Dual pH/redox-responsive hyperbranched polymeric nanocarriers with TME-trigger size shrinkage and charge reversible ability for amplified chemotherapy of breast cancer.

A novel pH/redox-responsive hyperbranched MeO-PEG-b-(NIPAAm-co-PBAE) nanoparticles (NPs) were designed with size shrinkage and charge-reversible potential for targeted delivery of docetaxel (DTX) to MDA-MB-231 cell lines. In the tumor microenvironment (TME), amine protonation induces charge reversal and disulfide bond cleavage under high TME GSH concentration causing size shrinkage, improved deep tumor penetration, and active targeting of the therapeutic agents. These nano drug delivery systems (NDDSs) significantly promoted cancer cell uptake (~ 100% at 0.5 h), facilitating site-specific delivery and deep tumor penetration. The MTT assay revealed significantly higher cytotoxicity (P value < 0.0001) for DTX-loaded NPs compared to free DTX. Cell cycle analysis revealed G2/M (58.3 ± 2.1%) and S (21.5 ± 1.3%) arrest for DTX-loaded NPs, while free DTX caused G2/M (67.9 ± 1.1%) and sub-G1 (10.3 ± 0.8%) arrest. DTX-loaded NPs induced higher apoptosis (P value < 0.001) in MDA-MB-231 cells (71.5 ± 2.8%) compared to free DTX (42.3 ± 3.1%). Western blotting and RT-PCR assays confirmed significant up-regulation of protein levels and apoptotic genes by DTX-loaded NPs compared to free DTX. In conclusion, TME-responsive charge reversal and size-shrinkable smart NDDSs designed based on low pH, and high glutathione (GSH), offer more effective site-specific delivery of therapeutic agents to tumors.

Dietary fiber intake and all-cause and cause-specific mortality: An updated systematic review and meta-analysis of prospective cohort studies.

BACKGROUND: Accumulating evidence supports the effects of dietary fiber on the risk of non-communicable diseases (NCDs). However, there is no updated systematic review and meta-analysis that compares and pools the effect of different types of fiber on mortality. METHODS: In this systematic review and meta-analysis, all prospective cohort studies that evaluated the relationship between dietary fiber intake and all-cause or cause-specific mortality were included. The PubMed, SCOPUS, and Web of Science databases were searched up to October 2022. Data extraction and quality assessment were performed by two researchers independently. Heterogeneity between studies was assessed using Chi-square based test. Random/fixed effect meta-analysis was used to pool the hazard ratios (HR) or relative risks (RR) and 95 % confidence intervals (CI) for the association between different types of fiber and mortality. RESULTS: This systematic review included 64 eligible studies, with a total sample size of 3512828 subjects, that investigated the association between dietary fiber intake and mortality from all-cause, cardiovascular disease (CVD), and cancer. Random-effect meta-analysis shows that higher consumption of total dietary fiber, significantly decreased the risk of all-cause mortality, CVD-related mortality, and cancer-related mortality by 23, 26 and 22 % (HR:0.77; 95%CI (0.73,0.82), HR:0.74; 95%CI (0.71,0.77) and HR:0.78; 95%CI (0.68,0.87)), respectively. The consumption of insoluble fiber tended to be more effective than soluble fiber intake in reducing the risk of total mortality and mortality due to CVD and cancer. Additionally, dietary fiber from whole grains, cereals, and vegetables was associated with a reduced risk of all-cause mortality, while dietary fiber from nuts and seeds reduced the risk of CVD-related death by 43 % (HR:0.57; 95 % CI (0.38,0.77)). CONCLUSION: This comprehensive meta-analysis provides additional evidence supporting the protective association between fiber intake and all-cause and cause-specific mortality rates.

pH/redox responsive size-switchable intelligent nanovehicle for tumor microenvironment targeted DOX release.

Tumor microenvironment (TME) targeted strategy could control the drug release in tumor cells more accurately and creates a new opportunity for enhanced site-specific targeted delivery. In this study, (PAA-b-PCL-S-S-PCL-b-PAA) copolymeric nanoparticles (NPs) with size-switchable ability and dual pH/redox-triggered drug release behavior were designed to significantly promote cancer uptake (cell internalization of around 100% at 30 min) and site-specific targeted doxorubicin (DOX) delivery in MDA-MB-231 tumor cells. NPs surface charge was shifted from - 17.8 to - 2.4 and their size shrunk from 170.3 to 93 nm in TME. The cell cycle results showed that DOX-loaded NPs showed G2/M (68%) arrest, while free DOX showed sub-G1 arrest (22%). Apoptosis tests confirmed that the cells treated with DOX-loaded NPs showed a higher amount of apoptosis (71.6%) than the free DOX (49.8%). Western blot and RT-PCR assays revealed that the apoptotic genes and protein levels were significantly upregulated using the DOX-loaded NPs vs. the free DOX (Pvalue < 0.001). In conclusion, dual pH/redox-responsive and size-switchable DOX-loaded NPs developed here showed outstanding anti-tumoral features compared with free DOX that might present a prospective platform for tumor site-specific accumulation and drug release that suggest further in vivo research.

The promising impact of Bemcentinib and Repotrectinib on sleep impairment in Alzheimer's disease.

Alzheimer's disease (AD), the most prevalent neurodegenerative disease, demands effective medication to alleviate symptoms. This study focused on sleep impairment as an overt clinical symptom and tauopathy as a prominent molecular symptom of this disease. Multiple compounds from three biomolecule libraries (719 compounds; ChemDiv:366 - ChEMBL:180 - PubChem:173) were evaluated for potential binding affinity and safety using AutoDock Vina and pkCSM, respectively, resulting in the selection of four candidate compounds (Lestaurtinib, Repotrectinib, Bemcentinib, and Zotiraciclib). Due to the similarity of Repotrectinib and Bemcentinib binding sites to ATP, 300 ns Martini 3 coarse-grained molecular dynamics (MD) was performed on these two molecules and ATP by NAMD. The stability of tau protein in the presence of drugs was assessed using a 200 ns Martini 3 MD simulation. Binding site analysis discloses Bemcentinib and Repotrectinib as two inhibitors occupying most amino acids in binding with ATP. The RMSD and RMS average correlation results revealed protein containing Bemcentinib and Repotrectinib to have a more stable state compared to ATP in the first 220 ns simulation. There was only a single detachment of Bemcentinib, while Repotrictinib detached twice at the end of the simulation. Eventually, adding Bemcentinib and Repotrectinib to the enzyme-tau complex significantly increased the number of tau detachments during the 200 ns simulation. We report Bemcentinib and Repotrectinib, formerly prescribed for cancer, as potential inhibitors of the CK1 δ. Besides their high binding affinity compared to ATP, they can inhibit all ATP-binding sites and alter the tau binding stability.Communicated by Ramaswamy H. Sarma.

Evaluation of photobiomodulation therapy (117 and 90s) on pain, regeneration, and epigenetic factors (HDAC 2, DNMT3a) expression following spinal cord injury in a rat model.

BACKGROUND: Photobiomodulation therapy (PBMT), due to its anti-inflammatory, analgesic effects, and most importantly as a non-invasive procedure, has currently gained a special setting in pain relief and the treatment of Spinal cord injuries (SCI). However, the mechanism of action of the PBM is not yet completely understood. METHODS: In this study, SCI is induced by an aneurysm clip, and PBM therapy was applied by a continuous-wave (CW) laser with a wavelength of 660 nm. Adult male rats were divided into four groups: Control, SCI, SCI + PBMT 90s, and SCI + PBMT 117s. After 7 weeks, hyperalgesia, allodynia, and functional recovery were assessed. Fibroblasts infiltrating the spinal cord were counted after H&E staining. The expression of epigenetic factors (HDAC2, DNMT3a), protein relevant for pain (GAD65), and astrocytes marker (GFAP) after 4 weeks of daily PBMT (90 and 117s) was probed by western blotting. RESULTS: Both PBMTs (90 and 117s) significantly improved the pain and ability to move and fibroblast invasion was reduced. SCI + PBMT 90s, increased GAD65, HDAC2, and DNMT3a expression. However, PBMT 117s decreased GFAP, HDAC2, and DNMT3a. CONCLUSION: PBMT 90 and 117s improved the pain, and functional recovery equally. The regulation of epigenetic mechanisms appears to be a significant effect of PBMT117s, which emphasizes on impact of radiation duration and accumulative energy.

Could conditioned medium be used instead of stem cell transplantation to repair spinal cord injury in animal models? Identifying knowledge gaps.

The drawbacks of stem cell (SC) therapies have led to investigations of SC conditioned medium (CM) instead of SC transplantation in the repair of spinal cord injury (SCI). However, the effectiveness of CM in comparison with cell transplantation in SCI models remain an open and intriguing question. The focus of this review was to survey existing publications addressing this comparison. The review included articles from electronic databases Medline, Embase, Scopus, and Web of Science that included comparisons of the effects of CM versus SC transplantation and versus controls on locomotion after SCI. The search yielded 5 studies and 6 experiments. The results indicated that there was insufficient evidence to conclude that treatment with CM and source cells were equally effective (SMD = 0.12; 95% CI = -0.36 to 0.59; p = 0.07). Regarding investigations of separate effects of SCs versus CM, there currently is limited evidence on efficacy in SCI models. This highlights a notable concern affecting this field. Thus, we identified critical knowledge gaps concerning comparisons of the efficacy of therapeutic application of SC and their derived CM on functional recovery following SCI.

Time-dependent photobiomodulation management of neuropathic pain induced by spinal cord injury in male rats.

Neuropathic pain (NP) following spinal cord injury (SCI) often lasts for a long time and causes a range of problems that reduce the quality of life. Current treatments are not generally effective; however, photobiomodulation therapy (PBMT) has made some progress in this area. Due to the novelty of this treatment, standard therapeutic protocols have not yet been agreed upon. In the present study, we compare the analgesic effect of two PBMT protocols (2 and 4 weeks of radiation). A total of thirty-two adult male Wistar rats were divided into four groups: control, SCI, 2 W PBMT, and 4 W PBMT. SCI was induced by an aneurism clip and PBMT used a 660-nm, initiated 30 min post-SCI, and continued daily for 2 or 4 weeks. Functional recovery, hyperalgesia, and allodynia were measured weekly. At the end of the study, the Gad65, interleukin 1-alpha (IL1α), interleukin 10 (IL10), IL4, and purinergic receptor (P2xR and P2yR) expressions were measured. Data were analyzed by Prism6. The results showed PBM irradiation for 2 and 4 weeks had the same effects in improving hyperalgesia. In the case of allodynia and functional recovery, 4 W PBMT was more effective (p<0.01). 4 W PBMT increased the Gad65 expression (p <0.001) and reduced P2Y4R (p <0.05) compared to SCI animals. The effects of 2 and 4 W PBMT were the same for IL1α, IL10, and P2X3 receptors. 4 W PBMT was more effective in reducing the complications of SCI such as pain and disability. PBMT therapy is an effective method aimed at immune system function modulation to reduce NP and motor dysfunction.

The Role of Intraspinal Administration of Self-Assembled Peptide on Locomotion Recovery After Spinal Cord Injury: A Systematic Review and Meta-Analysis Study.

BACKGROUND: Spinal cord injury (SCI) treatment is still a challenge and new treatments that help these patients are being considered. Recent studies showed that the use of self-assembled peptide (SAP) can be useful in SCI treatment. MATERIALS AND METHODS: In this meta-analysis, we investigated the effect of SAP administration on locomotion recovery after SCI. Records were obtained from a comprehensive search of data bases. Articles were scrutinized for inclusion and exclusion criteria. Data were analyzed and results were reported as standardized mean difference (SMD) with 95% CI. Subgroup analysis was also performed. RESULTS: A total of 14 studies and 17 separate experiments were included in the final analysis. Treatment with SAP structures after SCI resulted in a significant improvement in animal motor function (SMD = 1.13; 95% CI: 0.68-1.58; p < 0.0001). SAP treatment facilitated axon sprouting (SMD = 0.76; 95% CI: 0.33-1.18; p < 0.0001) and reduction of glial scar (SMD = -1.02; 95% CI: -1.94 to -0.09; p = 0.03). The difference in SAP type, its concentration, follow-up time, and SCI model had no effect on SAP effectiveness. In addition, SAP administration had a similar effect on improving locomotion in all three immediate, acute, and subacute phases which gives the good news of using this treatment for patients who are in the chronic phase. CONCLUSION: SAP treatment can be considered as a potential treatment to help the motor recovery of SCI and axon regeneration.

ERK/HIF-1α/VEGF pathway: a molecular target of ELABELA (ELA) peptide for attenuating cardiac ischemia-reperfusion injury in rats by promoting angiogenesis.

BACKGROUND: Myocardial ischemia-reperfusion (I/R) injury is caused by a chain of events such as endothelial dysfunction. This study was conducted to investigate protective effects of ELABELA against myocardial I/R in Wistar rats and clarify its possible mechanisms. METHODS AND RESULTS: MI model was established based on the left anterior descending coronary artery ligation for 30 min. Then, 5 µg/kg of ELA peptide was intraperitoneally infused in rats once per day for 4 days. Western blot assay was used to assay the expression of t-ERK1/2, and p-ERK1/2 in different groups. The amount of myocardial capillary density, the expression levels of VEGF and HIF-1α were evaluated using immunohistochemistry assay. Masson's trichrome staining was utilized to assay cardiac interstitial fibrosis. The results showed that establishment of MI significantly enhanced cardiac interstitial fibrosis and changed p-ERK1/2/ t-ERK1/2 ratio. Likewise, ELA post-treatment markedly increased myocardial capillary density, the expression of several angiogenic factors (VEGF-A, HIF-1α), and reduced cardiac interstitial fibrosis by activation of ERK1/2 signaling pathways. CONCLUSION: Collectively, ELA peptide has ability to reduce myocardial I/R injury by promoting angiogenesis and reducing cardiac interstitial fibrosis through activating ERK/HIF-1α/VEGF pathway.

Hybrid laser activated phycocyanin/capecitabine treatment of cancerous MCF7 cells.

Laser-induced fluorescence is recently used as an efficient technique in cancer diagnosis and non-invasive treatment. Here, the synergic therapeutical efficacies of the Capecitabine (CAP) chemodrug, photosensitive Phycocyanin (PC) and graphene oxide (GO) under laser irradiation were investigated. The therapeutical efficacies of diverse concentrations of CAP (0.001-10 mg/ml) and PC (0.5-10 mg/ml) alone and with laser irradiation on human breast adenocarcinoma (MCF-7) cells were examined. The interactional effects of 100 mW SHG Nd:YAG laser at 532nm and GaAs laser at 808 nm ranging power of 150 mW- 2.2W were considered. The contribution of graphene oxide (GO) in biocompatible concentrations of 2.5-20 ng/ml and thermal characteristics of laser exposure at 808 nm on GO + fluorophores have been studied. The effects of the bare and laser-excited CAP + PC on cell mortality have been obtained. Despite the laser irradiation could not hold up the cell proliferation in the absence of drug interaction considerably; however, the viability of the treated cells (by a combination of fluorophores) under laser exposure at 808 nm was significantly reduced. The laser at 532 nm excited the fluorescent PC in (CAP + PC) to trigger the photodynamic processes via oxygen generation. Through the in-vitro experiments of laser-induced fluorescence (LIF) spectroscopy of PC + CAP, the PC/CAP concentrations of the maximum fluorescence signal and spectral shifts have been characterized. The synergic effects of the laser exposures and (CAP + PC) treatment at different concentrations were confirmed. It has been shown here that the laser activation of (CAP + PC) can induce the mortality of the malignant cells by reducing the chemotherapeutic dose of CAP to avoid its non-desirable side effects and by approaching the minimally invasive treatment. Elevation of the laser intensity/exposure time could contribute to the therapeutic efficacy. Survival of the treated cells with a combination of GO and fluorophores could be reduced under laser exposure at 808 nm compared to the same combination therapy in the absence of GO. This survey could benefit the forthcoming clinical protocols based on laser spectroscopy for in-situ imaging/diagnosis/treatment of adenocarcinoma utilizing PC + CAP + GO.

Optimization of the Duration and Dose of Photobiomodulation Therapy (660 nm Laser) for Spinal Cord Injury in Rats.

Objective: Spinal cord injury (SCI) causes motor deficits, urinary incontinence, and neuropathic pain. This study was designed to optimize a photobiomodulation therapy (PBMT) protocol using a continuous wave (CW) 660 nm laser in rats with SCI. Specifically, the number of days of irradiation and the daily dose of PBMT were investigated. Methods: The study was performed in two steps. In the first step, a comparison between the effects of PBMT (45 sec) daily for 2 and 4 weeks on pain and movement [Basso, Beattie, and Brenham (BBB) score] was made. In the second step, a comparison between different durations of irradiation (27, 45, 90, and 117 sec) was performed. PBMT used a 100 mW laser delivered to 9 points on and around the lesion site. Oxidative stress, fibroblast invasion, and time to achieve spontaneous urination were also assessed. Results: The improvement in movement and pain stopped with discontinuation of radiation at week 2 and fibroblast invasion resumed. No improvement was seen in movement and pain in the group receiving PBMT for 27 sec compared with the groups receiving higher doses of laser radiation. Animals receiving 117 sec of photobiomodulation showed a higher BBB score even in the first 3 days. Conclusions: The number of days is an important factor for improving mobility; however, the daily dose of radiation is more important for pain relief.

Stigma and Quality of Life in Women With Breast Cancer: Mediation and Moderation Model of Social Support, Sense of Coherence, and Coping Strategies.

OBJECTIVES: The breast cancer stigma affects Health-related quality of life (HRQoL), while general resilience resources (GRRs), namely, sense of coherence (SOC), social support, and coping skills, are thought to alleviate this effect. The study aimed to explore the mediating/moderation role of GRRs in the relationship between stigma and HRQoL and its dimensions in Iranian patients with breast cancer. METHODS: In this cross-sectional study, Stigma Scale for Chronic Illness 8-item version (SSCI-8), SOC-13, Medical Outcome Survey- Social Support Scale (MOS-SSS), Brief COPE, and Functional Assessment of Cancer Therapy-Breast (FACT-B) were investigated in a convenience sample of Iranian women with confirmed non-metastatic breast cancer. Following the establishment of correlations using Pearson's correlation, single and parallel mediation analysis and moderation analysis were conducted to determine the extent to which each GRR might be impacted by stigma or decrease the adverse impact of stigma on HRQoL. RESULTS: An analysis of 221 women (response rate of 87.5%) with the mean age of 47.14 (9.13) showed that stigma was negatively correlated to all HRQoL's dimensions (r = -0.27∼0.51, p < 0.05), SOC (r = -0.26∼0.35, p < 0.01), social support (r = -0.23∼0.30, p < 0.01), and the bulk of coping skills. In the single mediation analysis, stigma affected all facets of SOC, all subscales of social support, and positive reframing, which partially reduced breast cancer HRQoL. Stigma affects general HRQoL through damaging meaningfulness, social support (except for tangible), and positive reframing. Meaningfulness was marked as the most impacted GRR in terms of all domains of HRQoL. In parallel mediation, reduced meaningfulness, total social support, and positive reframing were highlighted as the pathways of diminished breast cancer HRQoL. Moderation analysis indicated the higher levels of humor, behavioral disengagement, and use of instrumental support behaviors to be functional in protecting different dimensions of HRQoL, while the results were mixed for venting, especially in patients with mastectomy surgery. CONCLUSION: While GRRs may be impacted by stigma, they exert a relatively small protective effect against the impact of stigma on HRQoL. This study provides some novel findings, but longitudinal studies are needed to further verify these before any causal conclusion or recommendations for health policy can be drawn.

Frequency of Helicobacter pylori Infection in Patients with Peptic Ulcer Referred to the Endoscopy Departments of Khorramabad City Hospitals, Iran, During 2013-2016.

BACKGROUND: The present study investigated the prevalence of Helicobacter pylori infection in peptic ulcer patients referred to the endoscopy departments in Khorramabad hospitals during 2013- 2016. METHODS: The early pool of the study included all patients who had been referred to the endoscopy department and whose endoscopic and pathology reports were available and complete. After recording endoscopic reports, 1224 peptic ulcer (gastric or duodenal ulcer) cases, in which biopsy assays were performed to examine the type of ulcer and the presence of Helicobacter pylori bacteria, were selected. Pathology reports were collected by referring to the pathology departments. The information in the pathology report, including demographic information, was included in a pre-designed questionnaire to match the endoscopic reports, the location of the pathology sample, and other details, including the presence or absence of Helicobacter pylori bacteria. Finally, the data were analyzed using SPSS, version 21. RESULTS: For all the 1224 patients studied, the mean age was 15.5 ± 17.5 years old. A total of 664 (54.2%) cases had gastric ulcers, 445 (36.4%) cases had duodenal ulcers, and 115 (9.4%) had both gastric and duodenal ulcers. Among gastric ulcer patients, 512 (65.7%) had a gastric ulcer in the antrum area, and 74.3% (579 patients) of the gastric ulcers were clean base type. CONCLUSION: The prevalence of infection was statistically significant in terms of the type, location, and number of peptic ulcers, including both gastric ulcer and duodenal ulcer.

Curcumin-coated gold nanoparticles attenuate doxorubicin-induced cardiotoxicity via regulating apoptosis in a mouse model.

Doxorubicin (DOX) is one of the most widely used chemotherapy agents; however, its nonselective effect causes cardiotoxicity. Curcumin (Cur), a well known dietary polyphenol, could exert a significant cardioprotective effect, but the biological application of this substance is limited by its chemical insolubility. To overcome this limitation, in this study, we synthesised gold nanoparticles based on Cur (Cur-AuNPs). Ultraviolet-visible (UV-Vis) absorbance spectroscopy and transmission electron microscopy (TEM) were performed for the characterisation of synthesised NPs, and Fourier transform infrared (FTIR) spectroscopy were applied to detect Cur on the surface of AuNPs. Its cytotoxicity effect on H9c2 cells was evaluated using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The biological efficacy of Cur-AuNPs was assessed after acute cardiotoxicity induction in BALB/c mice with DOX injection. The serum biomarkers, myocardial histological changes, and cardiomyocyte apoptosis were then measured. The results revealed that the heart protection by Cur-AuNPs is more effective than Cur alone. Heart protective effect of Cur-AuNPs was evident both in the short-term (24 hours) and long-term (14 days) study. The results of Cur-AuNPs400 after 24 hours of toxicity induction displayed the reduction of the cardiac injury serum biomarkers (LDH, CK-MB, cTnI, ADT, and ALT) and apoptotic proteins (Bax and Caspase-3), as well as increase of Bcl-2 anti-apoptotic proteins without any sign of interfibrillar haemorrhage and intercellular spaces in the heart tissue microscopic images. Our long-term study signifies that Cur-AuNPs400 in DOX-intoxicated mice could successfully inhibit body and heart weight loss in comparison to DOX group.

Alginate scaffolds improve functional recovery after spinal cord injury.

PURPOSE: In this systematic review and meta-analysis, the use of alginate for the repair of the damaged spinal cord was investigated. METHODS: After an extensive search of databases including MEDLINE, SCOPUS, EMBASE and Web of Science, an initial screening was performed based on inclusion and exclusion criteria. The full text of related articles was reviewed and data mining was performed. Data were analyzed by calculating the mean of ratios between treated and untreated groups using STATA software. Subgroup analysis was also performed due to heterogeneity. Articles were subjected to quality control and PRISMA guidelines were followed. RESULTS: Twelve studies and 17 experiments were included in the study. After SCI, alginate hydrogel had a moderate effect on motor function recovery (SMD = 0.64; 95% CI 0.28-1.00; p < 0.0001) and alginate scaffolds loaded with drugs, growth factors, or cells on the SCI group compared with untreated SCI animals showed has a strong effect in the treatment of SCI (SMD = 2.82; 95% CI 1.49-4.145; p < 0.0001). Treatment with drug/cell in combination with alginate was more strongly significant compared to the groups treated with drug/cell alone (SMD = 4.55; 95% CI 1.42-7.69; p < 0.0001). Alginate alone or in combination therapy when used as an implant, had a more significant effect than injection. CONCLUSION: These findings suggest that alginate is an efficient scaffold for functional recovery and even a much better scaffold for drug/cell delivery after SCI.

Distribution of gold nanoparticles into the brain: a systematic review and meta-analysis.

Despite the widespread use of gold nanoparticles (GNPs), there is no consensus on their distribution to different tissues and organs. The present systematic review and meta-analysis addresses the accumulation of GNPs in brain tissue. Extensive searches were conducted in electronic databases, Medline, Web of Science, EMBASE, and Scopus. Based on inclusion and exclusion criteria, primary and secondary screening was performed. The value of brain accumulation of gold nanoparticle (the percentage of the injection dose of GNPs/gram of brain tissue that applied as effect size (ES) in analysis) and the standard error of the mean were extracted from articles and analyzed by calculating the pooled ES and the pooled confidence interval (CI) using STATA software. p ≤ 0.05 was considered significant. Thirty-eight studies were included in the meta-analysis. The results showed that the amount of GNPs was 0.06% of the injection dose/gram of brain tissue (ES = 0.06, %95 CI: 0.06-0.06, p < 0.0001). Considering the time between injection and tissue harvest (follow-up time), after 1 h the GNPs in brain tissue was 0.288% of the injection dose/gram of tissue (ES = 0.29, 95% CI: 0.25-0.33, p < 0.0001), while after four weeks it was only 0.02% (ES = 0.02, 95% CI: 0.01-0.03, p < 0.0001) of the injection dose/gram of tissue. The amount of GNPs in brain tissue was higher for PEG-coated GNPs compared to uncoated GNPs, and it was 5.6 times higher for rod-shaped GNPs compared to spherical GNPs. The mean amount of GNPs in the brain tissues of animals bearing a tumor was 5.8 times higher than in normal animals.

Zoledronic acid-loaded lipidic nanoparticles enhance apoptosis and attenuate invasiveness by inhibiting epithelial to mesenchymal transition (EMT) in HepG2 cancer cells.

The aim of this study was to evaluate the potential of zoledronic acid (ZOL)-loaded lipidic nanoparticles (ZOL-NLCs) in enhancing the efficiency of paclitaxel (Pac) in the context of cytotoxicity, apoptosis, and invasiveness of HepG2 hepatocellular carcinoma cells. ZOL-NLCs were characterized in terms of zeta potential, particle size, and scanning electron microscope (SEM) as well as cell internalization. To measure the anti-proliferative effects of ZOL-NLCs, annexin-V/PI and MTT assays were employed. Real-time PCR and western blot analysis were performed to identify the molecular mechanisms underlying the apoptosis in response to the studied conditions. Furthermore, the transwell migration assay was applied to clarify the role of applied formulations on the invasiveness of HepG2 cells. Our results demonstrated that the optimized ZOL had an average particle size of 105 ± 6 nm with a nearly narrow size distribution. The IC50 values for ZOL and ZOL-NLCs were 90 ± 3.1 and 54.6 ± 2.4 µM, respectively. The population of apoptotic cells was increased from 17 ± 2% to 27 ± 4% (p < 0.05) in response to treatment with ZOL-NLCs. ZOL-loaded nanoparticles triggered the mRNA expression of Bax as pro-apoptotic marker and E-cadherin as epithelial one along with a decrease in mesenchymal marker, N-cadherin, and Bcl-xl as an anti-apoptotic marker in HepG2 cells. These outcomes were consistent with western blot analysis of protein expressions. Besides, ZOL-incorporated lipidic nanoparticles reduced the migration of HepG2 cells significantly. Our data suggest that the formulation of ZOL into lipidic nanoparticles can be considered a potential therapeutic approach that can enhance the efficacy of Pac chemotherapy.

Up-down regulation of HIF-1α in cancer progression.

Hypoxia induicible factor-1 alpha (HIF-1α) is a key transcription factor in cancer progression and target therapy in cancer. HIF-1α acts differently depending on presence or absence of Oxygen. In an oxygen-immersed environment, HIF-1α completely deactivated and destroyed by the ubiquitin proteasome pathway (UPP). In contrast, in the oxygen-free environment, it escapes destruction and enters to the nucleus of cells then upregulates many genes involved in cancer progression. Overexpressed HIF-1α and downstream genes support cancer progression through various mechanisms including angiogenesis, proliferation and survival of cells, metabolism reprogramming, invasion and metastasis, cancer stem cell maintenance, induction of genetic instability, and treatment resistance. HIF-1α can be provoked by signaling pathways unrelated to hypoxia during cancer progression. Therefore, cancer development and progression can be modulated by targeting HIF-1α and its downstream signaling molecules. In this regard, HIF-1α inhibitors which are categorized into the agents that regulate HIF-1α in gene, mRNA and protein levels used as an efficient way in cancer treatment. Also, HIF-1α expression can be negatively affected by the agents suppressing the activation of mTOR, PI3k/Akt and MAPK pathways.

Necroptosis and RhoA/ROCK pathways: molecular targets of Nesfatin-1 in cardioprotection against myocardial ischemia/reperfusion injury in a rat model.

Nesfatin-1 as a new energy-regulating peptide has been known to display a pivotal role in modulation of cardiovascular functions and protection against ischemia/reperfusion injury. However, the detailed knowledge about molecular mechanisms underlying this protection has not been completely investigated yet. This study was designed to clarify the molecular mechanisms by which nesfatin-1 exert cardioprotection effects against myocardial ischemia-reperfusion (MI/R). Left anterior descending coronary artery (LAD) was ligated for 30 min to create a MI/R model in rats. MI/R rats were treated with three concentrations of nesfatin-1 (10, 15 and 20 µg/kg) then expression of necroptosis and necrosis mediators were measured by western blotting assay. Fibrosis, morphological damages, cardiac function, myocardial injury indictors and oxidative stress factors were evaluated as well. Induction of MI/R model resulted in cardiac dysfunction, oxidative stress, increased activity of RIPK1-RIPK3-MLKL axis and RhoA/ROCK pathway, extension of fibrosis and heart tissue damage. Highest tested concentration of nesfatin-1 markedly improved cardiac function. Moreover, it reduced oxidative stress, collagen deposition, and morphological damages, through inhibiting the expression of necroptosis mediators and also, necrosis including RIPK1, RIPK3, MLKL, ROCK1, and ROCK2 proteins. The lowest and middle tested concentrations of nesfatin-1 failed to exert protective effects against MI/R. These findings have shown that nesfatin-1 can exert cardioprotection against MI/R in a dose dependent manner by suppressing necroptosis via modulation of RIPK1-RIPK3-MLKL axis and RhoA/ROCK/RIP3 signaling pathway.

Sensitization of A-549 lung cancer cells to Cisplatin by Quinacrine-loaded lipidic nanoparticles via suppressing Nrf2 mediated defense mechanism.

Nuclear factor erythroid 2-related factor 2 (Nrf2) is believed to be responsible for the control mechanisms of cellular defense response and master regulator of antioxidant system by adjustment of endogenous antioxidants, phase II detoxifying enzymes and transporters, so inhibition of Nrf2 could be considered molecule target to overcome drug resistance and cancer progression. By harnessing liposome as an advanced nanoparticles transporter, we formulated Quinacrine known as nrf2 inhibitor into nano-carrier, and sensitized A-549 lung tumor cells to Cisplatin. The aim of this work was to prepare liposome nano-carriers to enhance the bioavailability of Quinacrine and to improve passive targeting in A549 cells. Quinacrine formulation into liposome exposed a mean particle size of 80±5 nm in passive targeting and 110±3 after decoration with chitosan oligosaccharides (COS), respectively. The highest amount of cell death (p<0.05) occurred with the co-incubation of the A549 cells with new formulation and Cisplatin. Additionally, Quinacrine-loaded liposomes declined Nrf2 expression more than Quinacrine alone (p<0.05). Correspondingly, the expression of Nrf2 downstream genes, MRP1, Trx, and bcl2 decreased significantly. Taking all the data into consideration, liposomes containing Quinacrine could ameliorate the effectiveness of Cisplatin by raising the permeability of cancer cells to the abovementioned chemical treatment and might be then given as a candidate to boost the therapeutic protocols in cancer patients.