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Over 50 million people have been infected with the SARS-CoV-2 virus, while around 1 million have died due to COVID-19 disease progression. COVID-19 presents flu-like symptoms that can escalate, in about 7-10 days from onset, into a cytokine storm causing respiratory failure and death. Although social distancing reduces transmissibility, COVID-19 vaccines and therapeutics are essential to regain socioeconomic normalcy. Even if effective and safe vaccines are found, pharmacological interventions are still needed to limit disease severity and mortality. Integrating current knowledge and drug candidates (approved drugs for repositioning among >35 candidates) undergoing clinical studies (>3000 registered in ClinicalTrials.gov), we employed Systems Pharmacology approaches to project how antivirals and immunoregulatory agents could be optimally evaluated for use. Antivirals are likely to be effective only at the early stage of infection, soon after exposure and before hospitalization, while immunomodulatory agents should be effective in the later-stage cytokine storm. As current antiviral candidates are administered in hospitals over 5-7 days, a long-acting combination that targets multiple SARS-CoV-2 lifecycle steps may provide a long-lasting, single-dose treatment in outpatient settings. Long-acting therapeutics may still be needed even when vaccines become available as vaccines are likely to be approved based on a 50% efficacy target.A dermal absorption model for small and macromolecules was previously proposed by Ibrahim et al. read more This model estimated absorption of therapeutics from the dermal tissue based on their molecular size and protein binding through blood and lymphatics. Blood absorption followed a two-pore theory and the lymphatic absorption was limited by the constant lymphatic flow rate. Current work builds on this steady-state concept by modeling the absorption from the dermis immediately after an injection is given (unsteady state). An injection in the dermis creates a localized pressure gradient which resolves itself over time. This phenomenon is captured in the model to estimate the impact of injection volume on the absorption rate constant. Blood absorption follows the two-pore theory but is time-dependent and the lymphatic absorption is determined based on valve opening and pressure driven convective flow, returning to steady-state as the molecule is absorbed. A direct comparison of the steady-state analysis, experimental data and the current model is made. The results indicate that accounting for the localized time-varying pressure can better predict the experimental absorption rate constants. This work significantly improves the existing understanding of macromolecule uptake from the interstitial fluid following intradermal injection.Accurate determination of fraction unbound in plasma is required for the interpretation of pharmacology and toxicology data, in addition to predicting human pharmacokinetics, dose, and drug-drug interaction potential. A trend, largely driven by changing target space and new chemical modalities, has increased the occurrence of compounds beyond the traditional rule of 5 physicochemical property space, meaning many drugs under development have high lipophilicity. This can present challenges for ADME assays, including non-specific binding to labware, low dynamic range and solubility. When determining unbound fraction, low recovery, due to non-specific binding, makes bioanalytical sensitivity limiting and prevents determination of free fraction for highly bound compounds. Here, mitigation of non-specific binding through the addition of 0.01% v/v of the excipient Solutol® to an equilibrium dialysis assay has been explored. Solutol® prevented non-specific binding to the dialysis membrane and showed no significant binding to plasma proteins. A test set of compounds demonstrates that this method gives comparable values of fraction unbound. In conclusion, the use of Solutol® as an additive in equilibrium dialysis formats could provide a method of mitigating non-specific binding, enabling the determination of fraction unbound values for highly lipophilic compounds.Ariá (Goeppertia allouia) is a tuber from the arrowroot's family widely found in the Brazilian Amazon. The tuber has a flavor similar to corn, besides high retrogradation when cooked, differing from other commercial starches. To enhance its added value, the Ariá starch was extracted to evaluate its potential as a food ingredient. The Ariá starch was compared to the commercially available corn and potato starches regarding their physicochemical, thermal, structural, and rheological properties based on the Duncan's test (p-value less then 0.05). The Ariá starch presented high amylose content (~38% w/w). Furthermore, the X-ray diffraction pattern confirmed its Type-C crystalline structure. The rheological properties showed that the starch gels presented high hardness and retrogradation as other studied starches. Ariá has great potential as a source of starch with low digestibility, increasing the satiety of food products.Many dietary polysaccharides have been shown to protect the intestinal barrier integrity against several noxious stimuli. Previously, we have isolated a polysaccharide RAMPtp from Atractylodis macrocephalae Koidz, and analyzed its structure. However, the effects of RAMPtp on intestinal barrier function have not been investigated. Here, we evaluated the protective effects of RAMPtp on Dextran sulfate sodium (DSS)-induced intestinal epithelial cells (IECs) injury. The findings showed that RAMPtp boosted the proliferation and survival of IECs during DSS stimulation. Furthermore, we found that RAMPtp protected the IECs from injury induced by DSS through maintaining the barrier function and inflammation response. Mechanistically, we identified a novel lncRNA ITSN1-OT1, which was induced by RAMPtp during DSS stimulation. link2 It blocked the nuclear import of phosphorylated STAT2 to prevent the DSS induced decreased expression and structural destroy of tight junction proteins. Hence, the study clarified the protective effects and mechanism of polysaccharides RAMPtp on DSS-induced intestinal barrier dysfunction.The increase in minute ventilation during exercise led to higher inhalation of air pollution and, consequently, to exacerbation of health issues. Therefore, the intensity of exercise and the air pollution concentration of the environment could be determinant variables to poor outcomes. This study aimed to investigate the inhaled dose of particulate matter 2.5 (PM2.5) during a moderate- and high-intensity interval exercise session performed in the morning and evening at different locations of Porto Alegre City. Eighteen individuals performed a cardiopulmonary exercise test, a moderate-intensity interval exercise (MIIE), and a high-intensity interval exercise (HIIE). Heart rate was monitored to estimate minute ventilation and total ventilation of the session. The concentration of PM2.5 was measured during the morning (6-8a.m.) and evening (6-8p.m.) by fixed-site monitors placed at five points of Porto Alegre City. The PM2.5 inhalation during MIIE and HIIE performed in the morning and evening in the monitoring points was estimated. HIIE showed higher minute ventilation (VE) (p = 0.0048) and total ventilation did not differ between groups (p = 0.4648). PM2.5 concentrations were higher during the mornings (p less then 0.001). Monitored point 1 had higher levels of PM2.5 in the morning and evening (p less then 0.001). The inhalation of PM2.5 in the morning showed no difference in MIIE (p = 0.8172) and HIIE (p = 0.7306) groups among the points. In the evening, the inhalation of PM2.5 was higher in point 1 in MIIE and HIIE group (p less then 0.001). MIIE and HIIE had higher inhalation of PM2.5 in the morning than in the evening (p less then 0.001). Total ventilation of exercise is a crucial factor that contributes to the inhalation dose of air pollution.The effective long-term cryopreservation of human mesenchymal stem cells is an essential prerequisite step and represents a critical approach for their sustained supply in basic research, regenerative medicine, and tissue engineering applications. Off-the-shelf availability of human umbilical cord-derived mesenchymal stromal cells (UC-MSCs) for regenerative medicine application requires the development of nontoxic, safe, and efficient protocols for cryopreservation. In the long-term low-temperature storage process of cells, traditional manual storage has a great impact on cell activity, recovery, and function due to repeated exposure of cells to room temperature. To minimize the effect of fluctuation in ambient temperature on stored cells, we designed an automatic cryopreservation system that handles cells under controlled temperatures. In this work, UC-MSCs were utilized to investigate and compare the influence of manual and automatic cryopreservation approaches. To simulate the manual process, the UC-MSCs we applications.Sperm cryopreservation is a common procedure to preserve viable sperm for an indefinite period. This procedure has numerous detrimental effects on sperm function due to increased generation of reactive oxygen species (ROS). During cryopreservation, while ROS increases, antioxidant enzymes level decreases. It has been shown that a relationship exist between lower antioxidant levels and infertility. l-Sulforaphane (SFN) is an isothiocyanate in cruciferous vegetables of the brassica class that has potent protective effects against oxidative stress. The purpose of the present study was to evaluate the effects of SFN supplementation during the freeze-thaw process on different parameters of human spermatozoa which can influence sperm fertilizing ability. Samples were collected from 25 healthy men and each sample was divided into three groups fresh, control (untreated frozen/thawed samples) and treatment (treated frozen/thawed with SFN) groups. Sperm parameters, ROS production (using flow cytometry), plasma membrane integrity (using flow cytometry), Lipid peroxidation (using ELISA) were evaluated. Our results demonstrated that 5 μM SFN improved all parameters of sperm including viability (P less then 0.001), motility, and morphology (P less then 0.05) after the freeze-thaw process. Furthermore, SFN reduced the levels of intracellular hydrogen peroxide (P less then 0.01) and superoxide anion (P less then 0.05). Also, SFN significantly increased the percentage of viable sperm cells with the intact plasma membrane (P less then 0.001) and decreased the level of lipid peroxidation after the freeze-thaw process (P less then 0.01).Our findings showed that spermatozoa treatment with 5 μM SFN before the freeze-thaw process has protective effects against oxidative stress and could decrease the detrimental effects of this process on sperm quality.The therapeutic effects of cryotherapy on skin and subcutaneous tumors in dogs were retrospectively studied in 20 dogs with 37 tumor lesions, of which 30 were benign and seven were malignant. Our results showed that during follow-up, 94.5% of lesions were completely exfoliated, without relapse or metastasis (mean time = 245.7 days). To investigate the effects of cryotherapy, we compared histopathological observations and microstructural changes in healthy tissues and tumor tissues, before and after cryotherapy. After cryotherapy, both normal skin and tumor tissue exhibited edema and hyperemia, with inflammatory cell infiltration. link3 The cell nuclei exhibited pyknosis, disintegration and necrosis, and tight junctions were decreased in size. Cell morphology was varied, along with fragmented cell nuclear envelopes, crenulated nuclei and indistinct and necrotic intracellular organelles. Vacuoles were apparent in the cytoplasm and intercellular desmosomes were absent. These observations suggested that cryosurgery inhibited skin and subcutaneous tumors via cold-induced injury to cells, and cellular microenvironment changes induced by apoptosis.