Therapeutic administration of Luteolin protects against Escherichia coli-derived Lipopolysaccharide-triggered inflammatory response and oxidative injury.

Endometritis reduces reproductive effectiveness and leads to significant financial losses in the dairy sector. Luteolin is a natural phyto-flavonoid compound with many biological activities. However, the therapeutic effect of Luteolin against lipopolysaccharides (LPS)-induced endometritis has not yet been explored. A total of eighty female Kunming mice were randomly assigned into four treatment groups (n = 20). Following a successful initiation of the endometritis model by LPS, Luteolin was intraperitoneally administered three times, at six-hour intervals between each injection in the Luteolin groups. The histopathological findings revealed that Luteolin significantly alleviated uterine injury induced by LPS. Moreover, Luteolin suppressed the synthesis of pro-inflammatory mediators [interleukin (IL)-1ß, IL-6, and tumor necrosis factor (TNF)-α] while promoting the synthesis of an anti-inflammatory mediator (IL-10) altered by LPS. Furthermore, Luteolin significantly mitigated the LPS-induced oxidative stress by scavenging malondialdehyde (MDA) and reactive oxygen species (ROS), accumulation and boosting the capacity of antioxidant enzyme activities such as superoxide dismutase 1 (SOD1), catalase (CAT), and glutathione peroxidase 1 (Gpx1) in the uterine tissue of mice. Additionally, injection of Luteolin markedly increased the expression of Toll-like receptors (TLR) 4 both at mRNA and protein levels under LPS stimulation. Western blotting and ELISA findings demonstrated that Luteolin suppressed the activation of the NF-κB pathway in response to LPS exposure in the uterine tissue of mice. Notably, Luteolin enhanced the anti-oxidant defense system by activating the Nrf2 signaling pathway under LPS exposure in the uterine tissue of mice. Conclusively, our findings demonstrated that Luteolin effectively alleviated LPS-induced endometritis via modulation of TLR4-associated Nrf2 and NF-κB signaling pathways.

Up-regulation of inflammatory, oxidative stress, and apoptotic mediators via inflammatory, oxidative stress, and apoptosis-associated pathways in bovine endometritis.

Endometritis is the inflammation of the endothelial lining of the uterine lumen and is multifactorial in etiology. Escherichia (E.) coli is a Gram-negative bacteria, generally considered as a primary causative agent for bovine endometritis. Bovine endometritis is characterized by the activation of Toll-like receptors (TLRs) by E. coli, which in turn triggers inflammation, oxidative stress, and apoptosis. The objective of this study was to investigate the gene expression of inflammatory, oxidative stress, and apoptotic markers related to endometritis in the uteri of cows. Twenty uterine tissues were collected from the abattoir. Histologically, congestion, edema, hyperemia, and hemorrhagic lesions with massive infiltration of neutrophil and cell necrosis were detected markedly (P < 0.05) in infected uterine samples. Additionally, we identify E. coli using the ybbW gene (177 base pairs; E. coli-specific gene) from infected uterine samples. Moreover, qPCR and western blot results indicated that TLR2, TLR4, proinflammatory mediators, and apoptosis-mediated genes upregulated except Bcl-2, which is antiapoptotic, and there were downregulations of oxidative stress-related genes in the infected uterine tissue. The results of our study suggested that different gene expression regimes related to the immune system reflex were activated in infected uteri. This research gives a novel understanding of active immunological response in bovine endometritis.

Biochemical properties of sheep colostrum and its potential benefits for lamb survival: a review.

Colostrum is the initial secretion of the mammary glands following parturition, which offers main food, protection, and biological active substances for the new born. The most threatening episode of neonate's life is the initial two weeks after birth. This period is associated with high neonatal mortality and morbidity. These worthwhile losses lead to a poor prolificacy rate, low profitability, and ultimately poor performance in animal production. Hence, both diseases and mortality cause valuable losses in terms of production and economic losses. The survival of neonate is correlated with their immune status and passive immune transfer (PIT). Colostrum provides the primary source of nutrition and immunity (PIT) that protects neonates against infections. It must be given as soon as possible after birth since its immunoglobulins are absorbed within the first 16-27 hours after birth, ideally within 2-4 hours. As a result, immunoglobulin (PIT) is the most important component of distressing infectious immunity, and a passable concentration of immunoglobulin in the blood of newborn lambs is linked to their health and survival rate. In this review, we summarized the importance of colostrum in early life and its association with neonatal lamb's survival, profitability and productivity of sheep farming.

Melting heat transfer analysis in magnetized bioconvection flow of sutterby nanoliquid conveying gyrotactic microorganisms.

In biotechnology and biosensors bioconvection along with microorganisms play a important role. This article communicates a theoretic numerical analysis concerning the bioconvective Sutterby nanofluid flow over a stretchable wedge surface. Bioconvection is a remarkable occurrence of undercurrents fluid that is produced owing to the turning of microbes. It is considered for hydrodynamics unsteadiness and forms classified in interruption of inclined swimming microbes. Bioconvection is perceived practically in many uses for example pharmaceutical products, bio sensing applications, biomedical, bio-micro systems, biotechnology advancements and refining of mathematical models. Additionally, unsteady parameter influences are taken into account. Furthermore, no mass flux as well as heat sink/source consequences are measured in existing analysis. The similarity transformation are established for the non-linear PDEs of microorganism's field, nanofluid concentration, energy, momentum and mass for bioconvection flow of Sutterby nanofluid. Then, altered non-linear ODEs are resolved by utilizing the bvp4c technique. Moreover, nanofluids are declining in thermal and concentration fields and the greater number of Peclet number declines the field of microorganisms. Acquired numerical data displays that temperature field of nanofluid increases for more thermophoretic and unsteady parameters.

Innovation modeling and simulation of thermal convective on cross nanofluid flow over exponentially stretchable surface.

This work reported to investigate convective flow of non-Newtonian fluid effect on an exponentially stretchable surface. Effect of nanoparticle is considered in heat and mass equation. The transformation technique utilized on dimensionless equations is converted to non-dimensionless equations are solved thought numerical approach Bvp4c. Influence of approatiate analysis of velocities, heat and mass transport are scrutinized through figures. Furthermore, the comparative analysis of drag forces, Nusselt number and Sherwood number are evaluated over and done with tabulated values. It is give details that the temperature field strengthens with intensification in thermophoresis and random diffusions. Similarly, rises in thermophoresis effect parameter both temperature and concentration profile increasing.

Ameliorative Effects of Luteolin and Activated Charcoal on Growth Performance, Immunity Function, and Antioxidant Capacity in Broiler Chickens Exposed to Deoxynivalenol.

Deoxynivalenol (DON, Vomitoxin) is a threatening mycotoxin that mainly produces oxidative stress and leads to hepatotoxicity in poultry. Antioxidant dietary supplements dramatically boost immunity, safeguarding animals from DON poisoning. Luteolin (LUT) is an active plant-derived compound that poses influential antioxidants. This study explored the effectiveness of LUT in combination with activated charcoal (AC) in detoxifying DON in broilers. The 180 one-day broiler chickens were allocated into five different groups having six replicates in each group, provided with ad libitum feed during the trial period (28 days) as follows: in the control group, basal diet (feed with no supplementation of LUT, AC or DON); in group 2, a basal diet added with 10 mg/kg DON from contaminated culture (DON); in group 3, a basal diet augmented by 350 mg/kg LUT and DON 10 mg/kg (DON + LUT); in group 4, a basal diet supplemented by DON 10 mg/kg + AC 200 mg/kg (DON + AC); and in group 5, a basal diet supplemented by 10 mg/kg DON + 350 mg/kg LUT + 200 mg/kg AC (DON + LUT + AC). Concerning the control group, the DON-treated broilers demonstrated a significant decrease in growth performance (p < 0.05) and serum immunoglobulin (p < 0.05) contents, negatively changing the serum biochemical contents and enzymatic activities and an increase in histopathological liver lesions. Furthermore, DON substantially increased (p < 0.05) malondialdehyde (MDA) concentration and decreased total superoxide dismutase (T-SOD), catalase (CAT), and glutathione peroxidase (GSH-Px) levels in the serum and liver. The intake of AC and LUT to the DON-contaminated diet decreased DON residue in the liver and potentially reduced the adverse effects of DON. Considering the results, supplementation of LUT with mycotoxin adsorbent has protective effects against mycotoxicosis caused by DON. It could be helpful for the development of novel treatments to combat liver diseases in poultry birds. Our findings may provide important information for applying LUT and AC in poultry production.

Comparative Antihyperglycemic and Antihyperlipidemic Effects of Lawsone Methyl Ether and Lawsone in Nicotinamide-Streptozotocin-Induced Diabetic Rats.

Our previous study uncovered potent inhibitory effects of two naphthoquinones from Impatiens balsamina, namely lawsone methyl ether (2-methoxy-1,4-naphthoquinone, LME) and lawsone (2-hydroxy-1,4-naphthoquinone), against α-glucosidase. This gave us the insight to compare the hypoglycemic and hypolipidemic effects of LME and lawsone in high-fat/high-fructose-diet- and nicotinamide-streptozotocin-induced diabetic rats for 28 days. LME and lawsone at the doses of 15, 30, and 45 mg/kg, respectively, produced a substantial and dose-dependent reduction in the levels of fasting blood glucose (FBG), HbA1c, and food/water intake while boosting the insulin levels and body weights of diabetic rats. Additionally, the levels of total cholesterol (TC), triglycerides (TGs), high-density lipoproteins (HDLs), low-density lipoproteins (LDLs), aspartate transaminase (AST), alanine transaminase (ALT), creatinine, and blood urea nitrogen (BUN) in diabetic rats were significantly normalized by LME and lawsone, without affecting the normal rats. LME at a dose of 45 mg/kg exhibited the most potent antihyperglycemic and antihyperlipidemic effects, which were significantly comparable to glibenclamide but higher than those of lawsone. Furthermore, the toxicity evaluation indicated that both naphthoquinones were entirely safe for use in rodent models at doses ≤ 50 mg/kg. Therefore, the remarkable antihyperglycemic and antihyperlipidemic potentials of LME make it a promising option for future drug development.

Flurbiprofen inhibits heme induced NLRP3 inflammasome in Berkeley sickle cell disease mice.

Sickle cell disease (SCD) is accompanied by several complications, which emanate from the sickling of erythrocytes due to a point mutation in the ß-globin chain of hemoglobin. Sickled erythrocytes are unable to move smoothly through small blood capillaries and therefore, cause vaso occlusion and severe pain. Apart from pain, continuous lysis of fragile sickled erythrocytes leads to the release of heme, which is a strong activator of the NLRP3 inflammasome, thus producing chronic inflammation in sickle cell disease. In this study, we identified flurbiprofen among other COX-2 inhibitors to be a potent inhibitor of heme-induced NLRP3 inflammasome. We found that apart from being a nociceptive agent, flurbiprofen exerts a strong anti-inflammatory effect by suppressing NF-κB signaling, which was evidenced by reduced levels of TNF-α and IL-6 in wild-type and sickle cell disease Berkeley mice models. Our data further demonstrated the protective effect of flurbiprofen on liver, lungs, and spleen in Berkeley mice. The current sickle cell disease pain management regime relies mainly on opiate drugs, which is accompanied by several side effects without modifying the sickle cell disease-related pathology. Considering the potent role of flurbiprofen in inhibiting NLRP3 inflammasome and other inflammatory cytokines in sickle cell disease, our data suggests that it can be explored further for better sickle cell disease pain management along with the possibility of disease modification.

Colorectal Cancer (CRC): Investigating the Expression of the Suppressor of Fused (SuFu) Gene and Its Relationship with Several Inflammatory Blood-Based Biomarkers.

BACKGROUND: Suppressor of fused (SuFu) is a tumor-suppressor gene that regulates hedgehog signaling. Its involvement in some malignancies is broadly accepted. However, its association with colorectal cancer (CRC) pathogenesis is not clear. Likewise, no study has clearly associated blood-based inflammatory biomarkers with cancer diagnosis/prognosis as yet. AIM: Our goal was to look at SuFu expression levels in CRC patients and its relationship with other clinicopathological factors. Additionally, we looked into the function of a few blood-based biomarkers in CRC and whether or not a combined strategy at the genetic and clinical levels can be applied in CRC. METHODS: The investigation included 98 histopathologically confirmed CRC samples and adjacent normal tissues (controls). A colonoscopy was followed by a targeted biopsy for each suspected colon cancer patient. A CT scan and MRI were also performed on every patient with rectal cancer. Real-time polymerase chain reaction and immunohistochemistry (IHC) were used for assessment. A Beckman Coulter DxH900 was used to examine blood parameters. A Beckman Coulter DxI800 was used to identify pretreatment carcinoma embryonic antigens (CEA) and carbohydrate antigens (CA 19-9) in CRC patients. RESULTS: The expression of SuFu was associated with gender, education, passive smoking, tumor grade, perineural invasion (PNI), lymph node metastasis (LNM), node status, stage, vital status, and recurrence (p < 0.05). In the combined analysis, the areas under the curve produced by the platelet-to-lymphocyte ratio (PLR), neutrophil-to-lymphocyte ratio (NLR), and red cell distribution width (RDW) were the greatest (AUCRDW+PLR+NLR = 0.91, 95% CI: 0.86-0.93, p < 0.05). Furthermore, the most severe pathological features were linked to RDW, PLR, NLR, and HPR. SuFu expression, node status, LNM, PNI, and stage all had significant correlations with OS and DFS rates in IHC-based univariate survival analysis (p < 0.05). According to the Cox regression, CA-19.9 had a strong independent predictive link with 3-year DFS (p < 0.05). CONCLUSION: In CRC, SuFu was downregulated both transcriptionally and translationally, was primarily nucleo-cytoplasmic, and was expressed less in high-grade tumors. In addition, SuFu was linked to a poor overall and disease-free survival rate. It may be possible to use SuFu as a therapeutic target for CRC in the future. However, SuFu expression had no effect on RDW, PLR, NLR, or HPR serum levels.

A p53-TLR3 axis ameliorates pulmonary hypertension by inducing BMPR2 via IRF3.

Pulmonary arterial hypertension (PAH) features pathogenic and abnormal endothelial cells (ECs), and one potential origin is clonal selection. We studied the role of p53 and toll-like receptor 3 (TLR3) in clonal expansion and pulmonary hypertension (PH) via regulation of bone morphogenetic protein (BMPR2) signaling. ECs of PAH patients had reduced p53 expression. EC-specific p53 knockout exaggerated PH, and clonal expansion reduced p53 and TLR3 expression in rat lung CD117+ ECs. Reduced p53 degradation (Nutlin 3a) abolished clonal EC expansion, induced TLR3 and BMPR2, and ameliorated PH. Polyinosinic/polycytidylic acid [Poly(I:C)] increased BMPR2 signaling in ECs via enhanced binding of interferon regulatory factor-3 (IRF3) to the BMPR2 promoter and reduced PH in p53-/- mice but not in mice with impaired TLR3 downstream signaling. Our data show that a p53/TLR3/IRF3 axis regulates BMPR2 expression and signaling in ECs. This link can be exploited for therapy of PH.

Combinatorial Effect of Arsenic and Herbal Compounds in Telomerase-Mediated Apoptosis Induction in Liver Cancer.

Tumour illness and its resistance against existing anticancer therapies pose a serious health concern globally despite the progressive advancement of therapeutic options. The prevailing treatment of HCC using numerous antitumor agents has inflated long-lived complete remissions, but a percentage of individuals still die due to disease recurrence, indicating a need for further exploration of possible anti-tumour regimes. We aim to boost the effectiveness of the HCC treatment by conducting current investigations evaluating the effect of arsenic trioxide (ATO) with different herbal compounds like quercetin and aloe-emodin against liver tumour via inhibition of telomerase, a pro-cancer enzyme. The anticancer activity of ATO with herbal compounds was investigated in human control liver cell line (Wrl-68) and cancer liver cell line (HepG2) at different time intervals. Viability and cytotoxicity in response to combinatorial drugs were assessed in vitro by trypan blue dye exclusion assay and MTT and WST assay. Apoptosis was analysed by annexin V/PI assay, and the expression of telomerase and apoptosis-regulating proteins was evaluated by immunoblotting and qRT-PCR. Arsenic trioxide in combination with quercetin and aloe-emodin reduced cell viability in cancerous cells compared to normal cells by inducing apoptosis, downregulating telomerase and Bcl-2 (anti-apoptotic protein) and upregulating the expression of Bax (pro-apoptotic protein). ATO exhibited significant anticancer effects due to the synergistic effects of quercetin and aloe-emodin in liver tumour cells. The current study data collectively suggest that a successful inhibition of cancer growth by the combination of ATO and tested herbal medicines against liver tumour growth is via the inhibition of telomerase activity.

Clinicopathological and Sero-Molecular Detection of Mycoplasma capricolum subsp. capripneumoniae in Goats in Southern Areas of Pakistan.

Contagious caprine pleuropneumonia (CCPP) is a highly fatal infectious disease of goats, caused by Mycoplasma capricolum subsp. capripneumoniae (Mccp). This disease is causing huge economic losses to the goat industry in Pakistan. However, little is known about the epidemiology of CCPP, especially in the hard areas of Khyber Pakhtunkhwa (KP), Pakistan, despite having a huge population of goats. Therefore, this study aimed to elucidate sero-molecular epidemiology and pathology associated with Mccp infection in goats in southern areas of KP including Dera Ismail Khan (DI Khan), Bannu, Karak, and Kohat. A total of 200 (50 from each area) serum samples were collected from clinically infected goats, whereas 600 various samples (nasal swab n = 50, pleural fluid n = 50, lungs n = 50 at each selected area of study) were collected from live goats showing respiratory clinical signs and dead/slaughter goats having lesions in the lungs/pleura. A commercial competitive ELISA kit confirmed anti-Mccp antibodies in altogether 17% of serum samples, while area-wise seroprevalence was recorded as follows: Kohat, 28%, Bannu, 18%, DI Khan, 14%, and Karak, 8%. Moreover, a total of 5.5% of samples collected from clinically positive live and dead goats for Mccp were found by species-specific PCR, whereas area-wise molecular prevalence of Mccp was found in 3% samples from Kohat, 7.33%, Bannu, 6%, Khan, 5.33%, and Karak, 3.33%. Of 400 clinically examined goats, 242 (60%) had nasal discharge, 207 (51%) had pyrexia, 50.75% (203) had coughing, 48.25% (193) had pneumonia, 23% (92) had lacrimation, 7.75% (31) had pneumonia with lacrimation, and 10 (2.5%) showed all signs. Of the total 200 dead/slaughtered goats, pleural fluid was found in 36 goats and consolidation and red hepatization were observed in 40 and 42 goats, respectively. The present study found the presence of prevailing Mccp strain in the goat population of the study area. The highest prevalence of Mccp was found in collected samples from Kohat by PCR. The highest seroprevalence of Mccp was found in serum samples collected from Kohat by ELISA.

Optimal control problem arising from COVID-19 transmission model with rapid-test.

The world health organization (WHO) has declared the Coronavirus (COVID-19) a pandemic. In light of this ongoing global issue, different health and safety measure has been recommended by the WHO to ensure the proactive, comprehensive, and coordinated steps to bring back the whole world into a normal situation. This is an infectious disease and can be modeled as a system of non-linear differential equations with reaction rates which consider the rapid-test as the intervention program. Therefore, we have developed the biologically feasible region, i.e., positively invariant for the model and boundedness solution of the system. Our system becomes well-posed mathematically and epidemiologically for sensitive analysis and our analytical result shows an occurrence of a forward bifurcation when the basic reproduction number is equal to unity. Further, the local sensitivities for each model state concerning the model parameters are computed using three different techniques: non-normalizations, half-normalizations, and full normalizations. The numerical approximations have been measured by using System Biology Toolbox (SBedit) with MATLAB, and the model is analyzed graphically. Our result on the sensitivity analysis shows a potential of rapid-test for the eradication program of COVID-19. Therefore, we continue our result by reconstructing our model as an optimal control problem. Our numerical simulation shows a time-dependent rapid test intervention succeeded in suppressing the spread of COVID-19 effectively with a low cost of the intervention. Finally, we forecast three COVID-19 incidence data from China, Italy, and Pakistan. Our result suggests that Italy already shows a decreasing trend of cases, while Pakistan is getting closer to the peak of COVID-19.

Tetramethoxystilbene Inhibits NLRP3 Inflammasome Assembly via Blocking the Oligomerization of Apoptosis-Associated Speck-like Protein Containing Caspase Recruitment Domain: In Vitro and In Vivo Evaluation.

Nucleotide-binding domain leucine-rich repeat family pyrin domain containing 3 (NLRP3) inflammasome complex regulates the caspase-1 activity and subsequent processing of interleukin-1ß (IL-1ß). Various inflammatory diseases involve the activation of inflammasome complexes; thus, the intervention in complex formation via small molecules offers a new therapeutic opportunity. The structure-guided design and synthesis of a series of methoxystilbenes and methoxy-2-phenylnaphthalenes identified new inhibitors of NLRP3 inflammasome complex. The tetramethoxystilbene 4o and trimethoxy 2-phenylnaphthalene 1t inhibit the release of a mature form of IL-1ß in J774A.1 cells with IC50 values of 1.39 and 2.07 µM, respectively. Mechanistic investigation revealed that tetramethoxystilbene 4o blocks the oligomerization of apoptosis-associated speck-like protein (ASC), which is the vital step in the formation of NLRP3 inflammasome assembly, thus preventing the activation of caspase-1 and the IL-1ß release. Treatment of LPS+ATP challenged mice with 20 mg/kg of 4o significantly suppressed the levels of IL-1ß. The data presented herein warrant further investigation of methoxystilbenes in disease-specific models of inflammatory diseases.

IIIM-941, a Stilbene Derivative Inhibits NLRP3 Inflammasome Activation by Inducing Autophagy.

Aberrant activation of NLRP3 inflammasome has been implicated in several inflammatory diseases. Autophagy is one of the primary mechanisms that regulate NLRP3 inflammasome activity. In this study, we attempted to target NLRP3 inflammasome activity by a synthetic compound IIIM-941. We found that IIIM-941 inhibits ATP induced NLRP3 inflammasome by induction of autophagy through AMPK pathway in bone marrow derived macrophages (BMDMs) and J774A.1 cells. It was interesting to observe that IIIM-941 did not show any inhibitory activity against LPS induced pro-inflammatory cytokines TNF-α and IL-6. The anti-NLRP3 activity of IIIM-941 was significantly reversed when we attempted to block autophagy by using either pharmacological inhibitor bafilomycin A1or by using siRNA against AMPK. Further, we found that IIIM-941 downregulated the expression of NLRP3 and prevented the oligomerization of ASC to exert its anti-NLRP3 inflammasome effect in J774A.1 cells. We validated inhibitory activity of IIIM-941 against NLRP3 in three different mice models. The anti-inflammatory effect of IIIM-941 was highly significant in ATP induced peritoneal inflammation model. IIIM-941 was similarly effective in suppressing MSU induced IL-1ß in the air pouch model of inflammation without affecting the levels of TNF-α and IL-6. Finally, oral efficacy of IIIM-941 was also proved in MSU indued foot paw edema model of inflammation in mice at 10 and 20 mg/kg (b.w.). The compounds like IIIM-941 can be explored further for the development of therapies against diseases such as Alzheimer's disease and Parkinson's disease, where hampered autophagy and NLRP3 activation play a crucial role in the pathological development.

Safranal inhibits NLRP3 inflammasome activation by preventing ASC oligomerization.

NLRP3 inflammasome is involved in several chronic inflammatory diseases. The inflammatory effect of the NLRP3 inflammasome is executed through IL-1ß and IL-18. Therefore, IL-1ß is one of the primary targets in chronic inflammatory conditions. However, current treatment regimens are dependent on anti- IL-1ß biologicals. The therapies targeting IL-1ß through inhibition of NLRP3 inflammasome are thus being actively explored. We identified safranal, a small molecule responsible for the essence of saffron as a potential inhibitor of the NLRP3 inflammasome. Safranal significantly suppressed the release of IL-1ß from ATP stimulated J774A.1 and bone marrow-derived macrophages (BMDMs) by regulating CASP1 and CASP8 dependent cleavage of pro-IL-1ß. Safranal markedly suppressed the expression of NLRP3 and its ATPase activity. Safranal treatment enhanced the expression of NRF2, whereas, si-RNA mediated silencing of Nrf2 abrogated the anti-NLRP3 effect of safranal. Furthermore, safranal inhibited ASC oligomerization and formation of ASC specks. Safranal also displayed anti-NLRP3 activity in multiple mice models. Treatment of animals with safranal reduced the production of IL-1ß in ATP elicited peritoneal inflammation, MSU induced air pouch inflammation, and MSU injected foot paw edema in mice. Thus, our data projects safranal as a potential preclinical drug candidate against NLRP3 inflammasome triggered chronic inflammation.

Differential Ser phosphorylation of vasodilator-stimulated phosphoprotein regulates colon tumor formation and growth.

AIMS: Vasodilator-stimulated phosphoprotein (VASP) controls actin dynamics associated with the malignant phenotype of colorectal tumors. Oncogenic VASP function, in turn, is finely regulated by cyclic nucleotide-dependent phosphorylation of serine (Ser) residues 157 and 239, whose differential expression determines cell survival behavior in colon cancer. However, the role of differential VASP Ser phosphorylation in colorectal carcinogenesis remains unclear. MAIN METHODS: Specific VASP phosphomutant constructs were employed to selectively silence Ser157 or Ser239 phosphorylation in human colon carcinoma cells. Cyclic nucleotide-dependent manipulation of VASP Ser phosphorylation was performed with 8-bromoadenosine 3',5'-cyclic adenosine monophosphate (8-Br-cAMP) or 8-chlorophenylthio 3',5'-cyclic guanosine monophosphate (8-CPT-cGMP). Tumorigenic and locomotory phenotypes were examined in vitro with clonogenic and wound healing assays, respectively. Finally, tumor formation and growth were investigated in vivo employing two distinct xenograft models of colorectal cancer. KEY FINDINGS: Disruption of VASP Ser157 phosphorylation weakened the clonogenic and migratory abilities of human colon cancer cells, effects mimicked by 8-CPT-cGMP-dependent regulation of VASP Ser239. In contrast, inhibition of VASP Ser239 phosphorylation enhanced cell clonogenicity and migration and was phenocopied by 8-Br-cAMP-dependent regulation of VASP Ser157. Importantly, cancer cells bearing the phosphomutant construct targeting VASP Ser157 decreased, while those with the phosphomutation at Ser239 improved their abilities to establish productive tumor colonies and grow in the peritoneal cavity or subcutaneous tissues of nude mice. SIGNIFICANCE: Together, present observations suggest differential VASP Ser phosphorylation is a relevant, targetable molecular event underlying tumor formation and progression in colon cancer.

Electrophysiological Maturation of Cerebral Organoids Correlates with Dynamic Morphological and Cellular Development.

Cerebral organoids (COs) are rapidly accelerating the rate of translational neuroscience based on their potential to model complex features of the developing human brain. Several studies have examined the electrophysiological and neural network features of COs; however, no study has comprehensively investigated the developmental trajectory of electrophysiological properties in whole-brain COs and correlated these properties with developmentally linked morphological and cellular features. Here, we profiled the neuroelectrical activities of COs over the span of 5 months with a multi-electrode array platform and observed the emergence and maturation of several electrophysiologic properties, including rapid firing rates and network bursting events. To complement these analyses, we characterized the complex molecular and cellular development that gives rise to these mature neuroelectrical properties with immunohistochemical and single-cell transcriptomic analyses. This integrated approach highlights the value of COs as an emerging model system of human brain development and neurological disease.

A quantitative and qualitative analysis of the COVID-19 pandemic model.

Global efforts around the world are focused on to discuss several health care strategies for minimizing the impact of the new coronavirus (COVID-19) on the community. As it is clear that this virus becomes a public health threat and spreading easily among individuals. Mathematical models with computational simulations are effective tools that help global efforts to estimate key transmission parameters and further improvements for controlling this disease. This is an infectious disease and can be modeled as a system of non-linear differential equations with reaction rates. This work reviews and develops some suggested models for the COVID-19 that can address important questions about global health care and suggest important notes. Then, we suggest an updated model that includes a system of differential equations with transmission parameters. Some key computational simulations and sensitivity analysis are investigated. Also, the local sensitivities for each model state concerning the model parameters are computed using three different techniques: non-normalizations, half normalizations, and full normalizations. Results based on the computational simulations show that the model dynamics are significantly changed for different key model parameters. Interestingly, we identify that transition rates between asymptomatic infected with both reported and unreported symptomatic infected individuals are very sensitive parameters concerning model variables in spreading this disease. This helps international efforts to reduce the number of infected individuals from the disease and to prevent the propagation of new coronavirus more widely on the community. Another novelty of this paper is the identification of the critical model parameters, which makes it easy to be used by biologists with less knowledge of mathematical modeling and also facilitates the improvement of the model for future development theoretically and practically.

Discovery of benzo[cd]indol-2-one and benzylidene-thiazolidine-2,4-dione as new classes of NLRP3 inflammasome inhibitors via ER-ß structure based virtual screening.

The structure-guided virtual screening (VS) has proved to be successful strategy in identification of new scaffolds for biological targets. The overactivity of NLRP3 inflammasome has been implicated in variety of inflammatory diseases including Alzheimer's disease. The up-regulation of estrogen-receptor ß (ER-ß) activity has been directly linked with inhibition of NLRP3 inflammasome activity. In the present study, we report discovery of new NLRP3 inflammasome inhibitors via ER-ß crystal structure (PDB: 5TOA) guided virtual screening of 20,000 compound library. For experimental validation, top 10 ligands were selected based on structure novelty, docking score, prime MMGB/SA binding affinity and interaction pattern analysis. Amongst the tested compounds, three thiazolidin-4-ones IIIM-1268, IIIM-1269 and IIIM-1270 and benzo[cd]indol-2-one IIIM-1266 have shown 73, 69, 75 and 77% suppression of IL-1ß release in mouse macrophages (J774A.1 cells) at 10 µM. Benzylidene-thiazolidine-2,4-diones IIIM-1268 and IIIM-1270 inhibited IL-1ß release with IC50 of 2.3 and 3.5 µM and also significantly decreased the protein expression level of mature form of IL-1ß in western-blot analysis. IIIM-1266 and IIIM-1270 displayed bidentate H-bonding with Arg 346 and Glu 305 residues in the active site of ER-ß; and they also strongly occupied the ADP-binding site of NLRP3 protein. The results presented herein, indicate that ER-ß guided VS can be successfully used to identify new NLRP3 inflammasome inhibitors, which may have potential in the development of novel anti-Alzheimer agents.