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A newly diagnosed coronavirus in 2019 (COVID-19) has affected all human activities since its discovery. Flavonoids commonly found in the human diet have attracted a lot of attention due to their remarkable biological activities. This paper provides a comprehensive review of the benefits of flavonoids in COVID-19 disease. Previously-reported effects of flavonoids on five RNA viruses with similar clinical manifestations and/or pharmacological treatments, including influenza, human immunodeficiency virus (HIV), severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), and Ebola, were considered. Flavonoids act via direct antiviral properties, where they inhibit different stages of the virus infective cycle and indirect effects when they modulate host responses to viral infection and subsequent complications. Flavonoids have shown antiviral activity via inhibition of viral protease, RNA polymerase, and mRNA, virus replication, and infectivity. The compounds were also effective for the regulation of interferons, pro-inflammatory cytokines, and sub-cellular inflammatory pathways such as nuclear factor-κB and Jun N-terminal kinases. Baicalin, quercetin and its derivatives, hesperidin, and catechins are the most studied flavonoids in this regard. In conclusion, dietary flavonoids are promising treatment options against COVID-19 infection; however, future investigations are recommended to assess the antiviral properties of these compounds on this disease.

Alzheimer’s disease (AD) is a progressive neuronal/cognitional dysfunction, leading to disability and death. Despite advances in revealing the pathophysiological mechanisms behind AD, no effective treatment has yet been provided. It urges the need for finding novel multi-target agents in combating the complex dysregulated mechanisms in AD. Amongst the dysregulated pathophysiological pathways in AD, oxidative stress seems to play a critical role in the pathogenesis progression of AD, with a dominant role of nuclear factor erythroid 2-related factor 2 (Nrf2)/Kelch-like ECH-associated protein-1 (Keap1)/antioxidant responsive elements (ARE) pathway. In the present study, a comprehensive review was conducted using the existing electronic databases, including PubMed, Medline, Web of Science, and Scopus, as well as related articles in the field. Nrf2/Keap1/ARE has shown to be the upstream orchestrate of oxidative pathways, which also ameliorates various inflammatory and apoptotic pathways. So, developing multi-target agents with higher efficacy and lower side effects could pave the road in the prevention/management of AD. The plant kingdom is now a great source of natural secondary metabolites in targeting Nrf2/Keap1/ARE. Among natural entities, phenolic compounds, alkaloids, terpene/terpenoids, carotenoids, sulfur-compounds, as well as some other miscellaneous plant-derived compounds have shown promising future accordingly. Prevailing evidence has shown that activating Nrf2/ARE and downstream antioxidant enzymes, as well as inhibiting Keap1 could play hopeful roles in overcoming AD. The current review highlights the neuroprotective effects of plant secondary metabolites through targeting Nrf2/Keap1/ARE and downstream interconnected mediators in combating AD.

As major public health concerns associated with a rapidly growing aging population, neurodegenerative diseases (NDDs) and neurological diseases are important causes of disability and mortality. Neurological diseases affect millions of people worldwide. Recent studies have indicated that apoptosis, inflammation, and oxidative stress are the main players of NDDs and have critical roles in neurodegenerative processes. During the aforementioned inflammatory/apoptotic/oxidative stress procedures, the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) pathway plays a crucial role. Considering the functional and structural aspects of the blood–brain barrier, drug delivery to the central nervous system is relatively challenging. Exosomes are nanoscale membrane-bound carriers that can be secreted by cells and carry several cargoes, including proteins, nucleic acids, lipids, and metabolites. Exosomes significantly take part in the intercellular communications due to their specific features including low immunogenicity, flexibility, and great tissue/cell penetration capabilities. Due to their ability to cross the blood–brain barrier, these nano-sized structures have been introduced as proper vehicles for central nervous system drug delivery by multiple studies. In the present systematic review, we highlight the potential therapeutic effects of exosomes in the context of NDDs and neurological diseases by targeting the PI3K/Akt/mTOR signaling pathway.

Saponins are one of the broadest classes of high-molecular-weight natural compounds, consisting mainly of a non-polar moiety with 27 to 30 carbons and a polar moiety containing sugars attached to the sapogenin structure. Saponins are found in more than 100 plant families as well as found in marine organisms. Saponins have several therapeutic effects, including their administration in the treatment of various cancers. These compounds also reveal noteworthy anti-angiogenesis effects as one of the critical strategies for inhibiting cancer growth and metastasis. In this study, a comprehensive review is performed on electronic databases, including PubMed, Scopus, ScienceDirect, and ProQuest. Accordingly, the structural characteristics of triterpenoid/steroid saponins and their anti-cancer effects were highlighted, focusing on their anti-angiogenic effects and related mechanisms. Consequently, the anti-angiogenic effects of saponins, inhibiting the expression of genes related to vascular endothelial growth factor (VEGF) and hypoxia-inducible factor 1-α (HIF-1α) are two main anti-angiogenic mechanisms of triterpenoid and steroidal saponins. The inhibition of inflammatory signaling pathways that stimulate angiogenesis, such as pro-inflammatory cytokines, mitogen-activated protein kinase (MAPKs), and phosphoinositide 3-kinases/protein kinase B (PI3K/Akt), are other anti-angiogenic mechanisms of saponins. Furthermore, the anti-angiogenic and anti-cancer activity of saponins was closely related to the binding site of the sugar moiety, the type and number of their monosaccharide units, as well as the presence of some functional groups in their aglycone structure. Therefore, saponins are suitable candidates for cancer treatment by inhibiting angiogenesis, for which extensive pre-clinical and comprehensive clinical trial studies are recommended.

A growing body of research is dedicated to developing new therapeutic agents for wound healing with fewer adverse effects. One of the proceedings being taken today in wound healing research is to identify promising biological materials that not only heal wounds but also vanish scarring. The effectiveness of nanofibers like polyvinyl alcohol (PVA), in improving wound healing can be related to their unique properties. Desf. subsp. (Zohary) Rech. f. ( ) [Anacardiaceae], also known as \"Baneh\" in traditional Iranian medicine, is one of the most effective herbal remedies for the treatment of different diseases like skin injuries due to its numerous pharmacological and biological properties, including anti-inflammatory, antioxidant, and anti-bacterial effects. Our study aimed to evaluate the wound-healing activity of nanofibers containing PVA/ oleo-gum-resin in two rat models of burn and excision wound repair. PVA/ nanofibers were prepared using the electrospinning method. Scanning electron microscope (SEM) images and mechanical properties of nanofibers were explored. Diffusion and releasing experiments of nanofibers were performed by the UV visible method at different time intervals and up to 72 h. The animal models were induced by excision and burn in Wistar rat's skin and the wound surface area was measured during the experiment for 10 and 21 days, respectively. On the last day, the wound tissue was removed for histological studies, and serum oxidative factors were measured to evaluate the antioxidant properties of the PVA/ . Data analysis was performed using ImageJ, Expert Design, and statistical analysis methods. PVA/ nanofibers were electrospun at different voltages (15, 18, and 20 kV). The most suitable fibers were obtained when the nozzle was positioned 15 cm away from the collector, with a working voltage of 15 kV, and an injection rate of 0.5 mm per hour, using the 30:70 w/v gum. In the SEM images, it was found that the surface tension of the polymer solution decreased by adding the gum and yield thinner and longer fibers at a voltage of 15 kV with an average diameter of 96 ± 24 nm. The mechanical properties of PVA/ nanofibers showed that the presence of gum increased the tensile strength and decreased the tensile strength of the fibers simultaneously. results showed that PVA/ nanofibers led to a significant reduction in wound size and tissue damage (regeneration of the epidermal layer, higher density of dermal collagen fibers, and lower presence of inflammatory cells) compared to the positive (phenytoin and silver sulfadiazine) and negative control (untreated) groups. Wound contraction was higher in rats treated with PVA/ nanofibers. Additionally, antioxidative serum levels of catalase and glutathione were higher in the PVA/ nanofiber groups even in comparison to positive control groups. oleo-gum-resin-loaded electrospun nanofibers potentially improve excision and burn models of skin scars in rats through antioxidative and tissue regeneration mechanisms.

Growing reports are dedicated to providing novel agents for wound healing with fewer adverse effects and higher efficacy. The efficacy of nanofibers composed of polyvinyl alcohol (PVA)/polyethylene oxide (PEO)/chitosan (CS) in promoting wound healing can be attributed to their ability to stimulate collagen production. Among the herbal agents with fewer adverse effects, DC. [Asteraceae] ( ), also called \"Sheng\" in traditional Iranian medicine, is one of the most efficacious plants for treating various skin injuries due to its several pharmacological and biological effects like anti-inflammatory and antioxidant properties. In the present study, our objective was to assess the wound-healing activity of PVA/PEO/CS nanofibers containing in a rat model of excision wound repair. Synthesized nanofibers from PVA, PEO, and CS were done by the electrospinning method and confirmed by scanning electron microscopy (SEM) and Fourier-transform infrared spectroscopy (FT-IR). The release tests of nanofibers were assessed through the UV-visible method at different time intervals, which were conducted for about 60 h. To evaluate the wound healing effects, rats were divided into four distinct groups, including negative control (untreated), phenytoin cream (as positive control), polymer (PVA/PEO/CS), and drug (nanofiber-containing 50% of extract; named PVA/PEO/CS/ ) groups. All treatments were administered topically once daily for 14 days. Wound size changes were investigated in different time intervals. On the 15th day, nitrite and catalase serum levels were measured. Furthermore, samples of skin tissue were extracted and subjected to histopathological analysis. PVA/PEO/CS nanofibers containing 1.2 g of PVA, 0.3 g of PEO, and 0.8 g of CS, along with 50% of extract (PVA/PEO/CS/ ) at 17 kV were selected based on its favorable morphology and uniform quality. PVA/PEO/CS/ represented a notable reduction in wound sizes. Moreover, in histopathological analysis, PVA/PEO/CS/ showed a lower presence of inflammatory cells, higher density of dermis collagen fibers, and better regeneration of the epidemic layer. In addition, PVA/PEO/CS/ elevated plasma antioxidant capacity via increasing catalase while reducing nitrite levels. PVA/PEO/CS/ is a promising wound dressing nanofiber with antioxidant and tissue regeneration potential. These results encourage further studies for the development of nanofibers as promising agents in treating and accelerating the process of excision wound repair.

The tumor microenvironment (TME) plays a pivotal role in cancer development and progression. In this line, revealing the precise mechanisms of the TME and associated signaling pathways of tumor resistance could pave the road for cancer prevention and efficient treatment. The use of nanomedicine could be a step forward in overcoming the barriers in tumor-targeted therapy. Novel delivery systems benefit from enhanced permeability and retention effect, decreasing tumor resistance, reducing tumor hypoxia, and targeting tumor-associated factors, including immune cells, endothelial cells, and fibroblasts. Emerging evidence also indicates the engagement of multiple dysregulated mediators in the TME, such as matrix metalloproteinase, vascular endothelial growth factor, cytokines/chemokines, Wnt/β-catenin, Notch, Hedgehog, and related inflammatory and apoptotic pathways. Hence, investigating novel multitargeted agents using a novel delivery system could be a promising strategy for regulating TME and drug resistance. In recent years, small molecules from natural sources have shown favorable anticancer responses by targeting TME components. Nanoformulations of natural compounds are promising therapeutic agents in simultaneously targeting multiple dysregulated factors and mediators of TME, reducing tumor resistance mechanisms, overcoming interstitial fluid pressure and pericyte coverage, and involvement of basement membrane. The novel nanoformulations employ a vascular normalization strategy, stromal/matrix normalization, and stress alleviation mechanisms to exert higher efficacy and lower side effects. Accordingly, the nanoformulations of anticancer monoclonal antibodies and conventional chemotherapeutic agents also improved their efficacy and lessened the pharmacokinetic limitations. Additionally, the coadministration of nanoformulations of natural compounds along with conventional chemotherapeutic agents, monoclonal antibodies, and nanomedicine-based radiotherapy exhibits encouraging results. This critical review evaluates the current body of knowledge in targeting TME components by nanoformulation-based delivery systems of natural small molecules, monoclonal antibodies, conventional chemotherapeutic agents, and combination therapies in both preclinical and clinical settings. Current challenges, pitfalls, limitations, and future perspectives are also discussed.

The grape seed extract (GSE) and its main active polyphenol, resveratrol (RES), have shown considerable antioxidant activities, besides possessed protective and therapeutic effects against various skin complications. This paper discusses the favorable effects of RES, GSE and their nanoformulations for dermatological approaches, with specific emphasis on clinical interventions. In this manner, electronic databases including PubMed, Science Direct and Google Scholar were searched. Data were collected from 1980 up to February 2019. The search terms included “Vitis vinifera”, “grape”, “resveratrol”, “skin”, “dermatology”, and “nanoformulation”. To increase the skin permeability of GSE and RES, several innovative nanoformulation such as liposomes, niosomes, solid–lipid nanoparticles, nanostructured lipid carriers, and lipid-core nanocapsule has been evaluated. According to our extensive searches, both RES and GSE have beneficial impacts on skin disorders such as chloasma, acne vulgaris, skin aging, as well as wound and facial redness. More clinical studies with nanoformulation approaches are recommended to achieve conclusive outcomes regarding the efficacy of RES and GSE in the management of skin diseases.

Background: Aseptic nonunion of femoral shafts after intramedullary nailing (IMN) can be a challenging condition that may lead to long-term disability and the need for multiple surgical procedures. This study compared the clinical and radiological outcomes between exchange nailing and augmentative plating with bone grafting. Methods: In this multicenter, prospective, single-blind, randomized controlled trial, patients with aseptic nonunion of the femoral shaft after IMN were randomly assigned to receive exchange nailing or augmentative plating. The primary outcomes measured were the time to bone union and union rate 12 months after revision surgery. The secondary outcomes included operative time, blood loss, hospitalization duration, pain level using the visual analog scale (VAS), knee range of motion (ROM), and complication rates. Results: The augmentative plating group had a significantly shorter mean time to union (5.39 ± 1.29 months) compared with the exchange nailing group (7.38 ± 1.97 months; p < 0.001). The union rates at 12 months were 100% in the augmentative plating group and 89.65% in the exchange nail group. Augmentative plating resulted in a shorter operation time (99.46 ± 11.08 min vs. 106.45 ± 12.22 min; p = 0.025) and reduced blood loss (514.79 ± 45.87 mL vs. 547.72 ± 54.35 mL; p = 0.016). Significant pain reduction was observed in the augmentative plating group, with preoperative VAS scores decreasing from 6.04 ± 2.28 to 2.64 ± 1.50, compared with a decrease from 5.66 ± 2.21 to 3.66 ± 2.19 in the exchange nailing group (p = 0.047). Knee ROM improved significantly in the augmentative plating group (p = 0.0176). The complication rate was lower in the augmentative plating group (3.57%) than in the exchange nail group (17.24%). Conclusions: Augmentative plating with autologous bone grafting is superior to exchange nailing for treating aseptic nonunion of femoral shafts. It is associated with faster healing, higher union rates, better clinical and functional outcomes, and fewer complications. We recommend this technique as the preferred treatment option for such complex cases.

The purpose of this study was to undertake a spatial analysis of total organic carbon, electrical conductivity and nitrate, in order to produce a pollution dispersion and prediction map for the investigated area in the province of Isfahan in Iran. The groundwater samples were collected from a zone as a pilot study area of 80 km2, including 25 water wells, based on the criteria of vulnerability assessment projects, that is, about one well per 3 km2, during four seasons in 2008-09. In order to make any inferences about the areas that did not have well data, a statistical relationship between explanatory total organic carbon, electrical conductivity and nitrate variables related to well coordination was developed. The probability of the presence of elevated levels of the three compounds in the groundwater was predicted using the best-fit variogram model. According to spatial analysis, the highest R2=0.789 achieved was related to electrical conductivity and followed the exponential model with 0.266 for NO3- (spherical model) and 0.322 for total organic carbon (exponential model) in the spring 2009. This showed the high confidence level for electrical conductivity dataset and forecasted trends. The results of the spatial analysis demonstrated that the transfer trends of electrical conductivity in the groundwater resources followed the route of groundwater movement in all seasons. However, for nitrate and total organic carbon, a definite trend was not obtained and pollution dispersion depended on many parameters.