Protective effect of kaempferol glucoside against lipopolysaccharide-caused acute lung injury via targeting Nrf2/NF-κB/NLRP3/GSDMD: Integrating experimental and computational studies.

The current study explored the protective potential of kaempferol 3-sophoroside-7-glucoside (KSG) against acute lung injury (ALI). Pre-treatment with KSG effectively secured mice from ALI and showed similar efficaciousness to dexamethasone. KSG markedly increased the survival rate and alleviated lung pathological lesions induced by lipopolysaccharide (LPS). Furthermore, KSG attenuated differential and total cell counts in BALF (bronchoalveolar lavage fluid) and MPO (myeloperoxidase) activity. KSG counteracted the NF-κB (nuclear factor-κB) activation and significantly ameliorated the downstream inflammatory cytokine, TNF-α (tumor necrosis factor-α). Simultaneously, KSG suppressed the over-expression of NLRP3 (NOD-like receptor protein 3), caspase-1, and pro-inflammatory cytokine interleukin IL-1ß (interleukine-1ß) and prohibited the elevation of the pyroptotic parameter GSDMD-N (N-terminal domain of gasdermin D) induced by LPS challenge. In addition, KSG significantly enhanced Nrf2 (nuclear-factor erythroid-2-related factor) and HO-1 (heme-oxygenase-1) expression. Meanwhile, KSG mitigated lipid peroxidative markers (malondialdehyde, protein carbonyl and 4-hydroxynonenal) and boosted endogenous antioxidants (superoxide dismutase/reduced glutathione/catalase) in lung tissue. In silico analyses revealed that KSG disrupts Keap1-Nrf2 protein-protein interactions by binding to the KEAP1 domain, consequently activating Nrf2. Specifically, molecular docking demonstrated superior binding affinity of KSG to KEAP1 compared to the reference inhibitor, with docking scores of -9.576 and -6.633 Kcal/mol, respectively. Additionally, the MM-GBSA binding free energy of KSG (-67.25 Kcal/mol) surpassed that of the reference inhibitor (-56.36 Kcal/mol). Furthermore, MD simulation analysis revealed that the KSG-KEAP1 complex exhibits substantial and stable binding interactions with various amino acids over a duration of 100 ns. These findings showed the protective anti-inflammatory and anti-oxidative modulatory efficiencies of KSG that effectively counteracted LPS-induced ALI and encouraged future research and clinical applications of KSG as a protective strategy for ALI.

Capsaicin ameliorate pulmonary fibrosis via antioxidant Nrf-2/ PPAR- γ pathway activation and inflammatory TGF-ß1/ NF-κB/COX II pathway inhibition.

Bleomycin is an effective antibiotic with a significant anticancer properties, but its use is limited due to its potential to induce dose-dependent pulmonary fibrosis. Therefore, this study aimed to assess the therapeutic potential of Capsaicin as an additional treatment to enhance patient tolerance to Bleomycin compared to the antifibrotic drug Pirfenidone. Pulmonary fibrosis was induced in rats through by a single intratracheal Bleomycin administration in day zero, followed by either Capsaicin or Pirfenidone treatment for 7 days. After the animals were sacrificed, their lungs were dissected and examined using various stains for macroscopic and histopathological evaluation. Additionally, the study assessed various antioxidant, anti-inflammatory, and antifibrotic parameters were assessed. Rats exposed to Bleomycin exhibited visible signs of fibrosis, histopathological alterations, increased collagen deposition, and elevated mucin content. Bleomycin also led to heightened increased inflammatory cells infiltration in the bronchoalveolar lavage, elevated fibrosis biomarkers such as hydroxyproline, alpha-smooth muscle actin (α-SMA) and transforming growth factor-beta (TGF-ß1), increased inflammatory markers including tumor necrosis factor-alpha (TNF-α), interlukine-6 (Il-6), interlukine-1ß (Il-1ß) nuclear factor-kappa B (NF-κB), and Cyclooxygenase-2 (COX-2), and transforming growth factor-beta (TGF-ß1),. Furthermore, it reduced the expression of peroxisome proliferator-activated receptor-gamma (PPAR-γ), increased oxidative stress biomarkers like nitric oxide (NO), malondialdehyde (MDA), myeloperoxidase (MPO) and protein carbonyl. Bleomycin also decreased the expression of nuclear factor erythroid 2-related factor 2 (Nrf-2), reduced glutathione (GSH), total antioxidant capacity, and the activities of catalase and superoxide dismutase (SOD). Treating the animals with Capsaicin and Pirfenidone following Bleomycin exposure resulted in improved lung macroscopic and microscopic characteristics, reduced collagen deposition (collagen I and collagen III) and mucin content, decreased inflammatory cell infiltration, lowered levels of hydroxyproline, α-SMA, and TGF-ß1, decreased TNF-α, Il-6, Il-1ß, NF-κB, and COX-2, increased PPAR-γ and Nrf-2 expression, and improvement improved in all oxidative stress biomarkers. In summary, Capsaicin demonstrates significant antifibrotic activity against Bleomycin-induced lung injury that may be attributed, at least in part, to the antioxidant and anti-inflammatory activities of Capsaicin mediated by upregulation of PPAR-γ and Nrf-2 expression and decreasing. TGF-ß1, NF-κB and COX II proteins concentrations.

Modulation of the crosstalk between Keap1/Nrf2/HO-1 and NF-κB signaling pathways by Tomatidine protects against inflammation/oxidative stress-driven fulminant hepatic failure in mice.

Fulminant hepatic failure (FHF) is the terminal phase of acute liver injury, which is characterized by massive hepatocyte necrosis and rapid hepatic dysfunction in patients without preexisting liver disease. There are currently no therapeutic options for such a life-threatening hepatic failure except liver transplantation; therefore, the terminal phase of the underlying acute liver injury should be avoided. Tomatidine (TOM), asteroidal alkaloid, may have different biological activities, including antioxidant and anti-inflammatory effects. Herein, the lipopolysaccharide (LPS)/D-galactosamine (D-GalN)-induced FHF mouse model was established to explore the protective potential of TOM and the underlying mechanisms of action. TOM pretreatment significantly inhibited hepatocyte necrosis and decreased serum aminotransferase activities in LPS/D-GalN-stimulated mice. TOM further increased the level of different antioxidant enzymes while reducing lipid peroxidation biomarkers in the liver. These beneficial effects of TOM were shown to be associated with targeting of NF-κB signaling pathways, where TOM repressed NF-κB activation and decreased LPS/D-GalN-induced TNF-α, IL-6, IL-1ß, and iNOS production. Moreover, TOM prevented LPS/D-GalN-induced upregulation of Keap1 expression and downregulation of Nrf2 and HO-1 expression, leading to increased Nrf2-binding activity and HO-1 levels. Besides, TOM pretreatment repressed LPS/D-GalN-induced upregulation of proliferating cell nuclear antigen (PCNA) expression, which spared the hepatocytes from damage and subsequent repair following the LPS/D-GalN challenge. Collectively, our findings revealed that TOM has a protective effect on LPS/D-GalN-induced FHF in mice, showing powerful antioxidant and anti-inflammatory effects, primarily mediated via modulating Keap1/Nrf2/HO-1 and NF-κB/TNF-α/IL-6/IL-1ß/iNOS signaling pathways.

RETRACTED: Awan et al. The Enhanced Cytotoxic and Pro-Apoptotic Effects of Optimized Simvastatin-Loaded Emulsomes on MCF-7 Breast Cancer Cells. Pharmaceutics 2020, 12, 597.

The journal retracts the article, "The Enhanced Cytotoxic and Pro-Apoptotic Effects of Optimized Simvastatin-Loaded Emulsomes on MCF-7 Breast Cancer Cells" [...].

Design, synthesis, molecular modeling, and biological evaluations of novel chalcone based 4-Nitroacetophenone derivatives as potent anticancer agents targeting EGFR-TKD.

A series of chalcone-based 4-Nitroacetophenone derivatives were designed and synthesized by the single-step condensation method. These compounds were identified by 1H NMR,13C NMR, MS, and FTIR analysis. Further, the derivatives were evaluated against four cancer cell lines H1299, MCF-7, HepG2, and K526. The IC50 value of potent compounds NCH-2, NCH-4, NCH-5, NCH-6, NCH-8, and NCH-10 was 4.5-11.4 µM in H1299, 4.3-15.7 µM in MCF-7, 2.7-4.1 µM in HepG2 and 4.9-19.7 µM in K562. To assess the toxicity against healthy cells all potent molecules were evaluated against the HEK-293T cell line, and IC50 values exhibited by NCH-2, and NCH-3 were 77.8, 74.3, and other molecules showed IC50 values > 100 µM. The EGFR expression was determined by using rabbit anti-EGFR monoclonal antibody and significant EGFR expression was knocked down observed in H1299 treated with NCH-10 as well as erlotinib. The underlying mechanism behind cell death was investigated through bioinformatics. First, the molecules were optimized and docked to the binding site of the EGFR kinase domain. The best complexes were simulated for 100-ns and compounds NCH-2, NCH-4, and NCH-10 achieved stability similar to the erlotinib bound kinase domain. The free energy binding (ΔGbind) of NCH-10 was found to be more negative -226.616 ± 2.148 kJ/mol calculated by Molecular Mechanics Poisson Boltzmann's Surface Area (MM-PBSA) method. Both in vitro and in silico results conclude that the present class of chalcone-based 4-Nitroacetophenone derivatives are potent anti-cancer agents targeting EGFR-TKD and are 39 folds more effective against H1299, MCF-7, HepG2, and K562 carcinoma cell lines than healthy HEK-293T cell lines.Communicated by Ramaswamy H. Sarma.

Prevalence and Factors Associated with Metabolic Syndrome among Non-Diabetic Saudi Adults: A Cross-Sectional Study.

(1) Introduction: given the high prevalence of metabolic syndrome (MetS) in Saudi Arabia, especially in Jeddah, this study aims to understand the dietary and lifestyle-related risk factors among Jeddah's non-diabetic adults. (2) Material and Methods: Employing a cross-sectional design, non-diabetic adults were sourced from public healthcare centers. Demographics, lifestyle, and dietary habits were surveyed. Blood pressure, anthropometrics, and fasting blood samples measuring plasma glucose, serum triglycerides, and HDL cholesterol were collected. The age cut-off for MetS was ascertained using the receiver operating characteristic curve. Variables influencing MetS were evaluated using univariate logistic regression, and consequential factors underwent multivariate analysis, adjusted for age and sex. (3) Results: Among 1339 participants, 16% had MetS, with age being the strongest predictor (p < 0.001). The optimal age cut-off was 32 years. For those <32, elevated BP in men and waist circumference (WC) in women were most prevalent. For those >32, elevated WC was dominant in both sexes. Univariate logistic regression revealed that higher income and education correlated with lower MetS prevalence, while marriage and smoking were risk factors. Adjusting for age and sex, only very high income had a significant low-risk association (p = 0.034). (4) Conclusion: MetS is notable in the studied group, with age as the pivotal predictor. High income reduces MetS risk, while marital status and smoking could increase it. Since this was a cross-sectional study, cohort studies are needed to validate our findings.

A study on DNA methylation modifying natural compounds identified EGCG for induction of IFI16 gene expression related to the innate immune response in cancer cells.

Innate immune sensor IFN-induced protein 16 (IFI16) exhibits anti-inflammatory effects via IFNß and IFN-stimulated gene (ISG)15 induction in cancer cells. Epigallocatechin gallate (EGCG) is a potent natural DNA methyltransferase inhibitor (DNMTi). Previous studies revealed that conventional DNMTis, such as 5-azacytidine (5-aza-dc), induce IFI16 expression and EGCG decreases DNMT mRNA expression and global methylation (5mC) level via promoter demethylation of tumor suppressor genes in cancer cell lines. To the best of our knowledge, however, EGCG-mediated IFI16 promoter methylation status has been overlooked. Here, initial screening was performed to determine IFI16 expression and its correlation with DNMTs in cancer cell lines from various databases. Following treatment of breast cancer cell lines with 5-aza-dc, vitamin C and EGCG, expression levels of IFI16 and its downstream transcription targets IFNß1 and ISG15 were assessed using RT-qPCR, and the 5mC level was assessed using ELISA. In silico molecular docking simulation was performed for all DNMTs to predict the mode of ligands binding with proteins. Finally, promoter methylation level in IFI16 gene was assessed following EGCG treatment. EGCG treatment induced IFI16 expression, interacted with certain amino acids residues in DNMT proteins and decreased 5mC level and promoter methylation of IFI16. The present results may provide a basis for targeting IFI16 expression as a therapeutic option in breast cancer cell lines.

Green Nanoemulsion Stabilized by In Situ Self-Assembled Natural Oil/Native Cyclodextrin Complexes: An Eco-Friendly Approach for Enhancing Anticancer Activity of Costunolide against Lung Cancer Cells.

Lung cancer is the second-most deadly malignancy worldwide, of which smoking is considered a major risk factor and causes 75-80% of lung cancer-related deaths. Costunolide (CTD) extracted from plant species Saussurea, Aucklandia, and Inula exhibits potent anticancer properties, specifically in lung cancer and leukemia. Several nanoemulsions were prepared and optimized using a three-factor Box-Behnken experimental design. The optimized green nanoemulsion (GNE) showed a vesicle size of 199.56 nm. The IC50 values revealed that A549 cells were significantly more sensitive to the optimized CTD formula than the plain formula and raw CTD. A cell cycle analysis revealed that the optimized CTD formula treatment resulted in significant cell cycle arrest at the S phase. The results also indicated that treatment with the CTD formula significantly increased caspase-3, Bax, Bcl-2, and p53 mRNA expression compared to the plain formula and CTD raw. In terms of the inflammatory markers, the optimized formula significantly reduced the activity of TNF-α and NF-κB in comparison with the plain formula and raw drug only. Overall, the findings from the study proved that a CTD GNE formulation could be a promising therapeutic approach for the treatment of lung cancer.

Elevated Levels of IL-33, IL-17 and IL-25 Indicate the Progression from Chronicity to Hepatocellular Carcinoma in Hepatitis C Virus Patients.

Hepatitis C virus (HCV) is one of the most epidemic viral infections in the world. Three-quarters of individuals infected with HCV become chronic. As a consequence of persistent inflammation, a considerable percentage of chronic patients progress to liver fibrosis, cirrhosis, and finally hepatocellular carcinoma. Cytokines, which are particularly produced from T-helper cells, play a crucial role in immune protection against HCV and the progression of the disease as well. In this study, the role of interleukins IL-33, IL-17, and IL-25 in HCV patients and progression of disease from chronicity to hepatocellular carcinoma will be characterized in order to use them as biomarkers of disease progression. The serum levels of the tested interleukins were measured in patients suffering from chronic hepatitis C (CHC), hepatocellular carcinoma (HCC), and healthy controls (C), and their levels were correlated to the degree of liver fibrosis, liver fibrosis markers and viral load. In contrast to the IL-25 serum level, which increased in patients suffering from HCC only, the serum levels of both IL-33 and IL-17 increased significantly in those patients suffering from CHC and HCC. In addition, IL-33 serum level was found to increase by liver fibrosis progression and viral load, in contrast to both IL-17 and IL-25. Current results indicate a significant role of IL-33 in liver inflammation and fibrosis progress in CHC, whereas IL-17 and IL-25 may be used as biomarkers for the development of hepatocellular carcinoma.

Updates on Molecular and Biochemical Development and Progression of Prostate Cancer.

Prostate cancer (PCa) represents the most commonly non-cutaneous diagnosed cancer in men worldwide and occupies a very wide area of preclinical and clinical research. Targeted therapy for any cancer depends on the understanding of the molecular bases and natural behaviour of the diseases. Despite the well-known effect of androgen deprivation on PCa, many patients develop resistance either for antiandrogen therapy or other new treatment modalities such as checkpoint inhibitors and chemotherapy. Comprehensive understanding of the development of PCa as well as of the mechanisms underlying its progression is mandatory to maximise the benefit of the current approved medications or to guide the future research for targeted therapy of PCa. The aim of this review was to provide updates on the most recent mechanisms regarding the development and the progression of PCa. According to the current understanding, future treatment strategies should include more predictive genetic and biomarker analysis to assign different patients to the expected most appropriate and effective treatment.

Ceftriaxone and Melittin Synergistically Promote Wound Healing in Diabetic Rats.

High glucose levels in diabetic patients are implicated in delay wound healing that could lead to more serious clinical complications. The aim of the present work was to examine the formulation of ceftriaxone (CTX) and melittin (MEL) as nanoconjugate (nanocomplex)-loaded hydroxypropyl methylcellulose (HPMC) (1.5% w/v)-based hydrogel for healing of acute wounds in diabetic rats. The CTX-MEL nanoconjugate, formulated by ion-pairing at different molar ratio, was characterized for size and zeta potential and investigated by transmission electron microscopy. CTX-MEL nanoconjugate was prepared, and its preclinical efficacy evaluated in an in vivo model of acute wound. In particular, the potential ability of the innovative CTX-MEL formulation to modulate wound closure, oxidative status, inflammatory markers, and hydroxyproline was evaluated by ELISA, while the histopathological examination was obtained by using hematoxylin and eosin or Masson's trichrome staining techniques. Quantitative real-time PCR (qRT-PCR) of the excised tissue to measure collagen, type I, alpha 1 (Col1A1) expression and immunohistochemical assessment of vascular endothelial growth factor A (VEGF-A) and transforming growth factor beta 1 (TGF-ß1) were also carried out to shed some light on the mechanism of wound healing. Our results show that the CTX-MEL nanocomplex has enhanced ability to regenerate epithelium, also giving better keratinization, epidermal proliferation, and granulation tissue formation, compared to MEL, CTX, or positive control. The nanocomplex also significantly ameliorated the antioxidant status by decreasing malondialdehyde (MDA) and increasing superoxide dismutase (SOD) levels. The treatment of wounded skin with the CTX-MEL nanocomplex also showed a significant reduction in interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α) pro-inflammatory cytokines combined with a substantial increase in hydroxyproline, VEFG-A, and TGF-ß1 protein expression compared to individual components or negative control group. Additionally, the CTX-MEL nanocomplex showed a significant increase in mRNA expression levels of Col1A1 as compared to individual compounds. In conclusion, the ion-pairing nanocomplex of CTX-MEL represents a promising carrier that can be topically applied to improve wound healing.

Development and Optimization of Cinnamon Oil Nanoemulgel for Enhancement of Solubility and Evaluation of Antibacterial, Antifungal and Analgesic Effects against Oral Microbiota.

Oral health is a key contributor to a person's overall health and well-being. Oral microbiota can pose a serious threat to oral health. Thus, the present study aimed to develop a cinnamon oil (CO)-loaded nanoemulsion gel (NEG1) to enhance the solubilization of oil within the oral cavity, which will enhance its antibacterial, antifungal, and analgesic actions against oral microbiota. For this purpose, the CO-loaded nanoemulsion (CO-NE) was optimized using I-optimal response surface design. A mixture of Pluracare L44 and PlurolOleique CC 497 was used as the surfactant and Capryol was used as the co-surfactant. The optimized CO-NE had a globule size of 92 ± 3 nm, stability index of 95% ± 2%, and a zone of inhibition of 23 ± 1.5 mm. This optimized CO-NE formulation was converted into NEG1 using 2.5% hydroxypropyl cellulose as the gelling agent. The rheological characterizations revealed that the NEG1 formulation exhibited pseudoplastic behavior. The in vitro release of eugenol (the marker molecule for CO) from NEG1 showed an enhanced release compared with that of pure CO. The ex vivo mucosal permeation was found to be highest for NEG1 compared to the aqueous dispersion of CO-NE and pure cinnamon oil. The latency reaction time during the hot-plate test in rats was highest (45 min) for the NEG1 sample at all-time points compared with those of the other tested formulations. The results showed that the CO-NEG formulation could be beneficial in enhancing the actions of CO against oral microbiota, as well as relieving pain and improving overall oral health.

Targeting allosteric sites of human aromatase: a comprehensive in-silico and in-vitro workflow to find potential plant-based anti-breast cancer therapeutics.

Recent findings suggested several allosteric pockets on human aromatase that could be utilised for the development of new modulators able to inhibit this enzyme in a new mechanism. Herein, we applied an integrated in-silico-based approach supported by in-vitro enzyme-based and cell-based validation assays to select the best leads able to target these allosteric binding sites from a small library of plant-derived natural products. Chrysin, apigenin, and resveratrol were found to be the best inhibitors targeting the enzyme's substrate access channel and were able to produce a competitive inhibition with IC50 values ranged from 1.7 to 15.8 µM. Moreover, they showed a more potent antiproliferative effect against ER+ (MCF-7) than ER- one (MDA-MB-231) cell lines. On the other hand, both pomiferin and berberine were the best hits for the enzyme's haem-proximal cavity producing a non-competitive inhibition (IC50 15.1 and 21.4 µM, respectively) and showed selective antiproliferative activity towards MCF-7 cell lines.

Oral gel loaded with penciclovir-lavender oil nanoemulsion to enhance bioavailability and alleviate pain associated with herpes labialis.

Herpes labialis, caused by herpes simplex virus type 1, is usually characterized by painful skin or mucosal lesions. Penciclovir (PV) tablets are found to be effective against herpes labialis but suffer from poor oral bioavailability. This study aimed to combine the benefits of PV and lavender oil (LO), which exhibits anesthetic activity, in the form of a self-nanoemulsifying drug delivery system (SNEDDS) for the treatment of herpes labialis. Toward this purpose, LO (oil), Labrasol:Labrafil M1944 CS in the ratio of 6:4 (surfactant mixture), and Lauroglycol-FCC (co-surfactant, selected based on the solubility of PV) were evaluated as the independent factors using a distance quadratic mixture design. The formulation was optimized for the minimum globule size and maximum stability index and was determined to contain 14% LO, 40.5% Labrasol:Labrafil 1944 (6:4), and 45.5% Lauroglycol-FCC. The optimized PV-LO-SNEDDS was embedded in chitosan hydrogel and the resulting formulations coded by (O3) were prepared and evaluated. The rheological studies demonstrated a combined pseudoplastic and thixotropic behavior with the highest flux of PV permeation across sheep buccal mucosa. Compared to a marketed 1% PV cream, the O3 formulation exhibited a significantly higher and sustained PV release, nearly twice the PV permeability, and a relative bioavailability of 180%. Overall, results confirm that the O3 formulation can provide an efficient delivery system for PV to reach oral mucosa and subsequent prolonged PV release. Thus, the PV-LO-SNEDDS embedded oral gel is promising and can be further evaluated in clinical settings to establish its therapeutic use in herpes labialis.

Peptide substrate screening for the diagnosis of SARS-CoV-2 using fluorescence resonance energy transfer (FRET) assay.

The novel corona (SARS-CoV-2) virus causes a global pandemic, which motivates researchers to develop reliable and effective methods for screening and detection of SARS-CoV-2. Though there are several methods available for the diagnosis of SARS-CoV-2 such as RT-PCR and ELSIA, nevertheless, these methods are time-consuming and may not apply at the point of care. In this study, we have developed a specific, sensitive, quantitative and fast detection method for SARS-CoV-2 by fluorescence resonance energy transfer (FRET) assay. The total extracellular protease proteolytic activity from the virus has been used as the biomarker. The specific peptide sequences from the library of 115 dipeptides were identified via changes in the fluorescence signal. The fluorogenic dipeptide substrates have the fluorophore and a quencher at the N- and the C- terminals, respectively. When the protease hydrolyzes the peptide bond between the two specific amino acids, it leads to a significant increase in the fluorescence signals. The specific fluorogenic peptide (H-d) produces a high fluorescence signal. A calibration plot was obtained from the changes in the fluorescence intensity against the different concentrations of the viral protease. The lowest limit of detection of this method was 9.7 ± 3 pfu/mL. The cross-reactivity of the SARS-CoV-2-specific peptide was tested against the MERS-CoV which does not affect the fluorescence signal. A significant change in the fluorescence signal with patient samples indicates that this FRET-based assay might be applied for the diagnosis of SARS-CoV-2 patients. Graphical abstract.

Scorpion Venom-Functionalized Quercetin Phytosomes for Breast Cancer Management: In Vitro Response Surface Optimization and Anticancer Activity against MCF-7 Cells.

Breast cancer is a dangerous type of cancer in women. Quercetin (QRT), a naturally occurring flavonoid, has wide biological effects including antioxidant, anticarcinogenic, anti-inflammatory, antiallergic, and antiviral activities. The anticancer activity is considered the most valuable effect of QRT against several types of cancer, including prostate, liver, lung, colon, and breast cancer. Scorpion venom peptides (SV) has been found to induce apoptosis and aggravate cancer cells, making it a promising anticancer agent. QRT, SV, and Phospholipon® 90H (PL) were incorporated in a nano-based delivery platform to assess QRT's cellular uptake and antiproliferative efficacy against a lung cancer cell line derived from human breast cancer cells MCF-7. Several nanovesicles were prepared and optimized, using four-factor Box-Behnken, in an experimental design. The optimized phytosomes showed vesicle size and zeta potential values of 116.9 nm and 31.5 mV, respectively. The IC50 values revealed that MCF-7 cells were significantly more sensitive to the optimized QRT formula than the plain formula and raw QRT. Cell cycle analysis revealed that optimized QRT formula treatment resulted in significant cell cycle arrest at the S phase. The results also indicated that treatment with QRT formula significantly increased caspase-9, Bax, Bcl-2, and p53 mRNA expression, compared with the plain formula and QRT. In terms of the inflammatory markers, the QRT formula significantly reduced the activity of TNF-α and NF-κB, in comparison with the plain formula and QRT only. Overall, the findings from the study proved that a QRT formulation could be a promising therapeutic approach for the treatment of breast cancer.

High Expression of Pd-1 in Circulating Cells of Patients With Advanced Colorectal Cancer Receiving Adjuvant Therapy.

Among all cancer types, colorectal cancer is the third most common in men and the second most common in women globally. Generally, the risk of colorectal cancer increases with age, and colorectal cancer is modulated by various genetic alterations. Alterations in the immune response serve a significant role in the development of colorectal cancer. In primary cancer types, immune cells express a variety of inhibitory molecules that dampen the immune response against tumor cells. Additionally, few reports have demonstrated that classical chemotherapy promotes the immunosuppressive microenvironment in both tissues and immune cells. This study assessed the expression levels of genes using RT-qPCR associated with the immune system, including interferon-γ, programmed death-1, ß2-microglobulin, human leukocyte antigen-A, CD3e, CD28 and intracellular adhesion molecule 1, in patients with colorectal cancer, as these genes are known to serve important roles in immune regulation during cancer incidence. Gene expression analysis was performed with the whole blood cells of patients with colorectal cancer and healthy volunteers. Compared with the normal controls, programmed death-1was highly expressed in patients with advanced-stage colorectal cancer. Furthermore, the expression of programmed death-1 was higher in patients receiving adjuvant therapy, which suggests the therapy dampened the immune response against tumor cells. The results of the present study indicate that classical adjuvant therapies, which are currently used for patients with colorectal cancer, should be modulated, and a combination of classical therapy with anti-programmed death-1 antibody should be conducted for improved management of patients with colorectal cancer.

Microneedles Drug Delivery Systems for Treatment of Cancer: A Recent Update.

Microneedles (MNs) are tiny needle like structures used in drug delivery through layers of the skin. They are non-invasive and are associated with significantly less or no pain at the site of administration to the skin. MNs are excellent in delivering both small and large molecules to the subjects in need thereof. There exist several strategies for drug delivery using MNs, wherein each strategy has its pros and cons. Research in this domain lead to product development and commercialization for clinical use. Additionally, several MN-based products are undergoing clinical trials to evaluate its safety, efficacy, and tolerability. The present review begins by providing bird's-eye view about the general characteristics of MNs followed by providing recent updates in the treatment of cancer using MNs. Particularly, we provide an overview of various aspects namely: anti-cancerous MNs that work based on sensor technology, MNs for treatment of breast cancer, skin carcinoma, prostate cancer, and MNs fabricated by additive manufacturing or 3 dimensional printing for treatment of cancer. Further, the review also provides limitations, safety concerns, and latest updates about the clinical trials on MNs for the treatment of cancer. Furthermore, we also provide a regulatory overview from the "United States Food and Drug Administration" about MNs.

Urolithins Attenuate Multiple Symptoms of Obesity in Rats Fed on a High-Fat Diet.

BACKGROUND: Urolithins are gut microbiota-derived polyphenol metabolites, produced following the consumption of pomegranate, berries, and nuts. Recent studies have shown the potentials of these metabolites on reducing triglycerides accumulation in cultured hepatocytes and adipocytes. In this study, we investigated the ability of both urolithin A (Uro-A) and urolithin B (Uro-B) to attenuate obesity and associated symptoms in a high-fat diet-induced obesity model in rats. METHODS: Twenty-four male Wistar rats were randomly assigned to four groups. Group 1 was fed on a normal diet while groups 2, 3, and 4 were fed on a high-fat diet for 10 weeks. After this, groups 3 and 4 were treated with 2.5mg/kg body weight of Uro-A and Uro-B intraperitoneally, respectively. Body weight, serum lipid profile, hepatic antioxidant activity, hepatic lipid accumulation, fecal lipid content, and the expressions of genes involved in lipogenesis and hepatic ER stress were quantified. RESULTS: Indeed, a high-fat diet resulted in increased body weight, visceral adipose tissue mass, and oxidative stress in rats. However, treatment with both Uro-A and Uro-B decreased body weight and visceral adipose tissue mass. These metabolites restored hepatic antioxidant capacity and decreased lipid accumulation in addition to an increase in fecal fat excretion. Moreover, both Uro-A and Uro-B treatment downregulated the expression of LXRα and SREBP1c; involved in de novo lipogenesis while upregulating PPARα expression for increased fatty acid oxidation. Furthermore, Uro-A and Uro-B decreased the expression of PERK and IRE1α; which are involved in hepatic ER stress. Taken together, our results showed the potentials of Uro-A and Uro-B in mitigating obesity symptoms and they could thus provide promising roles in the future as functional anti-obesity candidates.

Chitosan-Based Microparticles Enhance Ellagic Acid's Colon Targeting and Proapoptotic Activity.

This study aimed at improving the targeting and cytotoxic effect of ellagic acid (EA) on colon cancer cells. EA was encapsulated in chitosan (CHIT) polymers then coated by eudragit S100 (ES100) microparticles. The release of EA double-coated microparticles (MPs) was tested at simulative pH values. Maximum release was observed at 24 h and pH 7.4. The cytotoxicity of EA MPs on HCT 116 colon cancer cells was synergistically improved as compared with raw EA. Cell-cycle analysis by flow cytometry suggested enhanced G2-M phase colon cancer cell accumulation. In addition, a significantly higher cell fraction was observed in the pre-G phase, which highlighted the enhancement of the proapoptotic activity of EA formulated in the double-coat mixture. Annexin-V staining was used for substantiation of the observed cell-death-inducing activity. Cell fractions were significantly increased in early, late, and total cell death. This was backed by high elevation in cellular content of caspase 3. Effectiveness of the double-coated EA to target colonic tissues was confirmed using real-time iohexol dye X-ray radiography. In conclusion, CHIT loaded with EA and coated with ES100 formula exhibits improved colon targeting as well as enhanced cytotoxic and proapoptotic activity against HCT 116 colon cancer when compared with the administration of raw EA.