Natural compounds as antiatherogenic agents.

Atherosclerosis (AS) is a widespread pathological coronary heart disease (CHD), which, along with other cardiovascular diseases (CVDs), is the primary cause of global mortality. It is initiated by the accumulation of cholesterol-laden macrophages in the artery wall, thereby forming the foam-cells, the hallmark of AS. Increased influx of oxidized LDL and decreased efflux of free cholesterol from macrophages constitute major factors that mediate the progression of AS. Natural compounds treatment and prevention of AS being an effective approach for a long time. Currently, as interests in medicinally important natural products increased that including medicinal herbs, numerous studies on natural compounds effective forAS have been reported. In the current review, we shed light on the available plant-based natural compounds as AS modulators with underlying mechanisms that may lead to potential therapeutic implications.

JNK2 modulates the CD1d-dependent and -independent activation of iNKT cells.

Invariant natural killer T (iNKT) cells play critical roles in autoimmune, anti-tumor, and anti-microbial immune responses, and are activated by glycolipids presented by the MHC class I-like molecule, CD1d. How the activation of signaling pathways impacts antigen (Ag)-dependent iNKT cell activation is not well-known. In the current study, we found that the MAPK JNK2 not only negatively regulates CD1d-mediated Ag presentation in APCs, but also contributes to CD1d-independent iNKT cell activation. A deficiency in the JNK2 (but not JNK1) isoform enhanced Ag presentation by CD1d. Using a vaccinia virus (VV) infection model known to cause a loss in iNKT cells in a CD1d-independent, but IL-12-dependent manner, we found the virus-induced loss of iNKT cells in JNK2 KO mice was substantially lower than that observed in JNK1 KO or wild-type (WT) mice. Importantly, compared to WT mice, JNK2 KO mouse iNKT cells were found to express less surface IL-12 receptors. As with a VV infection, an IL-12 injection also resulted in a smaller decrease in JNK2 KO iNKT cells as compared to WT mice. Overall, our work strongly suggests JNK2 is a negative regulator of CD1d-mediated Ag presentation and contributes to IL-12-induced iNKT cell activation and loss during viral infections.

Mortality associated with Fournier's gangrene remains unchanged over 25 years.

OBJECTIVES: To report a case series of Fournier's gangrene (FG) from our institution, and to investigate its mortality over the past 25 years. PATIENTS AND METHODS: Case notes of men presenting to our institution from 2013 to 2016 with FG were reviewed. As well as age, diabetic history, length of stay, length of stay in critical care, and mortality; we calculated (where possible) the Uludag Fournier's Gangrene Severity Index (UFGSI). Published studies and cases series reporting the mortality rates for FG were reviewed from 1993 to 2018. The size of the study, country of origin, average age and gender ratio were collected, alongside mortality. RESULTS: Two of the 11 patients treated for FG at out institution died within 90 days of admission, a mortality rate of 18%. Predicted mortality was significantly higher. A total of 173 publications were identified from the Medical Literature Analysis and Retrieval System Online (MEDLINE) database published between 1993 and 2018, reporting data from 1975 to 2018. Analysis of heterogeneity, by both time and precision, supported exclusion of four retrospective coded database-driven studies from the analysis. From the remaining studies, mortality ranged from 0% to 42%. Of the 6152 reported cases, there were 1220 deaths, giving an overall mortality rate of 19.8%. There was no evidence of a significant change in the mortality rate for FG over time (P = 0.996). CONCLUSIONS: In our case series, the mortality rate for FG was 18%, despite a higher predicated mortality (based on UFGSI scores). The treatment of FG remains appropriate resuscitation, aggressive surgical debridement, and critical care management. Perceived high risk of mortality should not deter aggressive management. Mortality due to FG does not appear to have changed over the past 25 years, and is estimated at 19.8%. In studies identifying cases of FG, careful attention should be paid to case definition, particularly when cases are being abstracted retrospectively from large coded databases.

Comet assay measures of DNA damage are predictive of bladder cancer cell treatment sensitivity in vitro and outcome in vivo.

Bladder cancer patients suffer significant treatment failure, including high rates of recurrence and poor outcomes for advanced disease. If mechanisms to improve tumour cell treatment sensitivity could be identified and/or if tumour response could be predicted, it should be possible to improve local-control and survival. Previously, we have shown that radiation-induced DNA damage, measured by alkaline Comet assay (ACA), correlates bladder cancer cell radiosensitivity in vitro. In this study we first show that modified-ACA measures of cisplatin and mitomycin-C-induced damage also correlate bladder cancer cell chemosensitivity in vitro, with essentially the same rank order for chemosensitivity as for radiosensitivity. Furthermore, ACA studies of radiation-induced damage in different cell-DNA substrates (nuclei, nucleoids and intact parent cells) suggest that it is a feature retained in the prepared nucleoids that is responsible for the relative damage sensitivity of bladder cancer cells, suggestive of differences in the organisation of DNA within resistant vs. sensitive cells. Second, we show that ACA analysis of biopsies from bladder tumours reveal that reduced DNA damage sensitivity associates with poorer treatment outcomes, notably that tumours with a reduced damage response show a significant association with local recurrence of non-invasive disease and that reduced damage response was a better predictor of recurrence than the presence of high-risk histology in this cohort. In conclusion, this study demonstrates that mechanisms governing treatment-induced DNA damage are both central to and predictive of bladder cancer cell treatment sensitivity and exemplifies a link between DNA damage resistance and both treatment response and tumour aggression.

Transperineal template prostate biopsies in men with raised PSA despite two previous sets of negative TRUS-guided prostate biopsies.

BACKGROUND: The possibility of prostate cancer as a cause for steadily rising PSA despite previously negative transrectal ultrasound (TRUS)-guided prostate biopsies is a major concern. An initial negative TRUS-guided prostate biopsy does not necessarily exclude the presence of clinically significant prostate cancer. We determined the role of transperineal template prostate biopsy (TPTPB) in prostate cancer detection in men with raised PSA despite two previous sets of negative TRUS biopsies. METHODS: Between January 2008 and August 2012, a total of 122 men's records were reviewed after having 36-core TPTPB following two previous sets of negative TRUS biopsies despite raised PSA. A retrospective record of PSA levels, clinicopathological parameters and histological outcomes was made. RESULTS: Mean age was 63 years (range 49-77), and mean PSA was 18.0 (range 2.0-119.0). A total of 71/122 (58 %) men were diagnosed with prostate cancer on TPTPB. Of these, 28 (39 %), 34 (48 %), 5 (7 %), and 4 (6 %) had Gleason score 6, 7 (3 + 4), 7 (4 + 3), and 9 (4 + 5), respectively. The mean number of positive cores was 7 (range 1-22). Of these, only 15 (21 %) had ≤2 cores positive and Gleason score of 6. Of the 51 (42 %) men with a negative histology on TPTPB, 11 (22 %), 10 (19 %), and 30 (59 %) had atypical small acinar proliferation, high-grade prostatic intraepithelial neoplasia, or benign pathology. CONCLUSION: TPTPB is associated with a high rate of clinically significant prostate cancer diagnosis (58 %) in men with raised PSA despite two previous sets of negative TRUS biopsies.

Regulation of the actin cytoskeleton by Rho kinase controls antigen presentation by CD1d.

CD1d molecules are MHC class I-like molecules that present lipid Ags to NKT cells. Although we have previously shown that several different cell signaling molecules can play a role in the control of Ag presentation by CD1d, a defined mechanism by which a cell signaling pathway regulates CD1d function has been unclear. In the current study, we have found that the Rho kinases, Rho-associated, coiled-coil containing protein kinase (ROCK)1 and ROCK2, negatively regulate both human and mouse CD1d-mediated Ag presentation. Inhibition of ROCK pharmacologically, through specific ROCK1 and ROCK2 short hairpin RNA, or by using dendritic cells generated from ROCK1-deficient mice all resulted in enhanced CD1d-mediated Ag presentation compared with controls. ROCK regulates the actin cytoskeleton by phosphorylating LIM kinase, which, in turn, phosphorylates cofilin, prohibiting actin fiber depolymerization. Treatment of APCs with the actin filament depolymerizing agent, cytochalasin D, as well as knockdown of LIM kinase by short hairpin RNA, resulted in enhanced Ag presentation to NKT cells by CD1d, consistent with our ROCK inhibition data. Therefore, our overall results reveal a model whereby CD1d-mediated Ag presentation is negatively regulated by ROCK via its effects on the actin cytoskeleton.

Genome wide nucleosome landscape shapes 3D chromatin organization.

The hierarchical chromatin organization begins with formation of nucleosomes, which fold into chromatin domains punctuated by boundaries and ultimately chromosomes. In a hierarchal organization, lower levels shape higher levels. However, the dependence of higher-order 3D chromatin organization on the nucleosome-level organization has not been studied in cells. We investigated the relationship between nucleosome-level organization and higher-order chromatin organization by perturbing nucleosomes across the genome by deleting Imitation SWItch (ISWI) and Chromodomain Helicase DNA-binding (CHD1) chromatin remodeling factors in budding yeast. We find that changes in nucleosome-level properties are accompanied by changes in 3D chromatin organization. Short-range chromatin contacts up to a few kilo-base pairs decrease, chromatin domains weaken, and boundary strength decreases. Boundary strength scales with accessibility and moderately with width of nucleosome-depleted region. Change in nucleosome positioning seems to alter the stiffness of chromatin, which can affect formation of chromatin contacts. Our results suggest a biomechanical "bottom-up" mechanism by which nucleosome distribution across genome shapes 3D chromatin organization.

The role of a standardized 36 core template-assisted transperineal prostate biopsy technique in patients with previously negative transrectal ultrasonography-guided prostate biopsies.

OBJECTIVE: To determine the efficacy and safety of a standardized 36 core template-assisted transperineal biopsy technique for detecting prostate cancer in patients with previously negative transrectal ultrasonography-guided prostate biopsies and elevated prostate-specific antigen (PSA) levels. PATIENTS AND METHODS: Between April 2008 to September 2010, a total of 40 patients with a mean (range) age of 63 (49-73) years, a mean (range) elevated PSA level of 21.9 (4.7-87) ng/mL and two previous sets of negative TRUS-guided prostate biopsies underwent standardized 36 core template-assisted transperineal prostate biopsies under general anaesthetic as a day case procedure. The cancer detection rate and complications for all cases were evaluated. RESULTS: In total, 27 of 40 (68%) patients were found to have adenocarcinoma of the prostate, two patients (5.0%) had atypical small acinar proliferation, one had high-grade prostatic intraepithelial neoplasia (2.5%), four (10%) had chronic active inflammation and six (15%) had benign histology. Gleason scores were in the range 6-9, with a median Gleason score of 7. There were no cases of urosepsis, urinary tract infections or haematuria. A single patient experienced acute urinary retention, with a subsequent succesful trial without a catheter, and haematospermia was common, although minor. CONCLUSIONS: Our standardized 36 core template-assisted transperineal prostate biopsy technique is safe and associated with a high detection rate of prostate cancer. This technique should be considered in patients with elevated PSA levels and previously negative TRUS-guided prostate biopsies.

Intermediate-term efficacy of Tm:YAG laser prostate vaporesection for bladder outlet obstruction: initial experience from a UK teaching hospital.

OBJECTIVES: To assess the safety and clinical efficacy of Tm:YAG laser vaporesection of the prostate (ThuVaRP) at intermediate-term follow-up. PATIENTS AND METHODS: We identified the first 60 consecutive patients who underwent ThuVaRP at our institute. Operative outcomes assessed were resection time, resection weight, drop in haemoglobin, transfusion rate, catheter time and complication rate. The International Prostate Symptom Score (IPSS) was documented at a mean follow-up period of 19 months postoperatively. RESULTS: 45/60 patients underwent treatment due to lower urinary tract symptoms secondary to benign prostatic obstruction, 11/60 patients had a long-term catheter in situ for refractory urinary retention secondary to benign prostatic obstruction, and 4/60 patients had bladder outflow obstruction secondary to adenocarcinoma of the prostate. 1/60 patients developed urosepsis, 1/60 patients developed a urinary tract infection and 1/60 patients required 3-way catheterization and irrigation due to haematuria. No patients required a blood transfusion. The mean IPSS at a mean follow-up interval of 19 months (range 15-28 months) was 5.1 (range 1-23). Postoperative maximum flow rate improved from 7.9 to 17.1 ml/s, and post-micturition residual volume decreased from 254 to 86 ml. CONCLUSION: ThuVaRP is safe and appears to have durable efficacy at intermediate follow-up.

Risk of erectile dysfunction and retrograde ejaculation associated with thulium laser vaporesection of the prostate for bladder outflow obstruction: a retrospective study.

OBJECTIVE: The aim of this study was to determine the incidence of erectile dysfunction and retrograde ejaculation following thulium:yttrium-aluminium-garnet (Tm:YAG) laser prostate vaporesection (ThuVaRP). PATIENTS AND METHODS: Between January 2009 and June 2010, 113 consecutive patients underwent ThuVaRP for bladder outflow obstruction. Of these, 54 (48%) were included in the study as they were able to maintain an erection for sexual intercourse prior to undergoing ThuVaRP. All patients had benign pathology and had not undergone previous bladder neck surgery. The incidence of erectile dysfunction and retrograde ejaculation was reported at a mean follow-up period of 12 months post-operatively. RESULTS: The mean patient age was 71 years (range 46-90). The mean follow-up period was 12 months (range 4-21). 11 (20%) patients experienced worsening erectile function with 3 (6%) noticing an improvement. A total of 30 patients (56%) experienced some degree of retrograde ejaculation. 4 patients (7%) noticed an improvement in their ejaculation. Retrograde ejaculation was more common in patients with an indwelling catheter in situ for refractory urinary retention (43 vs. 17%, p = 0.04) and in diabetic patients (27 vs. 4%, p = 0.03). There was an increased trend of erectile dysfunction in men aged ≥70 years, with hypertension and with hypercholesterolaemia, but this was not significant. CONCLUSION: Our retrospective study has demonstrated that the overall risk of erectile dysfunction and retrograde ejaculation associated with ThuVaRP is 20 and 56%, respectively.

Thulium laser vapo-enucleation treatment for prostates >100 cc following urinary retention.

INTRODUCTION: Practical advantages of Thulium in the endoscopic treatment of BPH include its technical versatility, precision and safety, offering reduced need for haemostasis and risk of injury. Evidence has shown Holmium laser to be effective in the treatment of chronic retention, however no studies address the use of Thulium laser for larger prostates after urinary retention. OBJECTIVES: We have selected this group in our retrospective analysis on the efficacy of Thulium laser vapo-enucleation for men with both urinary retention and large prostate volumes greater than 100 cc. METHODS: We analysed a 10-year single centre operation database of 740 Thulium vapo-enucleation of prostates. An inclusion of 47 living patients with prostates over 100 cc who have undergone the procedure following urinary retention secondary to bladder outflow obstruction (BOO) from benign prostatic hyperplasia (BPH). Patients were sub grouped into Group 1: 100-149 cc and Group 2: >150 cc. RESULTS: Number of patients in sub groups 1 (n = 27) and 2 (n = 20) had mean prostate volumes of 116 and 173 cc respectively, with the largest measuring 234 cc. Mean resected volumes were 26 g (range 15-50.5 g) and 28 g (range 2-57 g). The overall trial without catheter (TWOC) pass rate for all patients in our series was 96% with comparable results between the two groups. Overall known early and late complication rates for all patients was 17% (UTI 13%, urosepsis 2%, AUR 2%) and 12.5% (failure 5%, OAB symptoms 5%, significant haematuria requiring surgical intervention 2.5%) respectively. Success of surgery was 96%, with an average follow-up of 5 months and no re-referrals for lower urinary tract symptoms following discharge. CONCLUSION: We show the use of Thulium laser vapo-enucleation to be safe and effective in the treatment of retention for large prostates. Results have demonstrated signs of long-term efficacy with a low failure rate.

Her-2-directed systemic delivery of fatty acid synthase (FASN) siRNA with novel liposomal carrier systems in the breast cancer mouse model.

Despite the current advancements in the gene silencing therapy in vitro, the systemic delivery of siRNA still remains a challenging task for its transition into clinics. We have previously developed the Her2-targeted fatty acid synthase (FASN) siRNA-encapsulating immunoliposomes (ILs) with a great stability in the presence of serum. We report here the therapeutic potential of the lipid-based novel formulations in the breast cancer mouse model. The growth inhibitory and gene silencing effects of various formulations were determined by measuring the size of the tumour, cell proliferation, apoptotic index and immunoassays against Her2-overexpressed tumour xenografts in nude mice. The pegylated DSPC/Chol and DOPE/CHEMS ILs containing FASN-siRNA significantly decreased the tumour growth relative to non-targeted liposomes. They induced the 1.5-fold increase in cellular apoptosis and several fold decrease in proliferation as compared to non-targeted liposomal formulations of FASN-siRNA. Moreover, FASN-siRNA-ILs produced several fold increase in the ratios of p53/p21 and Bax/Bcl-2. The gene silencing effects of targeted FASN-liposomes were found to be significantly superior, resulting in 30-40% downregulation in FASN as compared to non-targeted similar formulations. Both types of FASN ILs provided a highly efficient approach for targeted delivery in Her-2-expressed breast cancer and thus offered a promising anticancer strategy in the clinical therapy.

A Mutated Prostatic Acid Phosphatase (PAP) Peptide-Based Vaccine Induces PAP-Specific CD8+ T Cells with Ex Vivo Cytotoxic Capacities in HHDII/DR1 Transgenic Mice.

BACKGROUND: Current treatments for castrate (hormone)-resistant prostate cancer (CRPC) remain limited and are not curative, with a median survival from diagnosis of 23 months. The PAP-specific Sipuleucel-T vaccine, which was approved by the FDA in 2010, increases the Overall Survival (OS) by 4 months, but is extremely expensive. We have previously shown that a 15 amino accid (AA) PAP sequence-derived peptide could induce strong immune responses and delay the growth of murine TRAMP-C1 prostate tumors. We have now substituted one amino acid and elongated the sequence to include epitopes predicted to bind to several additional HLA haplotypes. Herein, we present the immunological properties of this 42mer-mutated PAP-derived sequence (MutPAP42mer). METHODS: The presence of PAP-135-143 epitope-specific CD8+ T cells in the blood of patients with prostate cancer (PCa) was assessed by flow cytometry using Dextramer™ technology. HHDII/DR1 transgenic mice were immunized with mutated and non-mutated PAP-derived 42mer peptides in the presence of CAF®09 or CpG ODN1826 (TLR-9 agonist) adjuvants. Vaccine-induced immune responses were measured by assessing the proportion and functionality of splenic PAP-specific T cells in vitro. RESULTS: PAP-135-143 epitope-specific CD8+ T cells were detected in the blood of patients with PCa and stimulation of PBMCs from patients with PCa with mutPAP42mer enhanced their capacity to kill human LNCaP PCa target cells expressing PAP. The MutPAP42mer peptide was significantly more immunogenic in HHDII/DR1 mice than the wild type sequence, and immunogenicity was further enhanced when combined with the CAF®09 adjuvant. The vaccine induced secretory (IFNγ and TNFα) and cytotoxic CD8+ T cells and effector memory splenic T cells. CONCLUSIONS: The periphery of patients with PCa exhibits immune responsiveness to the MutPAP42mer peptide and immunization of mice induces/expands T cell-driven, wild-type PAP immunity, and therefore, has the potential to drive protective anti-tumor immunity in patients with PCa.

Safety, Stability, and Therapeutic Efficacy of Long-Circulating TQ-Incorporated Liposomes: Implication in the Treatment of Lung Cancer.

Thymoquinone (TQ), which is one of the main bioactive constituents of Nigella sativa seeds, has demonstrated its potential against various cancer models. The poor solubility of TQ in aqueous solution limits its uses in clinical application. The present study aimed to develop a novel formulation of TQ to increase its bioavailability and therapeutic potential with minimal toxicity. Polyethylene glycol (PEG)-coated DSPC/cholesterol comprising TQ liposomes (PEG-Lip-TQ) were prepared and characterized on various aspects. A computational investigation using molecular docking was used to assess the possible binding interactions of TQ with 12 prospective anticancer drug targets. The in vitro anticancer activity was assessed in A549 and H460 lung cancer cells in a time- and dose-dependent manner, while the oral acute toxicity assay was evaluated in silico as well as in vivo in mice. TQ docked to the Hsp90 target had the lowest binding energy of -6.05 kcal/mol, whereas caspase 3 was recognized as the least likely target for TQ with a binding energy of -1.19 kcal/mol. The results showed 96% EE with 120 nm size, and -10.85 mv, ζ-potential of PEG-Lip-TQ, respectively. The cell cytotoxicity data demonstrated high sensitivity of PEG-Lip-TQ and a several fold decrease in the IC50 while comparing free TQ. The cell cycle analysis showed changes in the distribution of cells with doses. The in vivo data revealed an ~9-fold increase in the LD50 of PEG-Lip-TQ on free TQ as an estimated 775 and 89.5 mg/kg b.w, respectively. This study indicates that the pharmacological and efficacy profile of PEG-lip-TQ is superior to free TQ, which will pave the way for an exploration of the effect of TQ formulation in the treatment of lung cancer in clinical settings.

Experimental and Theoretical Insights on Chemopreventive Effect of the Liposomal Thymoquinone Against Benzo[a]pyrene-Induced Lung Cancer in Swiss Albino Mice.

Purpose: Thymoquinone (TQ), a phytoconstituent of Nigella sativa seeds, has been studied extensively in various cancer models. However, TQ's limited water solubility restricts its therapeutic applicability. Our work aims to prepare the novel formulation of TQ and assess its chemopreventive potential in chemically induced lung cancer animal model. Methods: The polyethylene glycol coated DOPE/CHEMS incorporating TQ-loaded pH-sensitive liposomes (TQPSL) were prepared and characterized. Mice were exposed to benzo[a]pyrene (BaP) thrice a week for 4 weeks to induce lung cancer. TQPSL was administered three times a week for 21 weeks, starting 2 weeks before the first dose of BaP. Results: The prepared TQPSL revealed 85% entrapment efficiency with 128 nm size and -19.5 mv ζ-potential showing high stability of the formulation. The pretreatment of TQPSL showed the recovery in BaP-modulated relative organ weight of lungs, cancer marker enzymes, and antioxidant enzymes in the serum. The histopathological analysis of the tissues showed that TQPSL protected the malignancy in the lungs. The flow cytometry data revealed the induction of apoptosis and decreased intracellular ROS by TQPSL. Molecular docking was performed to predict the TQ's affinity for eight possible anticancer drug targets linked to lung cancer etiology. The data assisted to identify the serine/threonine-protein kinase BRAF as the most suitable target of TQ with binding energy -6.8 kcal/mol. Conclusion: The current findings demonstrated the potential of TQPSL and its possible therapeutic targets of lung cancer. To our knowledge, this is the first research to outline the development of TQ formulation against lung cancer considering its low solubility as well as pulmonary delivery challenges.

Cytoprotective Antioxidant, Anti-Inflammatory, and Antifibrotic Impact of Celery Seed Oil and Manuka Honey Against Cyclophosphamide-Induced Cystitis in Rabbits.

Patients treated with cyclophosphamide (CP) usually suffer from severe hemorrhagic cystitis (HC). Our previous study exhibited that mesna + celery cotherapy partially ameliorated HC. Therefore, there is a substantial need to seek alternative regimens to get complete protection against CP-induced HC. The current study investigated the effects of mesna + celery seed oil (MCSO) or mesna + manuka honey (MMH) cotherapy against CP-induced HC in adult male rabbits. The forty rabbits were divided into four equal groups and treated for three weeks. The control group (G1) received distilled water and the second group (G2) received CP (50 mg/kg/week). The third group (G3) received CP + MCSO (CPMCSO regimen), and the fourth group (G4) received CP + MMH (CPMMH regimen). The urinary bladder (UB) specimens were processed to evaluate UB changes through histopathological, immunohistochemical, ultrastructural, and biochemical investigations. In G2, CP provoked HC features (urothelial necrosis, ulceration, and sloughing), UB fibrosis, and TNF-α immunoexpression. Besides, CP reduced the activity of antioxidant enzymes (GPx1, SOD3, and CAT) and elevated the serum levels of NF-κB, TNF-α, IL-1B, and IL-6 cytokines in G2 rabbits. In contrast, the CPMMH regimen caused significant increments of UB protection against HC in G4 rabbits compared to the partial protection by the CPMCSO regimen in G3. Therefore, our study indicated for the first time that the novel CPMMH regimen resulted in complete UB protection against CP-induced HC via combined antioxidant, anti-inflammatory, and antifibrotic properties.

Statins impair CD1d-mediated antigen presentation through the inhibition of prenylation.

Statins are widely used as cholesterol-lowering agents that also decrease inflammation and target enzymes essential for prenylation, an important process in the activation and intracellular transport of proteins vital for a wide variety of cellular functions. Here, we report that statins impair a critical component of the innate immune response, CD1d-mediated Ag presentation. The addition of specific intermediates in the isoprenylation pathway reversed this effect, whereas specific targeting of enzymes responsible for prenylation mimicked the inhibitory effects of statins on Ag presentation by CD1d as well as MHC class II molecules. This study demonstrates the importance of isoprenylation in the regulation of Ag presentation and suggests a mechanism by which statins reduce inflammatory responses.

Therapeutic Potential of Polyphenols and their Nanoformulations in the Treatment of Colorectal Cancer.

BACKGROUND: Colorectal Cancer (CRC) ranks third among all cancer-related deaths around the globe. Chemotherapy may prolong the survival of CRC patients to some extent, but its clinical use is associated with grave side effects on overall health. Contrary to chemotherapy, the use of plant-derived therapeutic molecules offered advantages because of their reduced toxicity. Polyphenol is a group of phytochemicals that impart many therapeutic benefits in the treatment of diabetes, cardiovascular disease and cancer. Various signaling pathways, including Wnt/ß-catenin, MAPK/PI3K and TGF-ß/Smad, play very important roles in the development and progression of CRC. Polyphenols inhibit CRC progressions by modulating these signaling pathways e.g. curcumin and resveratrol impede cancer cell proliferation by inhibiting Wnt signaling. Because of their lower aqueous solubility, the therapeutic efficacy of polyphenols is not fully exploited. In order to increase their bioavailability and efficacy, the nanoformulations of polyphenols have been formulated and investigated against various CRC test models. The main objective of this review is to explore the potential roles of polyphenols and their nanoformulations in the treatment of colorectal cancer. METHODS: We used PubMed, Web of Science, ScienceDirect, Google Scholar and Scopus electronic databases by searching the keywords: nanoparticles, polyphenols, colorectal cancer, cell signaling pathways. Mostly, the articles were retrieved directly from the journals licensed to the library of Qassim University, Saudi Arabia. RESULTS: Literature analysis has shown that the polyphenols contain several important bioactive compounds, which showed potential effectiveness against CRC. Incorporating polyphenols into nanoparticles further enhanced their bioavailability and efficacy. The findings from various studies demonstrated that polyphenol-nanoformulations accelerated the apoptosis in CRC cells by upregulating the levels of caspases and Bax, whereas inhibiting the CRC cell proliferation by downregulating the expression of Bcl-2 and ERK1/2. CONCLUSION: This review provides a valuable resource on the important anti-CRC role of polyphenols and their nanoformulations. This review will expand our knowledge about the anti-CRC roles of polyphenols and their mechanisms of action through the multiple cell signaling pathways.

Safety and Therapeutic Efficacy of Thymoquinone-Loaded Liposomes against Drug-Sensitive and Drug-Resistant Acinetobacter baumannii.

In the present study, we investigated the activity of free thymoquinone (TQ) or liposomal thymoquinone (Lip-TQ) in comparison to standard antibiotic amoxicillin (AMX) against the drug-sensitive and drug-resistant Acinetobacter baumannii. A liposomal formulation of TQ was prepared and characterized and its toxicity was evaluated by analyzing the hematological, liver and kidney function parameters. TQ was effective against both drug-sensitive and drug-resistant A. baumannii as shown by the findings of drug susceptibility testing and time kill kinetics. Moreover, the therapeutic efficacy of TQ or Lip-TQ against A. baumannii was assessed by the survival rate and the bacterial load in the lung tissues of treated mice. The mice infected with drug-sensitive A. baumannii exhibited a 90% survival rate on day 30 post treatment with Lip-TQ at a dose of 10 mg/kg, whereas the mice treated with AMX (10 mg/kg) had a 100% survival rate. On the other hand, the mice infected with drug-resistant A. baumannii had a 70% survival rate in the group treated with Lip-TQ, whereas AMX was ineffective against drug-resistant A. baumannii and all the mice died within day 30 after the treatment. Moreover, Lip-TQ treatment effectively reduced the bacterial load in the lung tissues of the mice infected with the drug-sensitive and drug-resistant A. baumannii. Moreover, the blood of the mice treated with Lip-TQ had reduced levels of inflammation markers, leukocytes and neutrophils. The results of the present study suggest that Lip-TQ may prove to be an effective therapeutic formulation in the treatment of the drug-sensitive or drug-resistant A. baumannii infection as well.

Prostate Cancer: Early Detection and Assessing Clinical Risk Using Deep Machine Learning of High Dimensional Peripheral Blood Flow Cytometric Phenotyping Data.

Detecting the presence of prostate cancer (PCa) and distinguishing low- or intermediate-risk disease from high-risk disease early, and without the need for potentially unnecessary invasive biopsies remains a significant clinical challenge. The aim of this study is to determine whether the T and B cell phenotypic features which we have previously identified as being able to distinguish between benign prostate disease and PCa in asymptomatic men having Prostate-Specific Antigen (PSA) levels < 20 ng/ml can also be used to detect the presence and clinical risk of PCa in a larger cohort of patients whose PSA levels ranged between 3 and 2617 ng/ml. The peripheral blood of 130 asymptomatic men having elevated Prostate-Specific Antigen (PSA) levels was immune profiled using multiparametric whole blood flow cytometry. Of these men, 42 were subsequently diagnosed as having benign prostate disease and 88 as having PCa on biopsy-based evidence. We built a bidirectional Long Short-Term Memory Deep Neural Network (biLSTM) model for detecting the presence of PCa in men which combined the previously-identified phenotypic features (CD8+CD45RA-CD27-CD28- (CD8+ Effector Memory cells), CD4+CD45RA-CD27-CD28- (CD4+ Effector Memory cells), CD4+CD45RA+CD27-CD28- (CD4+ Terminally Differentiated Effector Memory Cells re-expressing CD45RA), CD3-CD19+ (B cells), CD3+CD56+CD8+CD4+ (NKT cells) with Age. The performance of the PCa presence 'detection' model was: Acc: 86.79 ( ± 0.10), Sensitivity: 82.78% (± 0.15); Specificity: 95.83% (± 0.11) on the test set (test set that was not used during training and validation); AUC: 89.31% (± 0.07), ORP-FPR: 7.50% (± 0.20), ORP-TPR: 84.44% (± 0.14). A second biLSTM 'risk' model combined the immunophenotypic features with PSA to predict whether a patient with PCa has high-risk disease (defined by the D'Amico Risk Classification) achieved the following: Acc: 94.90% (± 6.29), Sensitivity: 92% (± 21.39); Specificity: 96.11 (± 0.00); AUC: 94.06% (± 10.69), ORP-FPR: 3.89% (± 0.00), ORP-TPR: 92% (± 21.39). The ORP-FPR for predicting the presence of PCa when combining FC+PSA was lower than that of PSA alone. This study demonstrates that AI approaches based on peripheral blood phenotyping profiles can distinguish between benign prostate disease and PCa and predict clinical risk in asymptomatic men having elevated PSA levels.