PEGylated chitosan-coated nanophotosensitizers for effective cancer treatment by photothermal-photodynamic therapy combined with glutathione depletion.

The combination of photothermal therapy (PTT) and photodynamic therapy (PDT) has emerged as a promising strategy for cancer treatment. However, the poor photostability and photothermal conversion efficiency (PCE) of organic small-molecule photosensitizers, and the intracellular glutathione (GSH)-mediated singlet oxygen scavenging largely decline the antitumor efficacy of PTT and PDT. Herein, a versatile nanophotosensitizer (NPS) system is developed by ingenious incorporation of indocyanine green (ICG) into the PEGylated chitosan (PEG-CS)-coated polydopamine (PDA) nanoparticles via multiple π-π stacking, hydrophobic and electrostatic interactions. The PEG-CS-covered NPS showed prominent colloidal and photothermal stability as well as high PCE (ca 62.8 %). Meanwhile, the Michael addition between NPS and GSH can consume GSH, thus reducing the GSH-induced singlet oxygen scavenging. After being internalized by CT26 cells, the NPS under near-infrared laser irradiation produced massive singlet oxygen with the aid of thermo-enhanced intracellular GSH depletion to elicit mitochondrial damage and lipid peroxide formation, thus leading to ferroptosis and apoptosis. Importantly, the combined PTT and PDT delivered by NPS effectively inhibited CT26 tumor growth in vivo by light-activated intense hyperthermia and redox homeostasis disturbance. Overall, this work presents a new tactic of boosting antitumor potency of ICG-mediated phototherapy by PEG-CS-covered NPS.

A potential novel cancer immunotherapy: Agonistic anti-CD40 antibodies.

CD40, a novel immunomodulatory cancer therapy target, is expressed by B cells, macrophages, and dendritic cells (DCs) and mediates cytotoxic T cell priming through the CD40 ligand. Some tumors show promising responses to monotherapy or combination therapy with agonistic anti-CD40 antibodies. The development of improved anti-CD40 antibodies makes CD40 activation an innovative strategy in cancer immunotherapy. In this review, we trace the history of CD40 research and summarize preclinical and clinical findings. We emphasize the ongoing development of improved anti-CD40 antibodies and explore strategies for effective combination therapies. Guided by predictive biomarkers, future research should identify patient populations benefiting the most from CD40 activation.

Enhanced serum levels of tumor necrosis factor-α, interleukin-1ß, and -6 in sarcopenia: alleviation through exercise and nutrition intervention.

BACKGROUND: Limited research has been conducted on the post-intervention inflammatory status in sarcopenic patients, despite previous studies revealing elevated pro-inflammatory markers. This study aimed to investigate the potential elevation of specific pro-inflammatory cytokines in sarcopenic patients and evaluate the effects of exercise and nutritional support interventions on these cytokine levels. METHODS: In this post-hoc analysis of a randomized controlled trial (RCT), 57 individuals with sarcopenia from the RCT and 57 non-sarcopenic participants from the same geriatric community cohort that did not participate in the RCT were enrolled. Grip strength and body composition measurements were recorded. Tumor necrotizing factor (TNF)-α, interleukin (IL)-1ß, IL-6, and IL-15 levels were assessed at baseline for both groups and after a 12-week intervention consisting of resistive exercise and supplementation with branched-chain amino acids, calcium, and vitamin D3 in the patients with sarcopenia. RESULTS: The sarcopenic group demonstrated significantly lower body weight, body mass index, grip strength, and skeletal muscle mass index. Moreover, sarcopenic patients exhibited higher levels of TNF-α (p=0.007), IL-1ß (p<0.001), and IL-6 (p<0.001), while no significant difference was observed in IL-15 (p=0.345) between participants with and those without sarcopenia. Following the intervention, the sarcopenic group experienced significant improvements in grip strength and skeletal muscle mass index with a notable reduction in TNF-α (p=0.003), IL-1ß (p=0.012) and IL-6 (p=0.001) levels. CONCLUSIONS: Sarcopenic patients exhibit elevated levels of TNF-α, IL-1ß, and IL-6, which declined after nutrition support and exercise interventions. However, further research is necessary to evaluate the long-term impact of these interventions on cytokine levels.

Genomic and Transcriptomic Landscape of an Oral Squamous Cell Carcinoma Mouse Model for Immunotherapy.

The immune checkpoint inhibitor (ICI), anti-programmed death-1 (anti-PD-1), has shown moderate efficacy in some patients with head and neck squamous cell carcinoma (HNSCC). Because of this, it is imperative to establish a mouse tumor model to explore mechanisms of antitumor immunity and to develop novel therapeutic options. Here, we examined the 4-nitroquinoline-1-oxide (4NQO)-induced oral squamous cell carcinoma (OSCC) model for genetic aberrations, transcriptomic profiles, and immune cell composition at different pathologic stages. Genomic exome analysis in OSCC-bearing mice showed conservation of critical mutations found in human HNSCC. Transcriptomic data revealed that a key signature comprised of immune-related genes was increased beginning at the moderate dysplasia stages. We first identified that macrophage composition in primary tumors differed across pathologic stages, leading to an oncogenic evolution through a change in the M1/M2 macrophage ratio during tumorigenesis. We treated the 4NQO-induced OSCC-bearing mice with anti-PD-1 and agonistic anti-CD40, which modulated multiple immune responses. The growth of tumor cells was significantly decreased by agonistic anti-CD40 by promoting an increase in the M1/M2 ratio. By examining cross-species genomic conservation in human and mouse tumors, our study demonstrates the molecular mechanisms underlying the development of OSCC and the regulation of contributing immune-related factors, and aims to facilitate the development of suitable ICI-based treatments for patients with HNSCC.

Photothermal nanozymes to self-augment combination cancer therapy by dual-glutathione depletion and hyperthermia/acidity-activated hydroxyl radical generation.

Chemodynamic therapy (CDT) has emerged as a promising strategy for tumor treatment. Nevertheless, the low Fenton catalytic efficiency and the high concentration of glutathione (GSH) in cancer cells largely decline antitumor efficacy of CDT. To self-augment antitumor effect of the CDT by combining with photothermal therapy (PTT), the unique photothermal nanozymes that doubly depleted GSH, and generated massive hydroxyl radicals (·OH) in the hyperthermia/acidity-activated manner were developed. Through the coordination of Fe3+ ions with PEGylated chitosan (PEG-CS)-modified polydopamine (PDA) nanoparticles, the attained Fe3+@PEG-CS/PDA nanozymes showed outstanding colloidal stability, photothermal conversion efficiency and acidity-triggered Fe3+ release. By GSH-mediated valence states transition of Fe3+ ions and Michael reaction between GSH and quinone-rich PDA, the nanozymes sufficiently executed dual depletion of GSH with the elevated temperature.Under mimic tumor acidity and near-infrared (NIR) irradiation condition, the endocytosed nanozymes effectively converted intracellular H2O2 into toxic ·OH upon amplified Fenton reaction, thereby potently killing 4T1 cancer cells and RAW 264.7 cells. Importantly, the nanozymes prominently suppressed 4T1 tumor growth in vivo and metastasis of cancer cells by CDT/PTT combination therapy without significant systemic toxicity. Our study provides novel visions in design of therapeutic nanozymes with great clinical translational prospect for tumor treatment.

SN-38, an active metabolite of irinotecan, enhances anti-PD-1 treatment efficacy in head and neck squamous cell carcinoma.

Anti-programmed cell death 1 (anti-PD-1) therapy shows definite but modest activity in patients with advanced/metastatic head and neck squamous cell carcinoma (HNSCC). Preliminary evidence suggests that SN-38, an activated form of irinotecan that increases expression of the transcription factor FoxO3a, can suppress programmed cell death ligand-1 (PD-L1) expression in breast and ovarian tumor models. We analyzed the SN-38-mediated activation of natural killer cells in vitro and explored the efficacy of SN-38 in combination with anti-PD-1 for treatment in vivo. In vitro, SN-38 enhanced the expression of FoxO3a and reduced the expression of c-Myc and PD-L1 dose-dependently in tumor cells. Low-dose SN-38 increased interferon-γ secretion by NK cells and promoted NK cell-mediated cytotoxicity in tumor cells. In vivo studies revealed that at non-cytotoxic drug concentrations, SN-38 significantly enhanced anti-PD-1 activity in suppressing murine tumor growth. We found increased NK cell and CD8+ T-cell infiltration in post-treatment tumors. RNA-seq analysis indicated that SN-38 increased the enrichment of immune cells and biological function genes related to the immune responses. SN-38 is a potentially beneficial adjunct to checkpoint inhibitor therapy in HNSCC. Further studies exploring its mechanism of action and possible applications are necessary. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Ethanol Extracts of Rice Bran and Whole Grain Adlay Seeds Mitigate Colonic Inflammation and Damage in Mice with Colitis.

Ulcerative colitis (UC) is a chronic inflammatory bowel disease with frequent relapsing inflammation in the colon. Whole grains have been promoted as healthy and sustainable foods; however, the use of whole gains in UC is inconclusive. The aim of this study was to investigate the effects of ethanol extracts of rice bran (RBE) and whole-grain adlay seeds (ADE) on inflammation, oxidative stress, and colonic damage in UC. Male C57BL/6JNarl mice were intra-rectal injected twice with 2,4-dinitrobenzene sulfonic acid to induce (day 0) and reactivate (day 21) UC. Control mice were fed AIN-93M diet (R group) and injected with a vehicle. UC mice were fed AIN-93M diet (UC group) supplemented with RBE (RBE group) or ADE (ADE group) for 21 days. The results showed that the UC group had an increased disease activity index, plasma interleukin (IL)-6 and glutathione levels, microscopic injury scores, and inflammatory cytokine and chemokine levels in the colon and decreased colonic claudin-4 compared to the R group. RBE and ADE supplementation significantly reduced UC-elevated plasma IL-6 and colonic glutathione and pro-inflammatory cytokines and a chemokine. In addition, RBE and ADE supplementation significantly decreased T-helper-cell-associated cytokines in the plasma and colon. Moreover, RBE supplementation increased colonic IL-10 and tight junction protein claudin-4 levels, and ADE supplementation alleviated diarrhea in UC mice. In conclusion, these results suggest that RBE and ADE may mitigate colonic inflammation, oxidative stress, and damage in UC relapse.

Harnessing natural-product-inspired combinatorial chemistry and computation-guided synthesis to develop N-glycan modulators as anticancer agents.

Modulation of N-glycosylation using human Golgi α-mannosidase II (α-hGMII) inhibitors is a potential anticancer approach, but the clinical utility of current α-hGMII inhibitors is limited by their co-inhibition of human lysosomal α-mannosidase (α-hLM), resulting in abnormal storage of oligomannoses. We describe the synthesis and screening of a small library of novel bicyclic iminosugar-based scaffolds, prepared via natural product-inspired combinatorial chemistry (NPICC), which resulted in the identification of a primary α-hGMII inhibitor with 13.5-fold selectivity over α-hLM. Derivatization of this primary inhibitor using computation-guided synthesis (CGS) yielded an advanced α-hGMII inhibitor with nanomolar potency and 106-fold selectivity over α-hLM. In vitro studies demonstrated its N-glycan modulation and inhibitory effect on hepatocellular carcinoma (HCC) cells. In vivo studies confirmed its encouraging anti-HCC activity, without evidence of oligomannose accumulation.

A deep learning-based precision volume calculation approach for kidney and tumor segmentation on computed tomography images.

Previously, doctors interpreted computed tomography (CT) images based on their experience in diagnosing kidney diseases. However, with the rapid increase in CT images, such interpretations were required considerable time and effort, producing inconsistent results. Several novel neural network models were proposed to automatically identify kidney or tumor areas in CT images for solving this problem. In most of these models, only the neural network structure was modified to improve accuracy. However, data pre-processing was also a crucial step in improving the results. This study systematically discussed the necessary pre-processing methods before processing medical images in a neural network model. The experimental results were shown that the proposed pre-processing methods or models significantly improve the accuracy rate compared with the case without data pre-processing. Specifically, the dice score was improved from 0.9436 to 0.9648 for kidney segmentation and 0.7294 for all types of tumor detections. The performance was suitable for clinical applications with lower computational resources based on the proposed medical image processing methods and deep learning models. The cost efficiency and effectiveness were also achieved for automatic kidney volume calculation and tumor detection accurately.

CRISPR-mediated knockout of VEGFR2/KDR inhibits cell growth in a squamous thyroid cancer cell line.

Squamous and anaplastic thyroid cancers are the most aggressive and life-threatening cancer types in humans, with the involvement of lymph nodes in 59% of cases and distant metastases in 26% of cases of all thyroid cancers. The median survival of squamous thyroid cancer patients is < 8 months and therefore is of high clinical concern. Here, we show that both VEGFC and VEGFR2/KDR are overexpressed in thyroid cancers, indicating that VEGF/VEGFR signaling plays a carcinogenic role in thyroid cancer development. Using CRISPR/Cas9, we established a KDR knockout (KO) SW579 squamous thyroid cancer cell line that exhibited dramatically decreased colony formation and invasion abilities (30% and 60% reduction, respectively) when compared to scrambled control cells. To validate the potential of KDR as a therapeutic target for thyroid cancers, we used the KDR RTK inhibitor sunitinib. Protein analysis and live/dead assay were performed to demonstrate that sunitinib significantly inhibited cell growth signal transduction and induced cell apoptosis of SW579 cells. These results suggest that selective targeting of KDR may have potential for development into novel anti-cancer therapies to suppress VEGF/VEGFR-mediated cancer development in patients with clinical advanced thyroid cancer.

Percentage of body fat is associated with increased risk of diverticulosis: A cross sectional study.

BACKGROUND: Obesity has been indicated to be a risk factor of diverticulosis. However, plausible relationship remained controversial. This cross-sectional study elucidated the association between percentage of body fat and the risk of diverticulosis. METHODS: The study was conducted at a single medical center in Taiwan from 2000-2016 which enrolled 5557 adults with age above 20 years old receiving a health examination including self-reported questionnaires, measurement of percentage of body fat (PBF), blood test and colonoscopy at the Tri-Service General Hospital (TSGH). Logistic regressions were used to analyze the association between PBF and diverticulosis. Further stratification of participants was based on age and gender and three extended models were established for multivariable adjustment. RESULTS: 243 of 3141 males and 103 of 2416 females were diagnosed with having diverticulosis. After covariates adjustment, only participants in the highest quartile of PBF (Q4 ≥33.8%) showed significantly positive association with the risk diverticulosis (OR 2.089, p <0.001). In subgroup analysis, the odds ratio for having diverticulosis in females was significantly higher than in males. In addition, We found that the odds ratio of having diverticulosis was higher in the group older than 60 years old compared to the younger group (OR 1.052; p<0.001; OR 1.043; p<0.001). CONCLUSIONS: In conclusion, PBF was a potential risk factor of diverticulosis. Individuals with higher PBF exhibits increased risk of diverticulosis, especially in females. Furthermore, bioelectrical impedance analysis may create a simple, available and radiation-free way to assess the risk of diverticulosis.

Retrieval of intrarenal coiled and ruptured guidewire by retrograde intrarenal surgery: A case report and literature review.

BACKGROUND: Foreign bodies in the kidney have rarely been reported. However, they can be a clinical problem for urologists. We report on a patient with a residual segment of guidewire coating embedded in the renal parenchyma following computed tomography (CT)-guided percutaneous nephrostomy drainage (PCND), and our successful minimally invasive management with retrograde intrarenal surgery (RIRS). CASE PRESENTATION: A 40-year-old female with urosepsis due to a right upper ureteral stone with hydronephrosis received emergent CT-guided PCND and subsequent ureteroscopic lithotripsy, double J stent insertion, and percutaneous catheter removal. Follow-up radiography showed a coiled object within the upper pole parenchyma of the right kidney, which might be the remnant of a guidewire used during the PCND procedure. Flexible ureteroscopy (fURS) was performed. Under fluoroscopy, the foreign body was localized, the renal parenchyma was incised with laser, and the foreign body was retrieved using a stone basket. CONCLUSION: Although guidewire breakage is uncommon, clinicians should keep it in mind during interventional procedures. Several methods can be used to eradicate foreign objects from the urinary tract, and the first choice should always be the least invasive one. RIRS with fURS is considered as a safe, efficient, and minimally invasive option for the extraction of foreign bodies from the kidney. To the best of our knowledge, this is the first comprehensive case report detailing the removal of a foreign object by RIRS in the English literature.

Intrathoracic ureteric stent migration through a reno-pleural fistula: a case report of rare antegrade ureteric stenting complication.

BACKGROUND: Malignant obstruction and associated hydronephrosis is a common complication of advanced cervical cancer. Percutaneous nephrostomy (PCN) followed by antegrade stenting is often required to relieve obstruction as retrograde access fails in considerable proportion of such patients. Reno-pleural fistula is a rare complication of PCN which creates a patent connection between the renal collecting system and the thoracic cavity, and urine accumulation in the pleural space can cause pleural effusion (i.e., urinothorax). Upward or downward migration is a complication of indwelling ureteric stents. Further migration with extrusion outside of the urinary tract is uncommon. Herein we present an unprecedented case in adult of ureteric stent upward migration through a reno-pleural fistula into the thoracic cavity managed by thoracoscopy. CASE PRESENTATION: A 66-year-old female was diagnosed of advanced stage cervical cancer with suspicious bladder invasion. Given her bilateral hydronephrosis with impaired renal function, she underwent bilateral PCN and subsequent antegrade ureteric stenting. However, she presented with dyspnea, right back pain, and oliguria four days after bilateral PCN catheter removal. Computed tomography reported massive right pleural effusion and an intrathoracic ureteric stent within reno-pleural fistula. Thoracoscopy with thoracostomy was performed to remove the ureteric stent and urine in right pleural space. A week later, urinothorax had resolved and right PCN was performed again. She was discharged after regaining normal renal function with right PCN and a left ureteric stent in place. CONCLUSIONS: A reno-pleural fistula can serve as a route for ureteric stent migration and that continuous drainage of urine can cause urinothorax once the stent reaches the thoracic cavity. Anytime a supracostal approach is used for PCN, even when using small caliber catheters, clinicians should pay special attention given the risk of pleural injury and subsequent complications.

Platelet-Derived Growth Factor Receptor-α Subunit Targeting Suppresses Metastasis in Advanced Thyroid Cancer In Vitro and In Vivo.

Thyroid cancer is the most common endocrine malignancy. Patients with well-differentiated thyroid cancers, such as papillary and follicular cancers, have a favorable prognosis. However, poorly differentiated thyroid cancers, such as medullary, squamous and anaplastic advanced thyroid cancers, are very aggressive and insensitive to radioiodine treatment. Thus, novel therapies that attenuate metastasis are urgently needed. We found that both PDGFC and PDGFRA are predominantly expressed in thyroid cancers and that the survival rate is significantly lower in patients with high PDGFRA expression. This finding indicates the important role of PDGF/PDGFR signaling in thyroid cancer development. Next, we established a SW579 squamous thyroid cancer cell line with 95.6% PDGFRA gene insertion and deletions (indels) through CRISPR/Cas9. Protein and invasion analysis showed a dramatic loss in EMT marker expression and metastatic ability. Furthermore, xenograft tumors derived from PDGFRA geneedited SW579 cells exhibited a minor decrease in tumor growth. However, distant lung metastasis was completely abolished upon PDGFRA gene editing, implying that PDGFRA could be an effective target to inhibit distant metastasis in advanced thyroid cancers. To translate this finding to the clinic, we used the most relevant multikinase inhibitor, imatinib, to inhibit PDGFRA signaling. The results showed that imatinib significantly suppressed cell growth, induced cell cycle arrest and cell death in SW579 cells. Our developed noninvasive apoptosis detection sensor (NIADS) indicated that imatinib induced cell apoptosis through caspase-3 activation. In conclusion, we believe that developing a specific and selective targeted therapy for PDGFRA would effectively suppress PDGFRA-mediated cancer aggressiveness in advanced thyroid cancers.

Constituents of Aquilaria sinensis Leaves Upregulate the Expression of Matrix Metalloproteases 2 and 9.

In this novel study, we isolated 28 compounds from the leaves of Aquilaria sinensis (Lour.) Gilg based on a bioassay-guided procedure and also discovered the possible matrix metalloprotease 2 (MMP-2) and 9 (MMP-9) modulatory effect of pheophorbide A (PA). To evaluate the regulatory activity on MMP-2 and MMP-9, the HT-1080 human fibrosarcoma cells were treated with various concentrations of extracted materials and isolated compounds. PA was extracted by methanol from the leaves of A. sinensis and separated from the fraction of the partitioned ethyl acetate layer. PA is believed to be an active component for MMP expression since it exhibited significant stimulation on MMP-2 and proMMP-9 activity. When treating with 50 µM of PA, the expression of MMP-2 and MMP-9 were increased 1.9-fold and 2.3-fold, respectively. PA also exhibited no cytotoxicity against HT-1080 cells when the cell viability was monitored. Furthermore, no significant MMP activity was observed when five PA analogues were evaluated. This study is the first to demonstrate that C-17 of PA is the deciding factor in determining the bioactivity of the compound. The MMP-2 and proMMP-9 modulatory activity of PA indicate its potential applications for reducing scar formation and comparative medical purposes.

The importance of risk of neoplasm as an outcome in cytologic-histologic correlation studies on thyroid fine needle aspiration.

BACKGROUND: The introduction of noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) altered the practice of thyroid pathology and reduced the risk of malignancy (ROM) associated with the indeterminate categories in the Bethesda system for reporting thyroid cytopathology (TBSRTC). It has been proposed that the evaluation of the risk of neoplasm (RON) is important in cytologic-histologic correlation studies. METHODS: A total of 5224 thyroid aspirates were performed at our institution during an 8-year period. Of the 1475 cases (28%) with surgical follow-up, the histologic diagnoses comprised benign non-neoplastic (BNN, n = 669), follicular adenoma (FA, n = 188), NIFTP (n = 42), papillary microcarcinoma (PMC) (n = 223), and malignant neoplasm excluding PMC (n = 353). The RON was calculated to include neoplasia with low risk biologic behavior (FA, NIFTP, PMC) and malignant neoplasms. In contrast, the ROM was reserved for malignant neoplasms excluding PMC. RESULTS: The RON for each TBSRTC category was: nondiagnostic (ND) 38.3%, benign 20.9%, atypia of undetermined significance/follicular lesion of undetermined significance (AUS/FLUS) 63.2%, follicular neoplasm or suspicious for follicular neoplasm (FN/SFN) 83.9%, suspicious for malignancy (SFM) 94%, and malignant 100%. The ROM excluding PMC was: ND 14%, benign 1.6%, AUS/FLUS 17.8%, FN/SFN 28.4%, SFM 84.4%, and malignant 99.5%. CONCLUSIONS: The RON and ROM support the recommended management guidelines from TBSRTC for all categories, except for FN/SFN. Histopathologic follow-up of FN/SFN aspirates in our study contain a very high rate of neoplasm (83.9%), which might support the management preference of conservative surgery.

Adlay Seed (Coix lacryma-jobi L.) Extracts Exhibit a Prophylactic Effect on Diet-Induced Metabolic Dysfunction and Nonalcoholic Fatty Liver Disease in Mice.

Nonalcoholic fatty liver disease (NAFLD) is common worldwide and closely associated with metabolic dysfunction. NAFLD leads to a higher risk of development of severe liver diseases, such as nonalcoholic steatohepatitis (NASH), liver cirrhosis, and hepatocellular carcinoma (HCC). To date, no pharmacotherapy targeting NAFLD has received general approval. Adlay is a plant that has been used as traditional herbal medicine in Asia and is a promising candidate to solve this global issue. We have established a mouse model of NAFLD by feeding a high-fat diet (HFD) for 10 weeks. Here, ethanolic or water extracts of adlay seed (ASE and ASW, respectively), mixed with HFD, were fed to the mice for 10 weeks. The ASE and ASW treatment ameliorated hyperglycemia and improved the glucose tolerance and insulin resistance in the HFD mice. Hyperlipidemia in HFD mice was prevented by the ASE and ASW diet. In addition, the ASE and ASW supplementation attenuated hepatic steatosis and inflammation, improved liver function, and caused no harm to the kidneys. Moreover, the mechanism of the effect of ASE and ASW on inhibiting hepatic lipogenesis and inducing fatty acid ß-oxidation was certified by the simulated human fatty liver cell model. Our study showed the regulatory potential of the extracts of adlay seeds for alleviating NAFLD, as well as related liver and metabolic diseases.

The production and bioactivity of prodigiosin: quo vadis?

Prodigiosin (PG), a red tripyrrole pigment, belongs to a member of the prodiginine family and is normally secreted by various sources including Serratia marcescens and other Gram-negative bacteria. The studies of PG have received innovative devotion as a result of reported antimicrobial, larvicidal and anti-nematoid immunomodulation and antitumor properties, owing to its antibiotic and cytotoxic activities. This review provides a comprehensive summary of research undertaken toward the isolation and structural elucidation of the prodiginine family of natural products. Additionally, the current evidence-based understanding of the biological activities and medicinal potential of PG is employed to determine the efficacy, with some reports of information related to pharmacokinetics, pharmacodynamics and toxicology.

Gene Regulatory Strategies that Decode the Duration of NFκB Dynamics Contribute to LPS- versus TNF-Specific Gene Expression.

Pathogen-derived lipopolysaccharide (LPS) and cytokine tumor necrosis factor (TNF) activate NFκB with distinct duration dynamics, but how immune response genes decode NFκB duration to produce stimulus-specific expression remains unclear. Here, detailed transcriptomic profiling of combinatorial and temporal control mutants identified 81 genes that depend on stimulus-specific NFκB duration for their stimulus-specificity. Combining quantitative experimentation with mathematical modeling, we found that for some genes a long mRNA half-life allowed effective decoding, but for many genes this was insufficient to account for the data; instead, we found that chromatin mechanisms, such as a slow transition rate between inactive and RelA-bound enhancer states, could also decode NFκB dynamics. Chromatin-mediated decoding is favored by genes acting as immune effectors (e.g., tissue remodelers and T cell recruiters) rather than immune regulators (e.g., signaling proteins and monocyte recruiters). Overall, our results delineate two gene regulatory strategies that decode stimulus-specific NFκB dynamics and determine distinct biological functions.

Probing Anti-Proliferative 24-Homoscalaranes from a Sponge Lendenfeldiasp.

In the current study, an NMR spectroscopic pattern-based procedure for probing scalarane derivatives was performed and four new 24-homoscalaranes, lendenfeldaranes A-D (1- 4), along with three known compounds, 12α-acetoxy-22-hydroxy-24-methyl-24-oxoscalar-16-en- 25-al (5), felixin F (6), and 24-methyl-12,24,25-trioxoscalar-16-en-22-oic acid (7) were isolated from the sponge Lendenfeldia sp. The structures of scalaranes 1-7 were elucidated on the basis of spectroscopic analysis. Scalaranes 1-7 were further evaluated for their cytotoxicity toward a series of human cancer cell lines and the results suggested that 5 and 7 dominated in the anti- proliferative activity of the extract. The 18-aldehyde functionality was found to play a key role in their activity.