The impact of Hyssop (Hyssopus officinalis) extract on activation of endosomal toll like receptors and their downstream signaling pathways.

OBJECTIVES: From the ancient, medicinal benefits of Hyssop (Hyssopus officinalis L.) have been implicated for respiratory and digestive diseases despite the effects of Hyssop on viral infections have not been mechanistically investigated. In this study, we examined whether the Hyssop extract activated anti-viral innate immunity, as a sentinel for immune system, through activation of endosomal TLRs recognizing nucleic acids and their downstream signaling. The Hyssop herb extracts was prepared and co-cultured with healthy individual's peripheral blood mononuclear cells (PBMCs). After viability assay, gene expression levels of TLR3,7,8,9, as well as MyD88 and NF-κB, were evaluated in treated PBMCs using Real-time PCR. Next, the secretion level of immune related cytokines was quantified via ELISA. RESULTS: Post 24 h, 40 µg/ml of the extract significantly inhibited the viability of less than 50% of cells compared to the control and had a maximum effect on cellular function. The Hyssop-treated PBMCs demonstrated an elevated expression of endosomal TLRs genes, as well as MyD88 and NF-κB. Moreover, the release of INF-α and ß notably enhanced in cell culture supernatant, while the content of inflammatory cytokines remarkably diminished (P < 0.05). The Hyssop extract was capable of inducing antiviral innate immune responses so can be promising in antiviral drug strategies.

Multifunctional Gold Helix Phototheranostic Biohybrid That Enables Targeted Image-Guided Photothermal Therapy in Breast Cancer.

The preparation of multifunctional smart theranostic systems is commonly achieved through complicated strategies, limiting their biomedical applications. Spirulina platensis (SP) microalgae, as a natural helix with some of the intrinsic theranostic functionalities (e.g., fluorescent and photosensitizer pigments), not only facilitates the fabrication process but also guarantees their biosafety for clinical applications. Herein, the helical architecture of gold nanoparticles (AuNPs) based on a SP biotemplate was engineered as a safe, biodegradable, and tumor-targeted biohybrid for imaging-guided photothermal therapy (PTT) to combat triple-negative breast cancer. The quasi-spherical AuNPs were embedded throughout the SP cell (Au-SP) with minimally involved reagents, only by controlling the original morphological stability of SP through pH adjustment of the synthesis media. SP thiolation increased the localization of AuNPs selectively on the cell wall without using a reducing agent (Au-TSP). SP autofluorescence, along with the high X-ray absorption of AuNPs, was employed for dual-modal fluorescence and computed tomography (FL/CT) imaging. Furthermore, the theranostic efficacy of Au-SP was improved through a targeting process with folic acid (Au-SP@CF). High tumor inhibition effects were obtained by the excellent photothermal performance of Au-SP@CF in both in vitro and in vivo analyses. Of particular note, a comparison of the photothermal effect of Au-SP@CF with the naked SP and calcined form of Au-SP@CF not only indicated the key role of the helical architecture of AuNPs in achieving a high photothermal effect but also led to the formation of new gold microspiral biohybrids (Au-MS) over the calcination process. In short, well-controllable immobilization of AuNPs, appropriate biodegradability, good hemocompatibility, long-term biosafety, accurate imaging, high tumor suppression, and low tumor metastasis effects under laser irradiation are an array of intriguing attributes, making the proposed biohybrid a promising theranostic system for FL/CT-imaging-guided PTT.

Biodegradable and biocompatible subcutaneous implants consisted of pH-sensitive mebendazole-loaded/folic acid-targeted chitosan nanoparticles for murine triple-negative breast cancer treatment.

BACKGROUND: Mebendazole (MBZ) is a well-known anti-parasite drug with significant anti-cancer properties. However, MBZ exhibits low solubility, limited absorption efficacy, extensive first-pass effect, and low bioavailability. Therefore, multiple oral administration of high dose MBZ is required daily for achieving the therapeutic serum level which can cause severe side effects and patients' non-compliance. METHOD: In the present study, MBZ-loaded/folic acid-targeted chitosan nanoparticles (CS-FA-MBZ) were synthesized, characterized, and used to form cylindrical subcutaneous implants for 4T1 triple-negative breast tumor (TNBC) treatment in BALB/c mice. The therapeutic efficacy of the CS-FA-MBZ implants was investigated after subcutaneous implantation in comparison with Control, MBZ (40 mg/kg, oral administration, twice a week for 2 weeks), and CS-FA implants, according to 4T1 tumors' growth progression, metastasis, and tumor-bearing mice survival time. Also, their biocompatibility was evaluated by blood biochemical analyzes and histopathological investigation of vital organs. RESULTS: The CS-FA-MBZ implants were completely degraded 15 days after implantation and caused about 73.3%, 49.2%, 57.4% decrease in the mean tumors' volume in comparison with the Control (1050.5 ± 120.7 mm3), MBZ (552.4 ± 76.1 mm3), and CS-FA (658.3 ± 88.1 mm3) groups, respectively. Average liver metastatic colonies' number per microscope field at the CS-FA-MBZ group (2.3 ± 0.7) was significantly (P < 0.05) lower than the Control (9.6 ± 1.7), MBZ (5.0 ± 1.5), and CS-FA (5.2 ± 1) groups. In addition, the CS-FA-MBZ treated mice exhibited about 52.1%, 27.3%, and 17% more survival days after the cancer cells injection in comparison with the Control, MBZ, and CS-FA groups, respectively. Moreover, the CS-FA-MBZ implants were completely biocompatible based on histopathology and blood biochemical analyzes. CONCLUSION: Taking together, CS-FA-MBZ implants were completely biodegradable and biocompatible with high therapeutic efficacy in a murine TNBC model.

The effect of Nigella sativa oil on vascular dysfunction assessed by flow-mediated dilation and vascular-related biomarkers in subject with cardiovascular disease risk factors: A randomized controlled trial.

Cardiovascular diseases (CVD) are the leading causes of mortality worldwide. Flow-mediated dilation (FMD) is a marker of vascular function. Beneficial cardiometabolic effects of Nigella sativa (N. sativa) have been observed. We evaluated the effect of N. sativa oil on FMD, plasma nitrite, and nitrate (NOx) as nitric oxide (NO) metabolites, and inflammatory markers in subjects with CVD risk factors. Fifty participants were randomly assigned to either the N. sativa (two capsules of 500 mg N. sativa oil) or the placebo group (two capsules of 500 mg mineral oil), for 2 months. The brachial FMD, plasma NOx, vascular cellular adhesion molecule-1 (VCAM-1), and intracellular adhesion molecule-1 (ICAM-1) were measured. FMD and plasma NOx levels was significantly increased in the N. sativa group compared to the placebo group (changes: 2.97 ± 2.11% vs. 0.71 ± 3.19%, p < 0.001 for FMD and 4.73 ± 7.25 µmol/L vs. 0.99 ± 5.37 µmol/L, p = 0.036 for plasma NOx). However, there was no significant difference in ICAM-1 and VCAM-1 levels between groups. Therefore, N. sativa oil improves vascular NO and FMD in subjects with cardiovascular risk factors. However, more studies are warranted to confirm the beneficial impacts of the N. sativa oil on vascular inflammation.

Percutaneous posterior tibial nerve stimulation (PTNS) for lower urinary tract symptoms (LUTSs) treatment in patients with multiple sclerosis (MS): A systematic review and meta-analysis.

BACKGROUND: Lower urinary tract symptoms (LUTSs) are common in patients with multiple sclerosis (MS). Percutaneous posterior tibial nerve stimulation (PTNS) is a minimally invasive treatment which is considered to be effective for patients who suffer from LUTS symptoms. In previous studies, the endpoints of treatment reported differently. So, we designed this systematic review and meta-analysis to estimate pooled efficacy of PTNS based on different assessment methods. METHODS: We systematically searched PubMed, Scopus, EMBASE, Web of Science, and google scholar. We also searched the gray literature including references of the included studies, and conference abstracts which were published up to May 2021. The search strategy included the MeSH and text words as (((Tibial Nerves) OR Posterior Tibial Nerve) OR (Posterior Tibial Nerves) OR (Medial Plantar Nerves) OR (Medial Plantar Nerve) OR (tibial Nerve Stimulation) OR (Trans-Cutaneous Tibial Nerve Stimulation) OR (Percutaneous Tibial Nerve Stimulation) OR (Cutaneous Tibial Nerve Stimulation) AND ((Multiple Sclerosis OR Sclerosis, Multiple) OR Sclerosis, Disseminated) OR Disseminated Sclerosis) OR MS (Multiple Sclerosis)) OR Multiple Sclerosis, Acute Fulminating).Two independent researchers independently evaluated the articles. RESULTS: We found 2430 articles by literature search, after deleting duplicates 2027 remained. Eight articles remained for meta-analysis The pooled SMD of post voiding residual (PVR) (post-treatment - pre-treatment) was -0.75 (95%CI:-0.93, -0.56)(I2=0, p = 0.67). The pooled SMD of voiding volume (post-treatment - pre-treatment) was 1.21 (95% CI:0.94-1.49) (I2:0%, p = 0.4). The pooled SMD of nocturia (post-treatment - pre-treatment) was -1.10 (95% CI:-1.33, -0.87) (I2:86.4%, p<0.001). The pooled SMD of leakage per day (post-treatment - pre-treatment) was -0.69 (95% CI:-0.93, -0.45) (I2:84.3%, p<0.001). The pooled frequency of responders was 66%(95% CI:59%-73%)(I2:0). CONCLUSION: The results of this systematic review and meta-analysis show that PTNS in effective in treating LUTS in patients with MS.

Tumor-derived exosomes encapsulating miR-34a promote apoptosis and inhibit migration and tumor progression of colorectal cancer cells under in vitro condition.

BACKGROUND: MicroRNA (miR)-34a, as a master tumor suppressor in colorectal cancer (CRC), could regulate multiple genes participating in tumor proliferation, invasion, immune evasion, and inflammation-induced progression. Exosomes, as novel nano-carriers, were found to be capable of shuttling crucial mediators to various cells. Since the conventional CRC therapeutics currently are a matter of debate, implication of microRNAs in malignancy remedies have been addressed illustrating promising outlooks. OBJECTIVES: In this study, we aimed to investigate the delivery of miR-34a to CRC cell line CT-26 by encapsulating into tumor-derived exosomes (TEXs), in order to evaluate the anti-proliferative and progressive effects of the novel nano-carrier complex under in vitro condition. METHODS: Exosomes were purified from the starved CT-26 cells and then enriched by miR-34a using the calcium chloride (Cacl2) modified solution. Following the detection of miR-34a expression in the enriched TEXs, the viability of CT-26 cells treated by multiplicity concentrations of either TEXs or TEX-miR-34a was examined. Moreover, the apoptosis rate of the cells was evaluated, and the migration of CT-26 cells subjected to both TEX-miR-34a and TEX was also measured. Thereafter, the expressions of miR-34a target genes, as IL-6R, STAT3, PD-L1, and VEGF-A, which play roles in tumor progression, were determined in the treated CT-26 cells. RESULTS: The viability of CT-26 cells was harnessed following the treatment with TEX-miR-34a and the apoptosis levels of the cells were also observed to be enhanced dose-dependently. TEX-miR-34a was able to diminish the migration rate of the TEX-miR-34a treated cells and the expressions of IL-6R, STAT3, PD-L1, and VEGF-A were significantly restricted. Moreover, TEXs alone increased the apoptosis rate of tumor cells and repressed the proliferation and migration of these cells which were boosted by enrichment of TEXs with miR-34a. CONCLUSION: Exosomes isolated from the starved CT-26 cells were found to have a potential to deliver miR-34a into tumor cells properly with high functionality maintenance for miR-34a in case of regulating genes related to tumor progression and TEXs which showed no positive effect favoring cancer cells, presumably act as a favorable adjuvant in the CRC therapy.

Eye-hand re-coordination: A pilot investigation of gaze and reach biofeedback in chronic stroke.

Within the domain of motor performance, eye-hand coordination centers on close relationships between visuo-perceptual, ocular and appendicular motor systems. This coordination is critically dependent on a cycle of feedforward predictions and feedback-based corrective mechanisms. While intrinsic feedback harnesses naturally available movement-dependent sensory channels to modify movement errors, extrinsic feedback may be provided synthetically by a third party for further supplementation. Extrinsic feedback has been robustly explored in hand-focused, motor control studies, such as through computer-based visual displays, highlighting the spatial errors of reaches. Similar attempts have never been tested for spatial errors related to eye movements, despite the potential to alter ocular motor performance. Stroke creates motor planning deficits, resulting in the inability to generate predictions of motor performance. In this study involving visually guided pointing, we use an interactive computer display to provide extrinsic feedback of hand endpoint errors in an initial baseline experiment (pre-) and then feedback of both eye and hand errors in a second experiment (post-) to chronic stroke participants following each reach trial. We tested the hypothesis that extrinsic feedback of eye and hand would improve predictions and therefore feedforward control. We noted this improvement through gains in the spatial and temporal aspects of eye-hand coordination or an improvement in the decoupling noted as incoordination post-stroke in previous studies, returning performance toward healthy, control behavior. More specifically, results show that stroke participants, following the interventional feedback for eye and hand, improved both their accuracy and timing. This was evident through a temporal re-synchronization between eyes and hands, improving correlations between movement timing, as well as reducing the overall time interval (delay) between effectors. These experiments provide a strong indication that an extrinsic feedback intervention at appropriate therapeutic doses may improve eye-hand coordination during stroke rehabilitation.

Magnetic bio-metal-organic framework nanocomposites decorated with folic acid conjugated chitosan as a promising biocompatible targeted theranostic system for cancer treatment.

In this work, a multifunctional magnetic Bio-Metal-Organic Framework (Fe3O4@Bio-MOF) coated with folic acid-chitosan conjugate (FC) was successfully prepared for tumor-targeted delivery of curcumin (CUR) and 5-fluorouracil (5-FU) simultaneously. Bio-MOF nanocomposite based on CUR as organic linker and zinc as metal ion was prepared by hydrothermal method in the presence of amine-functionalized Fe3O4 magnetic nanoparticles (Fe3O4@NH2 MNPs). 5-FU was loaded in the magnetic Bio-MOF and the obtained nanocarrier was then coated with FC network. The prepared nanocomposite (NC) was fully characterized by high resolution-transmission electron microscope (HR-TEM), field emission scanning electron microscopy (FE-SEM), Dynamic light scattering (DLS), X-ray diffraction analysis (XRD), thermogravimetric analysis (TGA), vibrating sample magnetometry (VSM), nuclear magnetic resonance (NMR), and UV-vis analyses. In vitro release study showed controlled release of CUR and 5-FU in acidic pH confirming high selectivity and performance of the carrier in cancerous microenvironments. The selective uptake of 5-FU-loaded Fe3O4@Bio-MOF-FC by folate receptor-positive MDA-MB-231 cells was investigated and verified. The ultimate nanocarrier exhibited no significant toxicity, while drug loaded nanocarrier showed selective and higher toxicity against the cancerous cells than normal cells. SDS PAGE was also utilized to determine the protein pattern attached on the surface of the nanocarriers. In vitro and in vivo MRI studies showed negative signal enhancement in tumor confirming the ability of the nanocarrier to be applied as diagnostic agent. Owing to the selective anticancer release and cellular uptake, acceptable blood compatibility as well as suitable T2 MRI contrast performance, the target nanocarrier could be considered as favorable theranostic in breast cancer.