Mining Real-World Big Data to Characterize Adverse Drug Reaction Quantitatively: Mixed Methods Study.

BACKGROUND: Adverse drug reactions (ADRs), which are the phenotypic manifestations of clinical drug toxicity in humans, are a major concern in precision clinical medicine. A comprehensive evaluation of ADRs is helpful for unbiased supervision of marketed drugs and for discovering new drugs with high success rates. OBJECTIVE: In current practice, drug safety evaluation is often oversimplified to the occurrence or nonoccurrence of ADRs. Given the limitations of current qualitative methods, there is an urgent need for a quantitative evaluation model to improve pharmacovigilance and the accurate assessment of drug safety. METHODS: In this study, we developed a mathematical model, namely the Adverse Drug Reaction Classification System (ADReCS) severity-grading model, for the quantitative characterization of ADR severity, a crucial feature for evaluating the impact of ADRs on human health. The model was constructed by mining millions of real-world historical adverse drug event reports. A new parameter called Severity_score was introduced to measure the severity of ADRs, and upper and lower score boundaries were determined for 5 severity grades. RESULTS: The ADReCS severity-grading model exhibited excellent consistency (99.22%) with the expert-grading system, the Common Terminology Criteria for Adverse Events. Hence, we graded the severity of 6277 standard ADRs for 129,407 drug-ADR pairs. Moreover, we calculated the occurrence rates of 6272 distinct ADRs for 127,763 drug-ADR pairs in large patient populations by mining real-world medication prescriptions. With the quantitative features, we demonstrated example applications in systematically elucidating ADR mechanisms and thereby discovered a list of drugs with improper dosages. CONCLUSIONS: In summary, this study represents the first comprehensive determination of both ADR severity grades and ADR frequencies. This endeavor establishes a strong foundation for future artificial intelligence applications in discovering new drugs with high efficacy and low toxicity. It also heralds a paradigm shift in clinical toxicity research, moving from qualitative description to quantitative evaluation.

Immunosuppressive role of BDNF in therapy-induced neuroendocrine prostate cancer.

Prostate stromal cells play a crucial role in the promotion of tumor growth and immune evasion in the tumor microenvironment (TME) through intricate molecular alterations in their interaction with prostate cancer (PCa) cells. While the impact of these cells on establishing an immunosuppressive response and influencing PCa aggressiveness remains incompletely understood. Our study shows that the activation of the leukemia inhibitory factor (LIF)/LIF receptor (LIFR) pathway in both prostate tumor and stromal cells, following androgen deprivation therapy (ADT), leads to the development of an immunosuppressive TME. Activation of LIF/LIFR signaling in PCa cells induces neuroendocrine differentiation (NED) and upregulates immune checkpoint expression. Inhibition of LIF/LIFR attenuates these effects, underscoring the crucial role of LIF/LIFR in linking NED to immunosuppression. Prostate stromal cells expressing LIFR contribute to NED and immunosuppressive marker abundance in PCa cells, while LIFR knockdown in prostate stromal cells reverses these effects. ADT-driven LIF/LIFR signaling induces brain-derived neurotrophic factor (BDNF) expression, which, in turn, promotes NED, aggressiveness, and immune evasion in PCa cells. Clinical analyses demonstrate elevated BDNF levels in metastatic castration-resistant PCa (CRPC) and a positive correlation with programmed death-ligand 1 (PDL1) and immunosuppressive signatures. This study shows that the crosstalk between PCa cells and prostate stromal cells enhances LIF/LIFR signaling, contributing to an immunosuppressive TME and NED in PCa cells through the upregulation of BDNF.

Cu(II) Coordination Polymers Containing Mixed Ligands with Different Flexibilities: Structural Diversity and Iodine Adsorption.

Reactions of N,N'-bis(3-methylpyridyl)oxalamide (L1), N,N'-bis(3-methylpyridyl)adipoamide (L2) and N,N'-bis(3-methylpyridyl)sebacoamide (L3) with tricarboxylic acids and Cu(II) salts afforded {[Cu(L1)(1,3,5-HBTC)]·H2O}n (1,3,5-H3BTC = 1,3,5-benzenetricarboxylic acid), 1, {[Cu1.5(L2)1.5(1,3,5-BTC)(H2O)2]·6.5H2O}n, 2, [Cu(L2)0.5(1,3,5-HBTB)]n (1,3,5-H3BTB = 1,3,5-tri(4-carboxyphenyl)benzene), 3, [Cu4(L3)(OH)2(1,3,5-BTC)2]n, 4, {[Cu3(L3)2(1,3,5-BTB)2]·2.5MeOH·2H2O}n, 5, and {[Cu3(L3)2(1,3,5-BTB)2 ]·DMF·2H2O}n, 6, which have been structurally characterized by using single crystal X-ray crystallography. Complexes 1-4 form a 2D layer with the {44.62}-sql topology, a 2D layer with the (4.62)2(42.62.82)-bex topology, a three-fold interpenetrated 3D net with the (412·63)-pcu topology and a 3D framework with the (410·632·83)(42·6)2(43·63) topology, respectively, whereas 5 and 6 are 3D frameworks with the (63)2(64·82)(68·85·102) topology. Complex 5 shows a better iodine adsorption factor of 290.0 mg g-1 at 60 °C for 360 min than the other ones, revealing that the flexibility of the spacer ligand governs the structural diversity and the adsorption capacity.

CHRM4/AKT/MYCN upregulates interferon alpha-17 in the tumor microenvironment to promote neuroendocrine differentiation of prostate cancer.

Current treatment options for prostate cancer focus on targeting androgen receptor (AR) signaling. Inhibiting effects of AR may activate neuroendocrine differentiation and lineage plasticity pathways, thereby promoting the development of neuroendocrine prostate cancer (NEPC). Understanding the regulatory mechanisms of AR has important clinical implications for this most aggressive type of prostate cancer. Here, we demonstrated the tumor-suppressive role of the AR and found that activated AR could directly bind to the regulatory sequence of muscarinic acetylcholine receptor 4 (CHRM4) and downregulate its expression. CHRM4 was highly expressed in prostate cancer cells after androgen-deprivation therapy (ADT). CHRM4 overexpression may drive neuroendocrine differentiation of prostate cancer cells and is associated with immunosuppressive cytokine responses in the tumor microenvironment (TME) of prostate cancer. Mechanistically, CHRM4-driven AKT/MYCN signaling upregulated the interferon alpha 17 (IFNA17) cytokine in the prostate cancer TME after ADT. IFNA17 mediates a feedback mechanism in the TME by activating the CHRM4/AKT/MYCN signaling-driven immune checkpoint pathway and neuroendocrine differentiation of prostate cancer cells. We explored the therapeutic efficacy of targeting CHRM4 as a potential treatment for NEPC and evaluated IFNA17 secretion in the TME as a possible predictive prognostic biomarker for NEPC.

Association of creatinine-albumin ratio with 28-day mortality in major burned patients: A retrospective cohort study.

BACKGROUND: Serum creatinine (Cr) and Albumin (Alb) have emerged as prognostic factors for mortality in many diseases including burned patients. However, few studies report the relationship between Cr/Alb ratio and major burned patients. The purpose of this study is to make evaluation of efficacy of Cr/Alb ratio in predicting 28-day mortality in major burned patients. METHOD: Based on a local largest tertiary hospital in South of China, we retrospectively analyzed data of 174 patients with total burn area surface (TBSA) ≥ 30% from January 2010 to December 2022. Receiver operating characteristic curve (ROC), logistic analysis, and Kaplan-Meier analysis were performed to evaluate the association between Cr/Alb ratio and 28-day mortality. Integrated discrimination improvement (IDI), and net reclassification improvement (NRI) were used to estimate the improvements in new model performance. RESULTS: 28-day mortality rate was 13.2% (23/174) in burned patients. Cr/Alb on admission at level of 3.340µmol/g showed the best discrimination between survivors and non-survivors after admission at 28 days. The result of multivariate logistic analysis suggested that age (OR, 1.058 [95%CI 1.016-1.102]; p = 0.006), higher FTSA (OR, 1.036 [95%CI 1.010-1.062]; p = 0.006), and higher level of Cr/Alb ratio (OR, 6.923 [95CI% 1.743-27.498]; p = 0.006) were independently associated with 28 day-mortality. A regression model was constructed by logit(p) = 0.057 *Age + 0.035 *FTBA + 1.935 * Cr/Alb - 6.822. The model showed a better discrimination and risk reclassification compared with ABSI and rBaux score. CONCLUSIONS: High Cr/Alb ratio at admission is a herald of poor outcome. The model generated from multivariate analysis could serve as an alternative prediction tool among major burned patients.

Mortality Evaluation and Life Expectancy Prediction of Patients with Hepatocellular Carcinoma with Data Mining.

BACKGROUND: The complexity of systemic variables and comorbidities makes it difficult to determine the best treatment for patients with hepatocellular carcinoma (HCC). It is impossible to perform a multidimensional evaluation of every patient, but the development of guidelines based on analyses of said complexities would be the next best option. Whereas conventional statistics are often inadequate for developing multivariate predictive models, data mining has proven more capable. Patients, methods and findings: Clinical profiles and treatment responses of 537 patients diagnosed with Barcelona Clinic Liver Cancer stages B and C from 2009 to 2019 were retrospectively analyzed using 4 decision tree algorithms. A combination of 19 treatments, 7 biomarkers, and 4 states of hepatitis was tested to determine which combinations would result in survival times greater than a year in duration. Just 2 of the algorithms produced complete models through single trees, which made them only the ones suitable for clinical judgement. A combination of alpha fetoprotein ≤210.5 mcg/L, glutamic oxaloacetic transaminase ≤1.13 µkat/L, and total bilirubin ≤ 0.0283 mmol/L was shown to be a good predictor of survival >1 year, and the most effective treatments for such patients were radio-frequency ablation (RFA) and transarterial chemoembolization (TACE) with radiation therapy (RT). In patients without this combination, the best treatments were RFA, TACE with RT and targeted drug therapy, and TACE with targeted drug therapy and immunotherapy. The main limitation of this study was its small sample. With a small sample size, we may have developed a less reliable model system, failing to produce any clinically important results or outcomes. CONCLUSION: Data mining can produce models to help clinicians predict survival time at the time of initial HCC diagnosis and then choose the most suitable treatment.

Targeting PKLR/MYCN/ROMO1 signaling suppresses neuroendocrine differentiation of castration-resistant prostate cancer.

Conventional treatment of prostate cancer (PCa) uses androgen-deprivation therapy (ADT) to inhibit androgen receptor (AR) signaling-driven tumor progression. ADT-induced PCa recurrence may progress to an AR-negative phenotype with neuroendocrine (NE) histologic features, which are associated with metabolic disturbances and poor prognoses. However, the metabolic pathways that regulate NE differentiation (NED) in PCa remain unclear. Herein, we show a regulatory mechanism in NED-associated metabolism dysfunction induced by ADT, whereby overexpression of pyruvate kinase L/R (PKLR) mediates oxidative stress through upregulation of reactive oxygen species modulator 1 (ROMO1), thereby promoting NED and aggressiveness. ADT mediates the nuclear translocation of PKLR, which binds to the MYCN/MAX complex to upregulate ROMO1 and NE-related genes, leading to altered mitochondrial function and NED of PCa. Targeting nuclear PKLR/MYCN using bromodomain and extra-terminal motif (BET) inhibitors has the potential to reduce PKLR/MYCN-driven NED. Abundant ROMO1 in serum samples may provide prognostic information in patients with ADT. Our results suggest that ADT resistance leads to upregulation of PKLR/MYCN/ROMO1 signaling, which may drive metabolic reprogramming and NED in PCa. We further show that increased abundance of serum ROMO1 may be associated with the development of NE-like PCa.

One new furanone analogue from the deep-sea fungus Purpureocillium sp. SCSIO 06693.

A new furanone analog, (E)-2-(8,9-dihydroxy-6,8-dimethyldec-4-en-2-yl)-met-hylfuran-3(2H)-one (1), together with six known compounds, including two diterpenoids (2 and 3), one butyrolactone (4) and three isocoumarins (5-7), were isolated from a deep-sea fungus, Purpureocillium sp. SCSIO 06693. Among them, compound 1 existed as two tautomeric forms (1a and 1b) differing in configuration of the furan ring. The chemical structures were elucidated by the basis of spectroscopic evidences, including HRESIMS, NMR and optical rotation. Isolated compounds were evaluated for their cytotoxic, antiviral, antibacterial, antioxidant, acetyl cholinesterase (AChE) and pancreatic lipase (PL) enzyme inhibitory activities. Biological evaluation results revealed that compound 4 showed modest antioxidant activity against DPPH with IC50 value of 72.03 µM. In addition, compounds 1-4 exhibited PL enzyme inhibitory activities.

Indole diketopiperazine alkaloids and aromatic polyketides from the Antarctic fungus Penicillium sp. SCSIO 05705.

A new indole diketopiperazine alkaloid, named penilline D (1), together with five known indole alkaloid analogues (2-5, 11), two meroterpenoids (6 and 12), and four butenolide derivatives (7-10), were isolated from the Antarctic fungus Penicillium sp. SCSIO 05705. Extensive spectroscopic analysis and electronic circular dichroism (ECD) calculation were used to elucidate the structure of penilline D (1), including its absolute configuration. All isolated compounds (1-12) were evaluated for their cytotoxic, antibacterial and enzyme inhibitory activities against acetylcholinesterase (AChE) and pancreatic lipase (PL). Among them, compound 5 exhibited moderate in vitro cytotoxic activity against the 143B cell line with IC50 value of 12.64 ± 0.78 µM. Compound 6 showed strong inhibitory activity against AChE with IC50 value of 0.36 nM (IC50 18.7 nM for Tacrine), while compounds 6 and 11 showed weak PL enzyme inhibitory activity. Furthermore, an in silico molecular docking study was also performed between 6 and AChE.

A glyoxylate-containing benzene derivative and butenolides from a marine algicolous fungus Aspergillus sp. SCSIO 41304.

A new glyoxylate-containing benzene derivative, methyl 2-(4-hydroxy-3-(3'-methyl-2'-butenyl)phenyl)-2-oxoacetate (1), together with ten known compounds (2-11), were isolated from the marine algicolous fungus, Aspergillus sp. SCSIO 41304. Their planar structures and absolute configurations were elucidated by detailed NMR, MS spectroscopic analysis and comparing with literature data. Compound 1 was isolated as a new fungal secondary metabolite, possessing a methyl glyoxylate moiety R-CO-CO-OCH3, which is rare in natural sources. All the isolated compounds (1-11) were tested for their antibacterial and enzyme inhibitory activities against acetylcholinesterase (AChE) and pancreatic lipase (PL). Among these compounds, aspulvinone H (4) showed moderate inhibition against AChE and PL with IC50 values of 25.95 and 47.06 µM, respectively. Further molecular docking simulation exhibited that compound 4 could well bind to the catalytic pockets of the AChE and PL.

Th1/Th2 cytokine levels: A potential diagnostic tool for patients with necrotizing fasciitis.

INTRODUCTION: Necrotizing fasciitis (NF) has emerged as rare but rapidly progressive, life-threatening severe skin and soft tissue infection. We conducted a study to investigate whether Th1/Th2 cytokines could serve as biomarkers to distinguish NF from class III skin and soft tissue infections (SSTIs). METHODS: A retrospective review was performed for 155 patients suffering from serious skin and soft tissue infections from October 2020 to February 2022. Th1/Th2 cytokines were obtained from peripheral blood and wound drainage fluid samples. Data on demographic characteristics, causative microbiological organisms, Th1/Th2 cytokines, c-reactive protein, procalcitonin and white blood cell (WBC) were extracted for analysis. Factors with statistical difference(p < 0.1) were included in the multivariate logistic regression model. The clinical differential diagnostic values of interleukin-2(IL-2), IL-6, IL-10, tumor necrosis factor-α (TNF-α) and interferon-r (IFN-r) were analyzed by receiver operating characteristic (ROC) curve. RESULTS: Among the 155 patients, 66(43%) patients were diagnosed as NF. We found no significant difference for sex, age, location of infection, coexisting condition, predisposition, duration of symptoms before admission and micro-organisms, WBC, procalcitonin and c-reactive protein in NF and class III SSTIs group. NF had higher levels of IL-6 in serum (50.46 [24.89, 108.89] vs. 11.87 [5.20, 25.32] pg/ml; p＜0.01), IL-10 in serum (3.45 [2.03, 5.12] vs. 2.51 [1.79, 3.29] pg/ml; p＜0.01), IL-2 in wound drainage fluid (0.89 [0.49, 1.33] vs. 0.63 [0.14, 1.14] pg/ml; p = 0.02), IL-6 in wound drainage fluid (5000.84 [1392.30, 13287.19] vs. 1927.82 (336.65, 6759.27) pg/ml; p＜0.01), TNF-a in wound drainage fluid (5.20 [1.49, 22.97] vs. 0.96 [0.12, 3.21] pg/ml; p＜0.01) and IFN-r in wound drainage fluid (1.32 [0.47, 4.62] vs. 0.68 [0.10, 1.88] pg/ml; p = 0.02) as compared to the class III SSTIs. Multivariate logistic regression analyses showed that IL-6 in serum, IL-10 in serum and TNF-a in wound drainage fluid exhibited independently significant associations with diagnosis of NF(p＜0.05). In ROC curve analysis of IL-2, IL-6, IL-10, TNF-a and IFN-r for diagnosis of NF, the area under the curve (AUC) of IL-6 in serum could reach to 0.80 (p＜0.001). Using 27.62 pg/ml as the cut off value, the sensitivity was 74% and the specificity was 79% in IL-6 in serum. CONCLUSIONS: Th1/Th2 cytokines, IL-6 in serum in particular, are potential biomarkers for the diagnosis of NF in the early stage. However, larger patient populations with multiple centers and prospective studies are necessary to ensure the prognostic role of Th1/Th2 cytokines.

Pyruvate kinase L/R links metabolism dysfunction to neuroendocrine differentiation of prostate cancer by ZBTB10 deficiency.

Neuroendocrine differentiation (NED) frequently occurs in androgen-deprivation therapy (ADT)-resistant prostate cancer (PCa) and is typically associated with metabolic pathway alterations, acquisition of lineage plasticity, and malignancy. There is no conventional therapeutic approach for PCa patients with NED pathologic features because the molecular targets are unknown. Here, we evaluated the regulatory mechanism of NED-associated metabolic reprogramming induced by ADT. We detected that the loss of the androgen-responsive transcription factor, zinc finger, and BTB domain containing 10 (ZBTB10), can activate pyruvate kinase L/R (PKLR) to enhance a NED response that is associated with glucose uptake by PCa cells. PKLR exhibits a tumor-promoting effect in PCa after ADT, but ZBTB10 can compensate for the glucose metabolism and NED capacity of PKLR through the direct transcriptional downregulation of PKLR. Targeting PKLR by drug repurposing with FDA-approved compounds can reduce the aggressiveness and NED of ADT-resistant PCa. We demonstrated that PKLR acts as a modulator to activate NED in PCa enhancement by loss of ZBTB10, thereby enabling PCa cells to mount a glycolysis response essential for therapeutic resistance. Our findings highlight the broad relation between NED and metabolic dysfunction to provide gene expression-based biomarkers for NEPC treatment.

Diketopiperazine and enterotoxin analogues from the mangrove derived-soil Streptomyces sp. SCSIO 41400 and their biological evaluation.

A new diketopiperazine, cyclo-(d-8-acetoxyl-Pro-l-Leu) (1), together with eight known compounds (2-9) including three enterotoxins (2-4), four diketopiperazines (5-8) and maltol (9), were isolated from the mangrove derived-soil Streptomyces sp. SCSIO 41400. The planar structures of all compounds were determined from analysis of NMR spectra, MS, optical rotation and comparing with literature data. The absolute configuration of compound 1 was assigned by electronic circular dichroism (ECD). The isolated compounds (1-9) were tested for their acetyl cholinesterase (AChE) and pancreatic lipase (PL) enzyme inhibitory activities. Among them, the new diketopiperazine (1) displayed preferable PL enzyme inhibitory activity with IC50 value of 27.3 µg/mL, while compounds 2, 5 and 6 showed weak PL enzyme inhibitory activity. Further molecular docking simulation exhibited that compound 1 could be well bind with the catalytic pocket of the PL. Besides, compound 9 showed moderate antibacterial activity against Methicillin-resistant Staphylococcus aureus with MIC value of 12.5 µg/mL, which was comparable to that of the positive control ampicillin with MIC value of 3.125 µg/mL.

PCK1 regulates neuroendocrine differentiation in a positive feedback loop of LIF/ZBTB46 signalling in castration-resistant prostate cancer.

BACKGROUND: Castration-resistant prostate cancer (CRPC) patients frequently develop neuroendocrine differentiation, with high mortality and no effective treatment. However, the regulatory mechanism that connects neuroendocrine differentiation and metabolic adaptation in response to therapeutic resistance of prostate cancer remain to be unravelled. METHODS: By unbiased cross-correlation between RNA-sequencing, database signatures, and ChIP analysis, combining in vitro cell lines and in vivo animal models, we identified that PCK1 is a pivotal regulator in therapy-induced neuroendocrine differentiation of prostate cancer through a LIF/ZBTB46-driven glucose metabolism pathway. RESULTS: Upregulation of PCK1 supports cell proliferation and reciprocally increases ZBTB46 levels to promote the expression of neuroendocrine markers that are conducive to the development of neuroendocrine characteristic CRPC. PCK1 and neuroendocrine marker expressions are regulated by the ZBTB46 transcription factor upon activation of LIF signalling. Targeting PCK1 can reduce the neuroendocrine phenotype and decrease the growth of prostate cancer cells in vitro and in vivo. CONCLUSION: Our study uncovers LIF/ZBTB46 signalling activation as a key mechanism for upregulating PCK1-driven glucose metabolism and neuroendocrine differentiation of CRPC, which may yield significant improvements in prostate cancer treatment after ADT using PCK1 inhibitors.

TCF7L1 regulates cytokine response and neuroendocrine differentiation of prostate cancer.

Neuroendocrine differentiation (NED) is associated with WNT signaling activation and can be significantly observed after failure of androgen-deprivation therapy (ADT) for prostatic adenocarcinomas. Cytokine signaling is stimulated in NED prostate cancer; however, how ADT-upregulated WNT signaling promotes activation of cytokine signaling and contributes to NED of prostate cancer is poorly understood. In this study, we identified ADT-mediated upregulation of transcription factor 7 like 1 (TCF7L1), which increases the cytokine response and enhances NED of prostate cancer through interleukin (IL)-8/C-X-C motif chemokine receptor type 2 (CXCR2) signaling activation. ADT induced the secretion of WNT4 which upon engagement of TCF7L1 in prostate cancer cells, enhanced IL-8 and CXCR2 expressions. TCF7L1 directly binds to the regulatory sequence region of IL-8 and CXCR2 through WNT4 activation, thus upregulating IL-8/CXCR2 signaling-driven NED and cell motility. Analysis of prostate tissue samples collected from small-cell neuroendocrine prostate cancer (SCPC) and castration-resistant prostate cancer (CRPC) tumors showed an increased intensity of nuclear TCF7L1 associated with CXCR2. Our results suggest that induction of WNT4/TCF7L1 results in increased NED and malignancy in prostate cancer that is linked to dysregulation of androgen receptor signaling and activation of the IL-8/CXCR2 pathway.

Zanubrutinib Treatment of Central Nervous System Posttransplant Lymphoproliferative Disorder After Allogeneic Hematopoietic Stem Cell Transplantation: A Case Report.

Posttransplant lymphoproliferative disorder (PTLD) is a rare complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT) with poor prognosis. We report a patient with PTLD involved central nervous system (CNS) who treated with zanubrutinib, a second-generation Bruton tyrosine kinase (BTK) inhibitor. Our report supports the efficacy of bruton tyrosine kinase inhibitor zanubrutinib in the treatment of CNS-PTLD, which provides a new therapeutic option.

Pyrrolyl 4-quinolone alkaloids from the mangrove endophytic fungus Penicillium steckii SCSIO 41025: Chiral resolution, configurational assignment, and enzyme inhibitory activities.

Six undescribed 4-quinolone alkaloids, including four racemic mixtures, (±)-oxypenicinolines A-D, and two related ones, penicinolines F and G, together with seven known analogues, were isolated from the mangrove-derived fungus Penicillium steckii SCSIO 41025 (Trichocomaceae). The racemates were separated by HPLC using chiral columns. Their structures including absolute configurations were elucidated by extensive spectroscopic analysis, electronic circular dichroism (ECD) experiments, and single-crystal X-ray diffraction analysis. Structurally, (±)-oxypenicinolines A-D shared with an unusual 6/6/5/5 tetracyclic system incorporating a rare tetrahydro-pyrrolyl moiety. A plausible biosynthetic pathway for pyrrolyl 4-quinolone alkaloids is proposed. (±)-oxypenicinoline A and quinolactacide displayed α-glucosidase inhibitory activity with the IC50 values of 317.8 and 365.9 µΜ, respectively, which were more potent than that of acarbose (461.0 µM). Additionally, penicinoline and penicinoline E showed weak inhibitions toward acetylcholinesterase (AChE).

Nerve growth factor interacts with CHRM4 and promotes neuroendocrine differentiation of prostate cancer and castration resistance.

Nerve growth factor (NGF) contributes to the progression of malignancy. However, the functional role and regulatory mechanisms of NGF in the development of neuroendocrine prostate cancer (NEPC) are unclear. Here, we show that an androgen-deprivation therapy (ADT)-stimulated transcription factor, ZBTB46, upregulated NGF via ZBTB46 mediated-transcriptional activation of NGF. NGF regulates NEPC differentiation by physically interacting with a G-protein-coupled receptor, cholinergic receptor muscarinic 4 (CHRM4), after ADT. Pharmacologic NGF blockade and NGF knockdown markedly inhibited CHRM4-mediated NEPC differentiation and AKT-MYCN signaling activation. CHRM4 stimulation was associated with ADT resistance and was significantly correlated with increased NGF in high-grade and small-cell neuroendocrine prostate cancer (SCNC) patient samples. Our results reveal a role of the NGF in the development of NEPC that is linked to ZBTB46 upregulation and CHRM4 accumulation. Our study provides evidence that the NGF-CHRM4 axis has potential to be considered as a therapeutic target to impair NEPC progression.

Antioxidant CPA-type indole alkaloids produced from the deep-sea derived fungus Aspergillus sp. SCSIO 41024.

Twelve indole alkaloids, including α-cyclopiazonic acid (CPA) (1), nine 2-oxo indole CPA derivatives (2-10), and two open-ring indole CPA derivatives (11 and 12), were isolated from the fermentation broth of a deep-sea derived fungus Aspergillus sp. SCSIO 41024. Their structures and absolute configurations were elucidated mainly by using extensive NMR spectroscopic, mass spectrometric and single crystal X-ray diffraction analysis. To the best of our knowledge, the crystallographic data of 3 and 7 were firstly reported, and the absolute configuration of 3 was confirmed for the first time by the single crystal X-ray diffraction analysis. Most isolated compounds were tested for their antimicrobial, antitumor and radical scavenging activities. In addition, compounds 1, 2 and 11 showed moderate antioxidative activity against DPPH with IC50 values of 190.1, 31.9, 228.4 µg/mL, respectively.