% of proteins require the chaperone PDI to promote disulfide bond formation. PDI oxidizes cysteines in nascent polypeptides to form disulfide bonds and can also reduce and isomerize disulfide bonds. ERO1 recycles reduced PDI family member PDIA1 using a FAD cofactor to transfer electrons to oxygen. ERO1 dysfunction critically affects several diseases states. Both ERO1 and PDIA1 are overexpressed in cancers and implicated in diabetes and neurodegenerative diseases. Cancer-associated ERO1 promotes cell migration and invasion. Furthermore, the ERO1-PDIA1 interaction is critical for epithelial-to-mesenchymal transition. Co-expression analysis of ERO1A gene expression in cancer patients demonstrated that ERO1A is significantly upregulated in lung adenocarcinoma (LUAD), glioblastoma and low-grade glioma (GBMLGG), pancreatic ductal adenocarcinoma (PAAD), and kidney renal papillary cell carcinoma (KIRP) cancers. ERO1Α knockdown gene signature correlates with knockdown of cancer signaling proteins including IGF1R, supporting the search for novel, selective ERO1 inhibitors for the treatment of cancer. In this review, we explore the functions of ERO1 and PDI to support inhibition of this interaction in cancer and other diseases.

Background: Metabolic syndrome (MetS) has been found to be prevalent in cancer and have implications in cancer outcomes. In this study, we attempted to evaluate the prognostic value of MetS in localized clear cell renal cell carcinoma (ccRCC) patients. Methods: We retrospectively collected clinicopathological data and pre-treatment laboratory test results of 480 patients with localized (T1–2N0M0) ccRCC undergoing radical or partial nephrectomy in Peking University First Hospital. MetS was diagnosed by criteria of the 2004 Chinese Medical Association Diabetes Society. Univariate and multivariate analyses were conducted to analyze the association between clinicopathological characteristics, MetS, and disease outcomes. Results: In our cohort, 136 patients (28.3%) were diagnosed with MetS. Among them, 113 (83.1%) were men, suggesting that men were more likely to have MetS. This syndrome was also associated with increased pre-treatment creatinine levels. Median follow-up time was 70 months (range, 1–118 months) and 5-year overall survival (OS) rate was 92%. MetS was an independent favorable factor of cancer-specific survival (CSS) (P=0.017), and similar results were observed in Fuhrman nuclear grade 1–2 ccRCC patients by further analysis. Neither of the four components of the MetS (hypertension, diabetes mellitus, overweight/obesity and dyslipidemia) was an independent predictor of CSS. Patients who met more than 3 of the 4 criteria for MetS had higher CSS than those who met fewer than 2 criteria. Conclusions: MetS is an independent prognostic factor for better CSS in localized ccRCC patients.

Background To investigate the relationship between time elapsed since completion of radiotherapy (RT) and quality of life (QOL) of patients with breast cancer. Methods A total of 300 patients with breast cancer were treated at the First Affiliated Hospital of Anhui Medical University between January 2013 and April 2016. Of these, 212 patients were included in the study. Patients were divided into 4 groups based on the time elapsed since completion of RT. The generic cancer questionnaire, EORTC QLQ-30, and the breast cancer-specific questionnaire, QLQ-BR23, were used to assess the QOL. Results Analysis of time elapsed since completion of RT and QOL revealed changes in the scores for role function with passage of time; the third year’s scores were the highest. Pain symptoms during the 3rd and 4th years after RT were lower than those during the 1st and 2nd years after RT; scores for financial difficulties fluctuated with passage of time; perception of own body scores improved within first 3 years; sexual activity and enjoyment of sexual activity showed a significant decrease during the 2nd to 4th year post RT. Scores pertaining to concerns about future state of health showed a significant increase during the 2nd to 4th year after RT, while breast symptoms score showed fluctuations with passage of time. Conclusions Social function, pain symptoms, and concerns about future state of health tended to improve with passage of time after RT. Other scales showed no correlation with time elapsed since completion of RT.

Autophagy is involved in aging-related cognitive impairment. Aerobic exercise training can improve cognitive function in the elderly and this effect may be associated with autophagic mechanisms and mitochondrial respiratory function. High intensity interval training (HIIT) has beneficial effects on heart and skeletal muscles by activating autophagy and/or mitophagy, but the effects of HIIT on autophagy/mitophagy in the aging brain are unknown. This study investigated the effects of HIIT on the mitochondrial respiratory complex and autophagy/mitophagy, and its relation to brain function. Thirteen middle-aged male ICR mice underwent HIIT for 7 weeks. The exercise program reduced the spontaneous behavior and exploration activities of the mice. The phosphorylation level of cAMP response element binding protein (CREB) and the protein expression of brain-derived neurotrophic factor (BDNF) decreased after the 7-week HIIT. Exercise downregulated the protein expression of Complex Ⅰ and upregulated the protein expression of Complex Ⅲ, Complex Ⅳ and Complex Ⅴ. HIIT also decreased the expression of mitophagy-related proteins in the mitochondrial fractions of the hippocampus. However, HIIT did not change the expression of autophagy-related proteins LC3, P62, Atg5, Atg7, Beclin-1 and Lamp2 in the total lysate of the hippocampus. These data indicated that HIIT might have negative effects on the plasticity of the hippocampus in middle-aged mice. The effects may be related to the dysregulation of CREB-BDNF signaling, mitochondrial respiratory complex and mitophagy induced by HIIT.

Chronic tubulointerstitial injury impacts the prognosis of focal segmental glomerulosclerosis (FSGS). We found that the level of versican V1 was increased in tubular cells of FSGS patients. Tubular cell–derived versican V1 induced proliferation and collagen synthesis by activating the CD44/Smad3 pathway in fibroblasts. Both urine C3a and suPAR were increased and bound to the tubular cells in FSGS patients. C3a promoted the transcription of versican by activating the AKT/β-catenin pathway. C3aR knockout decreased the expression of versican in Adriamycin-treated (ADR-treated) mice. On the other hand, suPAR bound to integrin β6 and activated Rac1, which bound to SRp40 at the 5′ end of exon 7 in versican pre-mRNA. This binding inhibited the 3′-end splicing of intron 6 and the base-pair interactions between intron 6 and intron 8, leading to the formation of versican V1. Cotreatment with ADR and suPAR specifically increased the level of versican V1 in tubulointerstitial tissues and caused more obvious interstitial fibrosis in mice than treatment with only ADR. Altogether, our results show that C3a and suPAR drive versican V1 expression in tubular cells by promoting transcription and splicing, respectively, and the increases in tubular cell–derived versican V1 induce interstitial fibrosis by activating fibroblasts in FSGS.

INTRODUCTION AND OBJECTIVES:Benign prostatic hyperplasia (BPH) is a disease characterized by stroma hyperplasia. Our previous studies, stroma–epithelium ratios and collagen deposition were prevalen...

Multiple obligatory intracellular bacteria in the genus Chlamydia are important pathogens. In humans, strains of C. trachomatis cause trachoma, chlamydia, and lymphogranuloma venereum. These diseases are all associated with extended courses of infection and reinfection that likely reflect the ability of chlamydiae to evade various aspects of host immune responses. Interferon-stimulated genes, driven in part by the cytokine interferon gamma, restrict the host range of various Chlamydia species, but how these pathogens evade interferon-stimulated genes in their definitive host is poorly understood. Various Chlamydia species can inhibit death of their host cells and may have evolved this strategy to evade prodeath signals elicited by host immune responses. We present evidence that chlamydia-induced programmed cell death resistance evolved to counter interferon- and immune-mediated killing of Chlamydia-infected cells., Interferon-regulated immune defenses protect mammals from pathogenically diverse obligate intracellular bacterial pathogens of the genus Chlamydia. Interferon gamma (IFN-γ) is especially important in controlling the virulence of Chlamydia species and thus impacts the modeling of human chlamydial infection and disease in mice. How IFN-γ contributes to cell-autonomous defenses against Chlamydia species and how these pathogens evade IFN-γ-mediated immunity in their natural hosts are not well understood. We conducted a genetic screen which identified 31 IFN-γ-sensitive (Igs) mutants of the mouse model pathogen Chlamydia muridarum. Genetic suppressor analysis and lateral gene transfer were used to map the phenotype of one of these mutants, Igs4, to a missense mutation in a putative chlamydial inclusion membrane protein, TC0574. We observed the lytic destruction of Igs4-occupied inclusions and accompanying host cell death in response to IFN-γ priming or various proapoptotic stimuli. However, Igs4 was insensitive to IFN-γ-regulated cell-autonomous defenses previously implicated in anti-Chlamydia trachomatis host defense in mice. Igs4 inclusion integrity was restored by caspase inhibitors, indicating that the IFN-γ-mediated destruction of Igs4 inclusions is dependent upon the function of caspases or related prodeath cysteine proteases. We further demonstrated that the Igs4 mutant is immune restricted in an IFN-γ-dependent manner in a mouse infection model, thereby implicating IFN-γ-mediated inclusion destruction and host cell death as potent in vivo host defense mechanisms to which wild-type C. muridarum is resistant. Overall, our results suggest that C. muridarum evolved resistance mechanisms to counter IFN-γ-elicited programmed cell death and the associated destruction of intravacuolar pathogens.

Grape seed proanthocyanidins (GSP) has been reported to attenuate endoplasmic reticulum (ER) stress-induced apoptosis, which is associated with ischemic stroke. However, whether GSP pays crucial roles in ischemic stroke still remains unclear. The purpose of this study is to explore the role of GSP in ischemic stroke and the underlying mechanism. The ischemic stroke mouse model was established by middle cerebral artery occlusion. GSP administration was performed intragastrically. Long-term neurological outcome was assessed by the foot fault test after reperfusion. Brain injury was identified by infarct volume from 2,3,5-triphenyltetrazolium chloride staining. Neuronal apoptosis was detected by terminal deoxynucleotidyl transferase dUTP nick end labeling. The expression levels of Bax, Bcl-2, Cleaved Caspase-3, phosphorylated ERK (p-ERK), ERK, Glucose-regulated protein 78 kDa (GRP78), Caspase-12 were detected by western blotting. In mice with ischemia stroke, GSP administration improved long-term neurological outcomes by attenuating ischemia–reperfusion induced neuronal apoptosis and brain injury. Mechanically, GSP performance inhibited the expression levels of ER stress-associated genes. GSP protects mice against ischemic stroke via attenuating neuronal apoptosis. Moreover, GSP attenuated ER stress-associated apoptosis by inhibiting GRP78 and Caspase-12. Our study indicates that GSP attenuates neuronal apoptosis in ischemic stroke, which shows the potential for ischemic stroke treatment.

Tubulointerstitial fibrosis impacts renal prognosis of focal segmental glomerulosclerosis (FSGS). Based on transcriptomic analysis, we found that the level of LOC105375913 was increased in tubular cells of FSGS patients. C3a induced the expression of LOC105375913, which promoted the expression of fibronectin and collagen I in tubular cells. Silence of snail reversed the level of fibronectin and collagen I in cells overexpressing LOC105375913. MiR-27b was predicted and confirmed to regulate the expression of snail in tubular cells, and LOC105375913 contained the response element of miR-27b. The competitive binding between LOC105375913 and miR-27b increased the level of snail and promoted fibrogenesis in tubular cells. Upstream, p38 and XBP-1s regulated the expression of LOC105375913. Inhibition of p38 or silence of XBP-1s decreased the level of LOC105375913, and suppressed the expression of snail, fibronectin and collagen I in tubular cells treated with C3a. Overexpression of LOC105375913 decreased the level of miR-27b, increased the level of snail and caused tubulointerstitial fibrosis in mice. In conclusion, the activation of C3a/p38/XBP-1s pathway induces the expression of LOC105375913 in tubular cells, and LOC105375913 increases the level of snail and induces tubulointerstitial fibrosis through competitive binding of miR-27b in tubular cells of FSGS patients.

Microparticles are sub-micron, membrane-bound particles released from virtually all cells and which are present in the circulation. In several autoimmune disorders their amount and composition in the circulation is altered. Microparticle surface protein expression has been explored as a differentiating tool in autoimmune disorders where the clinical pictures can overlap. Here, we examine the utility of a novel lipid-based marker&mdash, microparticle cholesterol, present in all microparticles regardless of cellular origin&mdash, to distinguish between rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). We first isolated a series of microparticle containing lipoprotein deficient fractions from patient and control plasma. There were no significant differences in the size, structure or protein content of microparticles isolated from each group. Compared to controls, both patient groups contained significantly greater amounts of platelet and endothelial cell-derived microparticles. The cholesterol content of microparticle fractions isolated from RA patients was significantly greater than those from either SLE patients or healthy controls. Our data indicate that circulating non-lipoprotein microparticle cholesterol, which may account for 1&ndash, 2% of measured cholesterol in patient samples, may represent a novel differentiator of disease, which is independent of cellular origin.

Prostatic neuroendocrine cells (NE) are an integral part of prostate cancer (PCa) that are associated with PCa progression. As the current androgen-deprivation therapy (ADT) with anti-androgens may promote the neuroendocrine PCa (NEPCa) development, and few therapies can effectively suppress NEPCa, understanding the impact of NEPCa on PCa progression may help us to develop better therapies to battle PCa. Here we found NEPCa cells could increase the docetaxel-resistance of their neighboring PCa cells. Mechanism dissection revealed that through secretion of PTHrP, NEPCa cells could alter the p38/MAPK/Hsp27 signals in their neighboring PCa cells that resulted in increased androgen receptor (AR) activity via promoting AR nuclear translocation. The consequences of increased AR function might then increase docetaxel-resistance via increasing p21 expression. In vivo xenograft mice experiments also confirmed NEPCa could increase the docetaxel-resistance of neighboring PCa, and targeting this newly identified PTHrP/p38/Hsp27/AR/p21 signaling pathway with either p38 inhibitor (SB203580) or sh-PTHrP may result in improving/restoring the docetaxel sensitivity to better suppress PCa.

BACKGROUND: Renal impairment (RI) is a common complication in patients with multiple myeloma (MM). Effective myeloma treatment can lead to reduction in urinary light-chain excretion and reversibility of RI. Our pooled analysis assessed the magnitude of improvement in renal function (RF) in patients with newly diagnosed (ND) or relapsed and/or refractory (RR) MM treated with novel agent induction therapies, including 3 immunomodulators, 3 proteasome inhibitors, 1 histone deacetylase inhibitor, 1 XP01 inhibitor and 2 monoclonal antibodies. METHODS: Seventeen registrational trials with 34 treatment arms that collected time profiles of RF during treatment with novel agent induction therapies in 3569 patients with NDMM and 7786 patients with RRMM at baseline were identified from various new drug applications submitted to the US FDA. Change in estimated glomerular filtration rate (eGFR, as estimated by Modification of Diet in Renal Disease formula) compared to baseline was summarized for each therapy. RESULTS: Increase in eGFR was observed in patients with MM and each category of RI (mild [eGFR 60 - Table 1:Improvement in eGFR in patients with MM and RI during the treatment of novel agent induction therapies between Month 3 and 6 as compared to baseline.PatientsTherapyMean (SD) increase in eGFR (mL/min/1.73 m2)% of patients with improvement in eGFR by at least 1 categoryRRMM (N=7786)Monotherapy A8.8 (15.3)33%Monotherapy B-1.5 (10.4)10%Monotherapy C5.9 (13.9)25%Combination D7.7 (15.4)30%Combination E8.9 (17.2)30%Combination F8.1 (14.9)33%Combination G7.6 (14.6)28%Combination H9.5 (16.1)34%Combination I6.5 (14.0)28%Combination J7.4 (14.6)27%Combination K7.6 (14.8)28%Combination L6.4 (12.0)17%Combination M3.1 (14.5)13%Combination N11.2 (17.1)38%NDMM (N-3569)Combination D7.8 (16.4)32%Combination J7.6 (16.0)29%Combination O6.0 (15.2)28%Combination P10.1 (16.7)38%Combination Q10.4 (17.5)37%Combination R11.5 (17.7)38% CONCLUSIONS: During the treatment with novel agent induction therapies for MM, frequent assessment of RF is needed in patients with RI to guide the proper dosing regimen. Citation Format: Liang Li, Shuai Hu, Hao Zhu, Yaning Wang, Lian Ma, Brian P. Booth, Nam Atiqur Rahman, Janice Schwartz, Gideon Blumenthal, Qi Liu. Improvement in renal function in patients with multiple myeloma and impaired renal function receiving novel agent induction therapies [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 587.

Currently, non-small cell lung cancer (NSCLC) is still the most common malignancy worldwide. Although miR-889 has been reported to play an important role in various malignancies, the physiological function of miR-889 in NSCLC remains unknown. This paper places emphasis on the influence of miR-889 on the development and progression of non-small cell lung cancer. To detect the expression level of miR-889 in NSCLC tissues and cell lines, quantitative real-time polymerase chain reaction (qRT-PCR) assay and In Situ Hybridization (ISH) were adopted in this study. Cell proliferation and colony forming ability were examined by Cell Counting Kit-8 (CCK-8) and colony formation assays. Furthermore, transwell experiments were conducted to determine the influence of miR-889 on migration. KLF9 expression was evaluated by qRT-PCR and Western blotting. First, miR-889 expression was increased in the cancer tissues of non-small cell lung cancer patients (n = 40) compared with adjacent tissues. Subsequently, knockdown of miR-889 significantly inhibited cell proliferation and migration, while overexpression of miR-889 had the opposite effect. KLF9 may be a potential target of miR-889. In addition, upregulation of miR-889 promotes tumorigenesis in vitro, and KLF9 protein levels are also reduced. The current study suggests that miR-889 may play a potential therapeutic role for NSCLC by targeting KLF9 to control NSCLC proliferation and migration.

Focal segmental glomerulosclerosis (FSGS) is a common kidney disease that results in nephrotic syndrome. FSGS arises from dysfunction and apoptosis of podocytes in the glomerulus of the kidney, leading to podocytopathy. The molecular mechanisms underlying podocyte apoptosis remain incompletely understood. Using an array of gene expression profiling, PCR, and in situ hybridization assay, we found here that the levels of the long noncoding RNA LOC105374325 were elevated in the renal podocytes of individuals with FSGS. We also observed that the microRNAs miR-34c and miR-196a/b down-regulated the expression of the apoptosis regulators BCL2-associated X, apoptosis regulator (Bax), and BCL2 antagonist/killer 1 (Bak) in podocytes. Competitive binding between LOC105374325 and miR-34c or miR-196a/b increased Bax and Bak levels and caused podocyte apoptosis. Of note, the mitogen-activated protein kinase P38 and the transcription factor CCAAT enhancer–binding protein β (C/EBPβ) up-regulated LOC105374325 expression. P38 inhibition or C/EBPβ silencing decreased LOC105374325 levels and inhibited apoptosis in adriamycin-treated podocytes. LOC105374325 overexpression decreased miR-34c and miR-196a/b levels, increased Bax and Bak levels, and induced proteinuria and focal segmental lesions in mice. In conclusion, activation of the P38/C/EBPβ pathway stimulates the expression of LOC105374325, which, in turn, increases Bax and Bak levels and causes apoptosis by competitively binding to miR-34c and miR-196a/b in the podocytes of individuals with FSGS.

Benign prostatic hyperplasia (BPH) is a progressive disease in elderly men, but potential factors accelerating its progression remain largely unknown. The aim of this study was to elucidate the factors affecting BPH progression by understanding the complex mechanisms causing early- progressed BPH, which progresses rapidly and requires surgical intervention before the age of 50. Three groups of human prostate tissue samples, from patients with early-progressed BPH, age-matched prostate and elderly BPH tissues, were collected (n = 25 each). We compared these tissues to determine the histologic features and molecular mechanisms underlying BPH progression. We found that early-progressed BPH samples were characterised by aberrant stromal hyper-proliferation, collagen deposition and increased M2 macrophage infiltration, compared to those from age-matched prostate and elderly BPH tissues. The M2 macrophage–fibroblast co-culture system demonstrated that the myofibroblast phenotypes were strongly induced only in fibroblasts from the early-progressed BPH samples, while the co-cultured M2 macrophages expressed high levels of pro-fibrotic cytokines, such as IL4 and TGFβ1. M2 macrophage-derived IL4, but not TGFβ1, selectively induced the myofibroblast phenotype through the JAK/STAT6, PI3K/AKT and MAPK/ERK signalling pathways in the early-progressed BPH prostate fibroblasts. Taken together, our results indicate that induction of the myofibroblast phenotype may lead to BPH progression through M2 macrophage-mediated IL4 signalling, and that IL4 may represent a potential therapeutic target, allowing the prevention of M2 macrophage activation and fibroblast-to-myofibroblast differentiation.