Cushing's syndrome caused by giant Ewing's sarcoma of the kidney: A case report and review of literature.

BACKGROUND: Primary renal Ewing's sarcoma (ES) is extremely rare, and only two cases causing Cushing's syndrome (CS) have been reported to date. We report that the case of an 18-year-old patient is diagnosed primary renal ES with typical CS characterized by purple stripes, weight gain, and hypertension. CASE SUMMARY: CS was first diagnosed by laboratory testing. A huge tumor was revealed in the kidney following an imaging examination. Moreover, brain and bone metastases were observed. After comprehensive treatment, primarily based on surgery, primary renal ES was pathologically diagnosed with a typical EWSR1-FLI1 genetic mutation through genetic testing. Furthermore, the glucocorticoid level returned to normal. By the ninth postoperative month of follow-up, the patient was recovering well. Cushing-related symptoms had improved, and a satisfactory curative effect was achieved. CONCLUSION: Primary renal ES, a rare adult malignant tumor, can cause CS and a poor prognosis.

Regulatory effect of Yinchenhao decoction on bile acid metabolism to improve the inflammatory microenvironment of hepatocellular carcinoma in mice.

Hepatocellular carcinoma (HCC) is a malignant tumor with extremely high mortality. The tumor microenvironment is the "soil" of its occurrence and development, and the inflammatory microenvironment is an important part of the "soil". Bile acid is closely related to the occurrence of HCC. Bile acid metabolism disorder is not only directly involved in the occurrence and development of HCC but also affects the inflammatory microenvironment of HCC. Yinchenhao decoction, a traditional Chinese medicine formula, can regulate bile acid metabolism and may affect the inflammatory microenvironment of HCC. To determine the effect of Yinchenhao decoction on bile acid metabolism in mice with HCC and to explore the possible mechanism by which Yinchenhao decoction improves the inflammatory microenvironment of HCC by regulating bile acid metabolism, we established mice model of orthotopic transplantation of hepatocellular carcinoma. These mice were treated with three doses of Yinchenhao decoction, then liver samples were collected and tested. Yinchenhao decoction can regulate the disorder of bile acid metabolism in liver cancer mice. Besides, it can improve inflammatory reactions, reduce hepatocyte degeneration and necrosis, and even reduce liver weight and the liver index. Taurochenodeoxycholic acid, hyodeoxycholic acid, and taurohyodeoxycholic acid are important molecules in the regulation of the liver inflammatory microenvironment, laying a foundation for the regulation of the liver tumor inflammatory microenvironment based on bile acids. Yinchenhao decoction may improve the inflammatory microenvironment of mice with HCC by ameliorating hepatic bile acid metabolism.

Association between perioperative self-reported sleep disturbances and delirium risk in elderly patients following total joint arthroplasty: a cohort study.

Perioperative sleep disturbance may increase delirium risk. However, the role of perioperative sleep disturbance in delirium following total joint arthroplasty remains unclear. This prospective cohort study aimed to observe the delirium risk in patients with sleep disturbances. After excluding pre-existing sleep disturbances, older patients scheduled for total joint arthroplasty from July 17, 2022, to January 12, 2023, were recruited. Preoperative sleep disturbance or postoperative sleep disturbance was defined as a Chinese version of the Richards-Campbell Sleep Questionnaire (RCSQ) score of <50 during hospitalisation. A cut-off score of 25 was used to classify the severity of sleep disturbance. The primary outcome was the incidence of postoperative delirium. In all, 11.6% of cohort patients (34/294) developed delirium. After multivariate analysis, a preoperative Day 1 RCSQ score of ≤25 (odds ratio [OR] 3.62, 95% confidence interval [CI] 1.19-10.92; p = 0.02), occurrence of sleep disturbances (OR 2.76, 95% CI 1.19-6.38; p = 0.02) and RCSQ score of ≤25(OR 2.91, 95% CI 1.33-6.37; p = 0.007) postoperatively were strong independent predictors of delirium. After sensitivity analysis for daily delirium, a postoperative Day 1 RCSQ score of ≤25 (OR 9.27, 95% CI 2.72-36.15; p < 0.001) was associated with a greater risk of delirium on postoperative Day 1, with a reasonable discriminative area under the curve of 0.730. We concluded that postoperative but not preoperative sleep disturbances may be an independent factor for delirium risk. Sleep disturbance on the first night after surgery was a good predictor of subsequent delirium, no matter the nature of self-reported sleep disturbance.

Fasting mimicking diet inhibits tumor-associated macrophage survival and pro-tumor function in hypoxia: implications for combination therapy with anti-angiogenic agent.

BACKGROUND: Recent research shows that tumor-associated macrophages (TAMs) are the primary consumers of glucose in tumor tissue, surpassing that of tumor cells. Our previous studies revealed that inhibiting glucose uptake impairs the survival and tumor-promoting function of hypoxic TAMs, suggesting that glucose reduction by energy restriction (calorie restriction or short-term fasting) may has a significant impact on TAMs. The purpose of this study is to verify the effect of fasting-mimicking diet (FMD) on TAMs, and to determine whether FMD synergizes with anti-angiogenic drug apatinib via TAMs. METHODS: The effect of FMD on TAMs and its synergistic effects with apatinib were observed using an orthotopic mouse breast cancer model. An in vitro cell model, utilizing M2 macrophages derived from THP-1 cell line, was intended to assess the effects of low glucose on TAMs under hypoxic and normoxic conditions. Bioinformatics was used to screen for potential mechanisms of action, which were then validated both in vivo and in vitro. RESULTS: FMD significantly inhibit the pro-tumor function of TAMs in vivo and in vitro, with the inhibitory effect being more pronounced under hypoxic conditions. Additionally, the combination of FMD-mediated TAMs inhibition with apatinib results in synergistic anti-tumor activity. This effect is partially mediated by the downregulation of CCL8 expression and secretion by the mTOR-HIF-1α signaling pathway. CONCLUSIONS: These results support further clinical combination studies of FMD and anti-angiogenic therapy as potential anti-tumor strategies.

Design, synthesis and bioevaluation of PI3Kα-selective inhibitors as potential colorectal cancer drugs.

The dysregulation of the phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin signaling pathway has been implicated in various human cancers, and isoform-selective inhibitors targeting PI3Kα have received significant interest in recent years. In this study, we have designed and synthesized three series of substituted benzoxazole derivatives based on the clinical candidate TAK-117 (8a). A detailed structure-activity relationship (SAR) study has identified the optimal compound 18a bearing a quinoxaline scaffold. Compared to the control 8a, 18a exhibited 4.4-fold more potent inhibitory activity against PI3Kα (IC50: 2.5 vs 11 nM) and better isoform-selective profiles over other PI3Ks. In addition, 18a showed a 1.5-fold more potent antiproliferative effect against HCT-116 cell lines (IC50: 3.79 vs 5.80 µM) and a better selectivity over the normal tissue cells. The potential antitumor mechanism and in vitro metabolic stability of 18a were also investigated. Notably, pharmacokinetic assays indicated that 18a had a higher plasma exposure, a higher maximum concentration and shorter elimination time compared to 8a.

Virtual screening of novel mTOR inhibitors for the potential treatment of human colorectal cancer.

The abnormal activation of the mTOR pathway is closely related to the occurrence and progression of cancer, especially colorectal cancer. In this study, a rational virtual screening strategy has been established and MT-5, a novel mTOR inhibitor with a quinoline scaffold, was obtained from the ChemDiv database. MT-5 showed potent kinase inhibitory activity (IC50: 8.90 µM) and antiproliferative effects against various cancer cell lines, especially HCT-116 cells (IC50: 4.61 µM), and this was 2.2-fold more potent than that of the cisplatin control (IC50: 9.99 µM). Western blot, cell migration, cycle arrest, and apoptosis assays were performed with HCT-116 cells to investigate the potential anticancer mechanism of MT-5. Metabolic stability results in vitro indicated that MT-5 exhibited good stability profiles in artificial gastrointestinal fluids, rat plasma, and liver microsomes. In addition, the key contribution of the residues around the binding pocket of MT-5 in binding to the mTOR protein was also investigated from a computational perspective.

Clinical feasibility and oncological safety of non-radioactive targeted axillary dissection after neoadjuvant chemotherapy in biopsy-proven node-positive breast cancer: a prospective diagnostic and prognostic study.

BACKGROUND: Targeted axillary dissection (TAD) includes biopsy of clipped lymph node and sentinel lymph nodes. However, clinical evidence regarding clinical feasibility and oncological safety of non-radioactive TAD in a real-world cohort remains limited. METHODS: In this prospective registry study, patients routinely underwent clip insertion into biopsy-confirmed lymph node. Eligible patients received neoadjuvant chemotherapy followed by axillary surgery. Main endpoints included the false-negative rate (FNR) of TAD and nodal recurrence rate. RESULTS: Data from 353 eligible patients were analyzed. After completion of neoadjuvant chemotherapy, 85 patients directly proceeded to axillary lymph node dissection (ALND), furthermore, TAD with or without ALND was performed in 152 and 85 patients, respectively. Overall detection rate of clipped node was 94.9% (95% CI, 91.3-97.4%) and FNR of TAD was 12.2% (95% CI, 6.0-21.3%) in our study, with FNR decreasing to 6.0% (95% CI, 1.7-14.6%) in initially cN1 patients. During a median follow-up of 36.6 months, 3 nodal recurrences occurred (3/237 with ALND; 0/85 with TAD alone), with a 3-year freedom-from-nodal-recurrence rate of 100.0% among the TAD-only patients and 98.7% among the ALND patients with axillary pathologic complete response ( P =0.29). CONCLUSIONS: TAD is feasible in initially cN1 breast cancer patients with biopsy-confirmed nodal metastases. ALND can safely be foregone in patients with negativity or a low volume of nodal positivity on TAD, with a low nodal failure rate and no compromise of 3-year recurrence-free survival.

Identifying novel selective PPO inhibitors through structure-based virtual screening and bio-evaluation.

Protoporphyrinogen oxidase (PPO) is a key enzyme in chlorophyll and heme biosynthesis, and the development of its inhibitors is of great importance both in the pharmaceutical and pesticide industries. However, the currently developed PPO inhibitors have insignificant bio-selectivity and have a serious impact on non-target organisms. In this study, a docking-based virtual screening approach combined with bio-activity testing was used to obtain novel selective inhibitors of PPO. The results of the bio-activity test showed that thirteen compounds showed 10-fold selectivity over human PPO. And the best selective compound, ZINC70338, has a K i value of 2.21 µM for Nicotiana tabacum PPO and >113-fold selectivity for human PPO. The selectivity mechanism of ZINC70338 in different species of PPO was then analyzed by molecular dynamics simulations to provide a design basis and theoretical guidance for the design of novel selective inhibitors.

Selective Photochromic Response to Low-Dose X-ray Radiation Detection in One-Dimensional Cadmium-Viologen Complexes.

Photochromic viologen-based materials have emerged as one of the most promising candidates for the development of X-ray light detection applications, including medical diagnosis and treatment, environmental radiation inspection, and industrial crack detection. However, the design and construction of low-dose X-ray-sensitive complexes remains an immense challenge, especially for the in-depth dissection of their response mechanisms. Herein, by using N,N'-4,4'-bipyridiniodipropionate (CV) as functional sensitive structural units and cadmium as heavy atoms, two cadmium-viologen complexes with one-dimensional chained structures, namely, [Cd2Cl4(CV)(H2O)2]n (1) and [CdBr2(CV)]n (2), have been constructed, which exhibit a remarkable and selective photochromic response to low-dose X-ray radiation detection. Compound 1 is visually sensitive to both X-ray and UV light due to the more accessible photoinduced electron transfer (ET) pathways, while compound 2 only shows a slight color-changing process in response to UV light, in conformity with UV-vis absorbance analyses and kinetic studies. Surprisingly, compound 2 has longer ET pathways than 1, but not in response to high-energy X-ray light, seeming to contradict the previous phenomena. On further analysis, the key point in achieving X-ray-sensitive behavior should be a good balance among the electron donor-acceptor distance, intermolecular interaction, and X-ray absorbing capacity, as verified by density functional theory (DFT) and X-ray absorption strength calculations, X-ray photoelectron spectra, electron paramagnetic resonance measurements, and independent gradient model analysis. In particular, compound 1 is unprecedentedly sensitive to soft X-ray radiation, accompanied by an X-ray detection limit of as low as 2.91 Gy. These findings push forward the further development of low-dose X-ray sensing materials.

[Activity of Codonopsis canescens against rheumatoid arthritis based on TLRs/MAPKs/NF-κB signaling pathways and its mechanism].

This paper aims to explore the activity of Codonopsis canescens extract against rheumatoid arthritis(RA) based on the Toll-like receptors(TLRs)/mitogen-activated protein kinases(MAPKs)/nuclear factor kappa B(NF-κB) signaling pathways and its mechanism. The ultra-performance liquid chromatography-quadrupole time-of-flight/mass spectrometry(UPLC-Q-TOF-MS) was used to identify the components of C. canescens extract. Forty-eight male SD rats were randomly divided into six groups, namely the normal group, the model group, the methotrexate(MTX) tablet group, and the low, medium, and high-dose C. canescens extract(ZDS-L, ZDS-M, and ZDS-H) groups, with 8 rats in each group. The model of collagen-induced arthritis in rats was induced by injection of bovine type Ⅱ collagen emulsion. MTX(2.5 mg·kg~(-1)), ZDS-L, ZDS-M, and ZDS-H(0.3 g·kg~(-1), 0.6 g·kg~(-1), and 1.2 g·kg~(-1)) were administrated by gavage. Rats in the normal group and the model group received distilled water. MTX was given once every three days for 28 days, and the rest medicines were given once daily for 28 days. Body weight, degree of foot swelling, arthritis index, immune organ index, synovial histopathological changes, and serum levels of tumor necrosis factor-α(TNF-α), interleukin-1ß(IL-1ß), and interleukin-6(IL-6) were observed. Protein expressions of TLR2, TLR4, NF-κB p65, p38 MAPK, and p-p38 MAPK in rats were determined by Western blot. Thirty-four main components were identified by UPLC-Q-TOF-MS, including 15 flavonoids, 7 phenylpropanoids, 4 terpenoids, 4 organic acids, 2 esters, and 2 polyalkynes. As compared with the normal group, the body weight of the model group was significantly decreased(P<0.01), and foot swelling(P<0.05, P<0.01), arthritis index(P<0.01), and the immune organ index(P<0.01) were significantly increased. The synovial histopathological injury was obviously observed in the model group. The serum levels of inflammatory factors TNF-α, IL-1ß, and IL-6 were significantly increased(P<0.01), and the protein expression levels of TLR2, TLR4, NF-κB p65, p-p38 MAPK/p38 MAPK in the synovial tissue were significantly increased(P<0.01) in the model group. As compared with the model group, the body weights of the ZDS dose groups were increased(P<0.01), and the degree of foot swelling(P<0.01) and the arthritis index were decreased(P<0.05, P<0.01). The immune organ index was decreased(P<0.01) in the ZDS dose groups, and the synovial tissue hyperplasia and inflammatory cell infiltration were alleviated. The serum levels of TNF-α, IL-1ß, and IL-6 were significantly decreased(P<0.05, P<0.01), and the protein expression levels of TLR2, TLR4, NF-κB p65, p-p38 MAPK/p38 MAPK were decreased(P<0.05, P<0.01) in the ZDS dose groups. C. canescens extract containing apigenin, tricin, chlorogenic acid, aesculin, ferulic acid, caffeic acid, and oleanolic acid has a good anti-RA effect, and the mechanism may be related to the inhibition of TLRs/MAPKs/NF-κB signaling pathways.

Hypophysitis induced by anti-programmed cell death protein 1 immunotherapy in non-small cell lung cancer: Three case reports.

BACKGROUND: Hypophysitis induced by programmed cell death 1 protein (PD-1) immune checkpoint inhibitors is rare and poorly described. We report three patients with non-small cell lung cancer who developed hypophysitis after anti-PD-1 immunotherapy. CASE SUMMARY: Both case 1 and case 2 presented with common symptoms of fatigue, nausea, and vomiting. However, case 3 showed rare acute severe symptoms such as hoarse voice, bucking, and difficulty in breathing even when sitting. Following two cycles of immunotherapy in case 3, the above severe symptoms and pituitary gland enlargement were found on magnetic resonance imaging at the onset of hypophysitis. These symptoms were relieved after 10 d of steroid treatment. Case 3 was the first patient with these specific symptoms, which provided a new insight into the diagnosis of hypophysitis. In addition, we found that the clinical prognosis of patients with hypophysitis was related to the dose of steroid therapy. Case 3 was treated with high-dose hormone therapy and her pituitary-corticotropic axis dysfunction returned to normal after more than 6 mo of steroid treatment. Cases 1 and 2 were treated with the low-dose hormone, and dysfunction of the pituitary-corticotropic axis was still present after up to 7 mo of steroid treatment. CONCLUSION: The clinical symptoms described in this study provide a valuable reference for the diagnosis and treatment of immune-related hypophysitis.

Serum iron is closely associated with metabolic dysfunction-associated fatty liver disease in type 2 diabetes: A real-world study.

Aims: There is still a debate about the relationship between serum iron and metabolic dysfunction-associated fatty liver disease (MAFLD). Furthermore, few relevant studies were conducted in type 2 diabetes mellitus (T2DM). Therefore, this study aimed to explore the association of serum iron levels with MAFLD in Chinese patients with T2DM. Methods: This cross-sectional, real-world study consisted of 1,467 Chinese T2DM patients. MAFLD was diagnosed by abdominal ultrasonography. Based on serum iron quartiles, the patients were classified into four groups. Clinical characteristics were compared among the four groups, and binary logistic analyses were used to assess the associations of serum iron levels and quartiles with the presence of MAFLD in T2DM. Results: After adjusting for gender, age, and diabetes duration, significantly higher prevalence of MAFLD was found in the second (45.7%), third (45.2%), and fourth (47.0%) serum iron quartiles than in the first quartiles (26.8%), with the highest MAFLD prevalence in the fourth quartile (p < 0.001 for trend). Moreover, increased HOMA2-IR (p = 0.003 for trend) and decreased HOMA2-S (p = 0.003 for trend) were observed across the serum iron quartiles. Fully adjusted binary logistic regression analyses indicated that both increased serum iron levels (OR: 1.725, 95% CI: 1.427 to 2.085, p < 0.001) and quartiles (p < 0.001 for trend) were still closely associated with the presence of MAFLD in T2DM patients even after controlling for multiple confounding factors. Conclusions: There is a positive correlation between the presence of MAFLD and serum iron levels in T2DM patients, which may be attributed to the close association between serum iron and insulin resistance. Serum iron levels may act as one of the indicators for evaluating the risk of MAFLD in T2DM individuals.

Clinical practice guideline for transurethral plasmakinetic resection of prostate for benign prostatic hyperplasia (2021 Edition).

Benign prostatic hyperplasia (BPH) is highly prevalent among older men, impacting on their quality of life, sexual function, and genitourinary health, and has become an important global burden of disease. Transurethral plasmakinetic resection of prostate (TUPKP) is one of the foremost surgical procedures for the treatment of BPH. It has become well established in clinical practice with good efficacy and safety. In 2018, we issued the guideline "2018 Standard Edition". However much new direct evidence has now emerged and this may change some of previous recommendations. The time is ripe to develop new evidence-based guidelines, so we formed a working group of clinical experts and methodologists. The steering group members posed 31 questions relevant to the management of TUPKP for BPH covering the following areas: questions relevant to the perioperative period (preoperative, intraoperative, and postoperative) of TUPKP in the treatment of BPH, postoperative complications and the level of surgeons' surgical skill. We searched the literature for direct evidence on the management of TUPKP for BPH, and assessed its certainty generated recommendations using the grade criteria by the European Association of Urology. Recommendations were either strong or weak, or in the form of an ungraded consensus-based statement. Finally, we issued 36 statements. Among them, 23 carried strong recommendations, and 13 carried weak recommendations for the stated procedure. They covered questions relevant to the aforementioned three areas. The preoperative period for TUPKP in the treatment of BPH included indications and contraindications for TUPKP, precautions for preoperative preparation in patients with renal impairment and urinary tract infection due to urinary retention, and preoperative prophylactic use of antibiotics. Questions relevant to the intraoperative period incorporated surgical operation techniques and prevention and management of bladder explosion. The application to different populations incorporating the efficacy and safety of TUPKP in the treatment of normal volume (< 80 ml) and large-volume (≥ 80 ml) BPH compared with transurethral urethral resection prostate, transurethral plasmakinetic enucleation of prostate and open prostatectomy; the efficacy and safety of TUPKP in high-risk populations and among people taking anticoagulant (antithrombotic) drugs. Questions relevant to the postoperative period incorporated the time and speed of flushing, the time indwelling catheters are needed, principles of postoperative therapeutic use of antibiotics, follow-up time and follow-up content. Questions related to complications incorporated types of complications and their incidence, postoperative leukocyturia, the treatment measures for the perforation and extravasation of the capsule, transurethral resection syndrome, postoperative bleeding, urinary catheter blockage, bladder spasm, overactive bladder, urinary incontinence, urethral stricture, rectal injury during surgery, postoperative erectile dysfunction and retrograde ejaculation. Final questions were related to surgeons' skills when performing TUPKP for the treatment of BPH. We hope these recommendations can help support healthcare workers caring for patients having TUPKP for the treatment of BPH.

Machine learning predicts cancer-associated deep vein thrombosis using clinically available variables.

PURPOSE: To develop and validate machine learning (ML) models for cancer-associated deep vein thrombosis (DVT) and to compare the performance of these models with the Khorana score (KS). METHODS: We randomly extracted data of 2100 patients with cancer between Jan. 1, 2017, and Oct. 31, 2019, and 1035 patients who underwent Doppler ultrasonography were enrolled. Univariate analysis and Lasso regression were applied to select important predictors. Model training and hyperparameter tuning were implemented on 70% of the data using a ten-fold cross-validation method. The remaining 30% of the data were used to compare the performance with seven indicators (area under the receiver operating characteristic curve [AUC], sensitivity, specificity, accuracy, balanced accuracy, Brier score, and calibration curve), among all five ML models (linear discriminant analysis [LDA], logistic regression [LR], classification tree [CT], random forest [RF], and support vector machine [SVM]), and the KS. RESULTS: The incidence of cancer-associated DVT was 22.3%. The top five predictors were D-dimer level, age, Charlson Comorbidity Index (CCI), length of stay (LOS), and previous VTE (venous thromboembolism) history according to RF. Only LDA (AUC = 0.773) and LR (AUC = 0.772) outperformed KS (AUC = 0.642), and combination with D-dimer showed improved performance in all models. A nomogram and web calculator https://webcalculatorofcancerassociateddvt.shinyapps.io/dynnomapp/ were used to visualize the best recommended LR model. CONCLUSION: This study developed and validated cancer-associated DVT predictive models using five ML algorithms and visualized the best recommended model using a nomogram and web calculator. The nomogram and web calculator developed in this study may assist doctors and nurses in evaluating individualized cancer-associated DVT risk and making decisions. However, other prospective cohort studies should be conducted to externally validate the recommended model.

Expansion of bilin-based red light sensors in the subaerial desert cyanobacterium Nostoc flagelliforme.

Light is the crucial environmental signal for desiccation-tolerant cyanobacteria to activate photosynthesis and prepare for desiccation at dawn. However, the photobiological characteristics of desert cyanobacteria adaptation to one of the harshest habitats on Earth remain unresolved. In this study, we surveyed the genome of a subaerial desert cyanobacterium Nostoc flagelliforme and identified two phytochromes and seven cyanobacteriochromes (CBCRs) with one or more bilin-binding GAF (cGMP phosphodiesterase/adenylyl cyclase/FhlA) domains. Biochemical and spectroscopic analyses of 69 purified GAF-containing proteins from recombinant phycocyanobilin (PCB), biliverdin or phycoerythrobilin-producing Escherichia coli indicated that nine of these proteins bind chromophores. Further investigation revealed that 11 GAFs form covalent adducts responsive to near-UV and visible light: eight GAFs contained PCB chromophores, three GAFs contained biliverdin chromophores and one contained the PCB isomer, phycoviolobilin. Interestingly, COO91_03972 is the first-ever reported GAF-only CBCR capable of sensing five wavelengths of light. Bioinformatics and biochemical analyses revealed that residue P132 of COO91_03972 is essential for chromophore binding to dual-cysteine CBCRs. Furthermore, the complement of N. flagelliforme CBCRs is enriched in red light sensors. We hypothesize that these sensors are critical for the acclimatization of N. flagelliforme to weak light environments at dawn.

Observation of synergistic antibacterial properties of prodigiosin from Serratia marcescens jx-1 with metal ions in clinical isolates of Staphylococcus aureus.

Methicillin-resistant Staphylococcus aureus (MRSA) infections are a major global health problem, and novel and effective antimicrobial drugs are urgently required to combat this life-threatening pathogen. Prodigiosin (PG) is a bacterial secondary metabolite with excellent anticancer and antibacterial properties. However, little is known about the antibacterial function of PG against MRSA. Therefore, the antibacterial efficacy of PG alone and PG in combination with different metal ions against clinic isolates of MRSA and methicillin-sensitive S. aureus (MSSA) strain was evaluated in the present study. The minimum inhibitory concentration of PG against both MRSA and MSSA was 0.25 µg/mL. However, 0.1 µg/mL PG showed a stronger inhibitory effect on MSSA cell growth (47.12%) than on MRSA cell growth (35.87%). Surprisingly, we observed a significant difference (p < 0.01) in membrane integrity between PG-treated MRSA and MSSA using the propidium iodide staining assay. Further, we found that in combination with PG, Zn2+, Al3+, and Cu2+ showed synergistic antibacterial effects against MRSA and MSSA. Our results could increase the current knowledge regarding the efficacy of PG in inhibiting the growth of different types of S. aureus clinical isolates and also offer a novel strategy for developing efficient antibacterial agents.

Design and synthesis of new lenalidomide analogs via Suzuki cross-coupling reaction.

Lenalidomide is a cereblon modulator known for its antitumor, anti-inflammatory, and immunomodulatory properties in clinical applications. Recently, some reported lenalidomide analogs could exhibit a significant bioactivity through various modifications in the isoindolinone ring. In this study, we designed and synthesized a series of novel lenalidomide analogs on the basis of the installation of a methylene chain at the C-4 position of isoindolinone via the Suzuki cross-coupling reaction. These new compounds were further evaluated for their in vitro antiproliferative activities against two tumor cell lines (MM.1S and Mino). Specifically, compound 4c displayed the strongest antiproliferative activity against the MM.1S (IC50 = 0.27 ± 0.03 µM) and Mino (IC50 = 5.65 ± 0.58 µM) tumor cell lines. In summary, we have developed a new synthetic strategy for C-4 derivatization of lenalidomide, providing a bioactive scaffold that could be used to discover further potential antitumor lead compounds in pharmaceutical research.

Inhibitory Effect of Corilagin on miR-21-Regulated Hepatic Fibrosis Signaling Pathway.

Corilagin is a polyphenol that can be extracted from many medicinal plants and shows multiple pharmacological effects. We aimed to investigate the role of corilagin on miR-21-regulated hepatic fibrosis, especially miR-21-regulated TGF-ß1/Smad signaling pathway, in hepatic stellate LX2 cell line and Sprague-Dawley rats. The mRNA or protein levels of miR-21, Smad7, connective tissue growth factor (CTGF), α-smooth muscle actin (α-SMA), tissue inhibitor of metalloproteinase-1 (TIMP-1), matrix metalloproteinase-9 (MMP-9), collagen type I alpha 1 (COL1A1), Smad2, Smad3, Smad2/3, p-Smad2, p-Smad3, p-Smad2/3, and transforming growth factor-ß1 (TGF-ß1) in LX2 cells and liver tissues were determined. Furthermore, gain-of and loss-of function of miR-21 in miR-21-regulated TGF-ß1/Smad signaling pathway were analyzed in LX2 cells. Liver tissues and serum were collected for pathological analysis, immunohistochemical staining, and enzyme-linked immunosorbent assay (ELISA). Corilagin treatment reduced mRNA or protein levels of miR-21, CTGF, α-SMA, TIMP-1, TGF-ß1, COL1A1, p-Smad2, p-Smad3, and p-Smad2/3 both in vitro and in vivo. While corilagin increased mRNA and protein levels of Smad7 and MMP-9. After gain-of and loss-of function of miR-21, the downstream effectors of miR-21-regulated TGF-ß1/Smad signaling pathway in LX2 cells changed accordingly, and the changes were inhibited by corilagin. Simultaneously, administration of corilagin not only ameliorated pathological manifestation of liver fibrosis but also reduced levels of α-SMA and COL1A1 in liver tissues and TGF-ß1, ALT levels in serum. Corilagin is able to potentially prevent liver fibrosis by blocking the miR-21-regulated TGF-ß1/Smad signaling pathway in LX2 cells and CCl4-induced liver fibrosis rats, which may provide a novel therapeutic strategy for liver fibrosis.

MTMR3 is upregulated in patients with breast cancer and regulates proliferation, cell cycle progression and autophagy in breast cancer cells.

As a member of the myotubularin family, myotubularin related protein 3 (MTMR3) has been demonstrated to participate in tumor development, including oral and colon cancer. However, little is known about its functional roles in breast cancer. In the present study, the expression of MTMR3 in breast cancer was evaluated by immunohistochemical staining of tumor tissues from 172 patients. Online data was then used for survival analysis from the PROGgeneV2 database. In vitro, MTMR3 expression was silenced in MDA­MB­231 cells via lentiviral shRNA transduction. MTT, colony formation and flow cytometry assays were performed in the control and MTMR3­silenced cells to evaluate the cell growth, proliferation and cell cycle phase distribution, respectively. Western blotting was used to evaluate the protein expression levels of autophagy­related markers. The results demonstrated that the expression of MTMR3 in breast cancer tissues was significantly increased compared with adjacent normal tissues. MTMR3 was highly expressed in triple­negative breast cancer and was associated with disease recurrence. MTMR3 knockdown in MDA­MB­231 cells inhibited cell proliferation and induced cell cycle arrest and autophagy. The present results indicated that MTMR3 may have an important role in promoting the progression of breast cancer, and its inhibition may serve as a promising therapeutic target for breast cancer treatment.

Design, synthesis and biological evaluation of the thioether-containing lenalidomide analogs with anti-proliferative activities.

Lenalidomide and its analogs have exhibited extensive anti-tumor, anti-inflammatory and immunomodulatory properties in pharmaceutical research. In this work, a series of novel thioether-containing lenalidomide analogs were designed and synthesized for biological evaluation. Lenalidomide showed significant anti-proliferative activity against the MM.1S cell line (IC50 = 50 nM) while it displayed no anti-proliferative activity against other treated tumor cell lines. Compared with lenalidomide, compound 3j exhibited preferable anti-proliferative activity against the MM.1S (IC50 = 1.1 nM), Mino (IC50 = 2.3 nM) and RPMI 8226 cell lines (IC50 = 5.5 nM). In addition, compound 3j displayed selective anti-proliferative activity against several tumor cell lines, including various B-NHL, MM and AML cell lines, and showed no cytotoxicity on the normal human cell line PBMC, suggesting a good safety profile. Following oral administration, compound 3j achieved a Cmax of 283 ng/mL at 0.83 h, and had a higher relative oral bioavailability value (F = 39.2%) than that of CC-220 (F = 22.8%), but its oral exposure in vivo was somewhat low (AUC = 755 h ng/mL). Furthermore, it was found that oral administration of compound 3j at dosages of 60 mg/kg could delay RPMI 8226 tumor growth in the female CB-17 SCID mice. The current work confirmed that installing thioether moiety at the 4-position of isoindolinone is an effective strategy for identifying new promising lenalidomide analogs with anti-tumor activities in preclinical study.