Exploring the intricacies of Pasteurella multocida dynamics in high-altitude livestock and its consequences for bovine health: A Personal Exploration of the yak paradox.

Pasturella multocida (P. multocida), a gram-negative bacterium, has long been a focus of interest in animal health because of its capacity to cause different infections, including hemorrhagic septicemia. Yaks, primarily found in high-altitude environments, are among the several livestock animals affected by these bacteria. Yaks are essential to the socioeconomic life of the people who depend on them since they are adapted to the cold and hypoxic conditions of highland environments. Nevertheless, these terrains exhibit a greater incidence of P. multocida despite the severe environmental complications. This predominance has been linked to the possible attenuation of the yak's immunological responses in such circumstances and the evolution of some bacterial strains to favor survival in the respiratory passages of the animals. Moreover, these particular strains threaten other cattle populations that interact with yaks, which might result in unanticipated outbreaks in areas previously thought to be low risk. Considering these findings, designing and executing preventative and control strategies suited explicitly for these distinct biological environments is imperative. Through such strategies, yaks' health will be guaranteed, and a larger bovine population will be safeguarded against unanticipated epidemics. The current review provides thorough insights that were previously dispersed among several investigations. Its distinct method of connecting the ecology of yaks with the dynamics of infection offers substantial background information for further studies and livestock management plans.

Isolation, identification and characteristics of Bibersteinia trehalosi from goat.

A conditionally pathogenic bacterium called Bibersteinia trehalosi inhabits the upper respiratory tract of ruminants and is becoming a significant cause of pneumonia, especially in goats. In this study, we identified a gram-negative bacteria strain isolated from dead goat's lungs, which was named M01. By integrating the outcomes of its morphological and biochemical characterization with the investigation of the 16S rRNA gene sequence analysis, the isolate was identified as B. trehalosi. Based on antibiotic susceptibility tests, the isolate was shown to be resistant to ß-lactams, tetracyclines, and amphenicols. Its genome was discovered to comprise 2115 encoded genes and a circular chromosome measuring 2,345,568 bp using whole genome sequencing. Annotation of the VFBD database revealed that isolate M01 had four virulence genes encoding three virulence factors. The CARD database revealed that its genome has two antibiotic-resistance genes. Based on pathogenicity testing, isolate M01 was highly pathogenic to mice, primarily causing pneumonia, with an LD50 of 1.31 × 107 CFU/ml. Moreover, histopathology showed loss of alveolar structure and infiltration of lung inflammatory cells. Hence, the current study could provide sufficient information for prevention and control strategies for future epidemics of B. trehalosi in goat species.

Modulation of apoptosis and Inflammasome activation in chondrocytes: co-regulatory role of Chlorogenic acid.

BACKGROUND: The B-cell lymphoma 2 (Bcl-2) protein regulates programmed cell death throughout the disease conditions by upholding apoptotic pathways. However, the mechanism by which it's expressed in chondrocytes still needs to be studied in chondrocyte-related disorders. Additionally, exploring the potential therapeutic role of Chlorogenic acid (CGA) in confluence with Bcl-2 modulation is of significant interest. METHODS: In vivo and in vitro studies were performed according to our previous methodologies. The chondrocytes were cultured in specific growth media under standard conditions after expression verification of different microRNAs through high-throughput sequencing and verification of Bcl-2 involvement in tibial growth plates. The effect of Bcl-2 expression was investigated by transfecting chondrocytes with miR-460a, siRNA, and their negative controls alone or in combination with CGA. The RNA was extracted and subjected to a reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Western blot analysis and immunofluorescence assays were performed to visualize the intracellular localization of Bcl-2 and associated proteins related to apoptotic and inflammasome pathways. Moreover, apoptosis through flow cytometry was also performed to understand the modulation of concerning pathways. RESULTS: The suppression of Bcl-2 induced higher apoptosis and mitochondrial dysfunction, leading to IL-1ß maturation and affecting the inflammasome during chondrocyte proliferation. Conversely, overexpression attenuated the activation, as evidenced by reduced caspase activity and IL-1ß maturation. In parallel, CGA successfully reduced siRNA-induced apoptosis by decreasing Cytochrome C (Cyto C) release from the mitochondria to the cytoplasm, which in turn decreased Caspase-3 and Caspase-7 cleavage with Bcl-2-associated X protein (Bax). Furthermore, siBcl-2 transfection and CGA therapy increased chondrocyte proliferation and survival. The CGA also showed a promising approach to maintaining chondrocyte viability by inhibiting siRNA-induced apoptosis. CONCLUSIONS: Targeting Bcl-2-mediated regulation might be a possible treatment for chondrocyte-related conditions. Moreover, these results add knowledge of the complicated processes underlying chondrocyte function and the pathophysiology of related diseases, highlighting the significance of target specific therapies. Video Abstract.

Evaluating the between-day reliability and likelihood of change of a test battery incorporating vastus lateralis muscle thickness, ankle-brachial pressure index, maximal voluntary torque, and six-minute walk test in patients with claudication.

OBJECTIVE: The study aims to evaluate the between-day reliability of a proposed test battery for patients with claudication that can be used for monitoring the effectiveness of exercise interventions and other therapeutic strategies tailored to this patient population. METHODS: Twenty-five men with claudication were recruited. The test battery consisted of the Vastus Lateralis muscle thickness (VL-MT), ankle-brachial pressure index (ABI), unilateral isometric knee extension maximal voluntary torque (MVT) and 6-minute walk test (6MWT). A single investigator conducted the tests for each patient on two separate testing sessions (T1 and T2) 5-7 days apart. RESULTS: Good to excellent reliability was observed for VL-MT (ICC = 0.95, 95% LOA = ±3.10 mm, SEM = 0.81 mm), ABI (ICC = 0.97, 95% LOA = ±0.10, SEM = 0.02), MVT (ICC = 0.97, 95% LOA = ±24.0 N·m, SEM = 6.31 N·m), 6MWT distance (ICC = 0.99, 95% LOA = ±39.6 m, SEM = 11.0 m), 6MWT time to claudication (ICC = 0.99, 95% LOA = ±30.8 s, SEM = 7.8 s), and 6MWT ratings of pain (ICC = 0.87, 95% LOA = ±2.4 CR-10+, SEM = 0.7 CR-10+ ). Analysis derived from reliability data indicates a change of 1.4 mm for VL-MT, 0.14 for ABI, 12 N·m for MVT, 25 m for 6MWT distance, 15 s for 6MWT time to claudication and 1 CR-10+ for 6MWT ratings of pain is required to be interpreted as the minimum 'likely' change (76% chance). CONCLUSIONS: The test battery provides a reliable assessment of patients with claudication and can be widely used to evaluate the effects of exercise programmes and other therapeutic interventions. For the individual, changes in VL-MT, ABI, MVT, and 6MWT greater than the minimum likely change as a result of an exercise programme or an intervention are likely changes and less influenced by error associated with the test.

Leucine improves thiram-induced tibial dyschondroplasia and gut microbiota dysbiosis in broilers.

Thiram, a commonly used agricultural insecticide and fungicide, has been found to cause tibial dyschondroplasia (TD) in broilers, leading to substantial economic losses in the poultry industry. In this study, we aimed to investigate the mechanism of action of leucine in mitigating thiram-induced TD and leucine effects on gut microbial diversity. Broiler chickens were randomly divided into five equal groups: control group (standard diet), thiram-induced group (thiram 80 mg/kg from day 3 to day 7), and different concentrations of leucine groups (0.3%, 0.6%, 0.9% leucine from day 8 to day 18). Performance indicator analysis and tibial parameter analysis showed that leucine positively affected thiram-induced TD broilers. Additionally, mRNA expressions and protein levels of HIF-1α/VEGFA and Ihh/PTHrP genes were determined via quantitative real-time polymerase chain reaction and western blot. The results showed that leucine recovered lameness disorder by downregulating the expression of HIF-1α, VEGFA, and PTHrP while upregulating the expression of Ihh. Moreover, the 16 S rRNA sequencing revealed that the leucine group demonstrated a decrease in the abundance of harmful bacteria compared to the TD group, with an enrichment of beneficial bacteria responsible for producing short-chain fatty acids, including Alistipes, Paludicola, CHKCI002, Lactobacillus, and Erysipelatoclostridium. In summary, the current study suggests that leucine could improve the symptoms of thiram-induced TD and maintain gut microbiota homeostasis.

Characterization, estimation of virulence and drug resistance of diarrheagenic escherichia coli (DEC) isolated from Tibetan pigs.

In this study, we collected feces of Tibetan piglets from Nyingchi area for isolation, culture, identification, virulence gene analysis and drug resistance analysis of Escherichia Coli. The results demonstrated a 41.3% isolation rate of Diarrheagenic Escherichia Coli from Tibetan pigs with the main phylogenetic groups: group A (68.6%) and group B2 (15.7%). Typical E.coli accounted for 76.5%. The highest detection rates of porcine virulence genes were E.coli heat-resistant enterotoxin STb (58.82%) and F107 fimbrial subunit (23.53%). The highest detection rates of virulence genes from Tibetan pigs were fimC (80.39%) and ompA (76.47%). A drug sensitivity test showed that Diarrheagenic Escherichia Coli from Tibetan pigs had high drug resistance rates to mezlocillin, doxycycline and gentamicin. This study comprehensively analyzed the species composition, virulence and drug resistance of Diarrheagenic Escherichia Coli from Tibetan pigs, which provided a clearer and more targeted idea for the prevention and treatment of yellow and white dysentery in Tibetan pigs in the future.

Whether the Golgi protein 73 could be a diagnostic serological marker in hepatocellular carcinoma: a meta analysis.

BACKGROUND: The Value of Golgi protein 73 (GP73) in the diagnosis of Hepatocellular carcinoma (HCC) remains controversial, especially in its differentiation between HCC and cirrhosis. Besides, some papers showed that GP73 levels are correlated with liver fibrosis. This study conducts a meta-analysis to evaluate the value of GP73 in diagnosing HCC and differential diagnosing HCC from liver cirrhosis. METHODS: 36 studies with a sample size of 8314 cases concerning the accuracy of GP73 in the diagnosis of HCC were selected through a systematic review. Seven of these studies included a total of 438 HCC samples and 426 cirrhosis samples and calculated the sensitivity and specificity of GP73 for differential diagnosing HCC from cirrhosis. QUADAS (quality assessment of diagnostic accuracy studies) was used to evaluate the quality of literature. Statistical analyses were performed using StataSE16 software. RESULTS: The pooled sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, diagnostic odds ratio and the area under the curve were 0.79(95%CI 0.74-0.83),0.85(95%CI 0.80-0.89),5.4(95%CI 3.8-7.5), 0.25(95%CI 0.20-0.31), 22(95%CI 13-35), and 0.88 for GP73 diagnosing HCC;0.74(95%CI 0.64-0.81),0.70(95%CI 0.49-0.85),2.40(95%CI 1.3-4.7),0.38(95%CI 0.23-0.61),6(95%CI 2-19), and 0.78 for GP73 differential diagnosing HCC from liver cirrhosis. CONCLUSION: The results suggest that GP73 has a high diagnostic value for HCC and a moderate value for differential diagnosis of HCC from liver cirrhosis.

Low-intensity resistance exercise with blood flow restriction for patients with claudication: A randomized controlled feasibility trial.

BACKGROUND: Claudication is a common and debilitating symptom of peripheral artery disease, resulting in poor exercise performance and quality of life (QoL). Supervised exercise programs are an effective rehabilitation for patients with claudication, but they are poorly adhered to, in part due to the high pain and effort associated with walking, aerobic, and resistance exercise. Low-intensity resistance exercise with blood flow restriction (BFR) represents an alternative exercise method for individuals who are intolerant to high-intensity protocols. The aim of this study was to evaluate the feasibility of a supervised BFR program in patients with claudication. METHODS: Thirty patients with stable claudication completed an 8-week supervised exercise program and were randomized to either BFR (n = 15) or a control of matched exercise without BFR (control; n = 15). Feasibility, safety, and efficacy were assessed. RESULTS: All success criteria of the feasibility trial were met. Exercise adherence was high (BFR = 78.3%, control = 83.8%), loss to follow up was 10%, and there were no adverse events. Clinical improvement in walking was achieved in 86% of patients in the BFR group but in only 46% of patients in the control group. Time to claudication pain during walking increased by 35% for BFR but was unchanged for the control. QoL for the BFR group showed improved mobility, ability to do usual activities, pain, depression, and overall health at follow up. CONCLUSION: A supervised blood flow restriction program is feasible in patients with claudication and has the potential to increase exercise performance, reduce pain, and improve QoL. (Clinicaltrials.gov Identifier: NCT04890275).

Identification and structural characterization of a pathogenic ARSA missense variant in two consanguineous families from Jammu and Kashmir (India) with late infantile metachromatic leukodystrophy.

BACKGROUND: Metachromatic leukodystrophy (MLD) is a rare lysosomal storage disorder caused by a deficiency of Arylsulfatase A (ARSA) enzyme activity. Its clinical manifestations include progressive motor and cognitive decline. ARSA gene mutations are frequent in MLD. METHODS AND RESULTS: In the present study, whole exome sequencing (WES) was employed to decipher the genetic cause of motor and cognitive decline in proband's of two consanguineous families from J&K (India). Clinical investigations using radiological and biochemical analysis revealed MLD-like features. WES confirmed a pathogenic variant in the ARSA gene. Molecular simulation dynamics was applied for structural characterization of the variant. CONCLUSION: We report the identification of a pathogenic missense variant (c.1174 C > T; p.Arg390Trp) in the ARSA gene in two cases of late infantile MLD from consanguineous families in Jammu and Kashmir, India. Our study utilized genetic analysis and molecular dynamics simulations to identify and investigate the structural consequences of this mutation. The molecular dynamics simulations revealed significant alterations in the structural dynamics, residue interactions, and stability of the ARSA protein harbouring the p.Arg390Trp mutation. These findings provide valuable insights into the molecular mechanisms underlying the pathogenicity of this variant in MLD.

Baicalin inhibits apoptosis and enhances chondrocyte proliferation in thiram-induced tibial dyschondroplasia in chickens by regulating Bcl-2/Caspase-9 and Sox-9/Collagen-II expressions.

Avian tibial dyschondroplasia (TD) is a skeletal disease affecting fast growing chickens, resulting in non-mineralized avascular cartilage. This metabolic disorder is characterized by lameness and reduced growth performance causing economic losses. The aim of this study was to investigate the protective effects of baicalin against TD caused by thiram exposure. A total of two hundred and forty (n = 240) one day-old broiler chickens were uniformly and randomly allocated into three different groups (n = 80) viz. control, TD, and baicalin groups. All chickens received standard feed, however, to induce TD, the TD and baicalin groups received thiram (tetramethylthiuram disulfide) at a rate of 50 mg/kg feed from days 4-7. The thiram induction in TD and baicalin groups resulted in lameness, high mortality, and enlarged growth-plate, poor production performance, reduction in ALP, GSH-Px, SOD, and T-AOC levels, and increased AST and ALT, and MDA levels. Furthermore, histopathological results showed less vascularization, and mRNA and protein expression levels of Sox-9, Col-II, and Bcl-2 showed significant downward trend, while caspase-9 displayed significant up-regulation in TD-affected chickens. After the TD induction, the baicalin group was orally administered with baicalin at a rate of 200 mg/kg from days 8-18. Baicalin administration increased the vascularization, and chondrocytes with intact nuclei, alleviated lameness, decreased GP size, increased productive capacity, and restored the liver antioxidant enzymes and serum biochemical levels. Furthermore, baicalin significantly up-regulated the gene and protein expressions of Sox-9, Col-II, and Bcl-2, and significantly down-regulated the expression of caspase-9 (p < 0.05). Therefore, the obtained results suggest that baicalin could be a possible choice in thiram toxicity alleviation by regulating apoptosis and chondrocyte proliferation in thiram-induced tibial dyschondroplasia.

Swertia bimaculata moderated liver damage in mice by regulating intestine microbiota.

Swertia bimaculata (SB) is a medicinal herb in China having an array of therapeutic and biological properties. This study aimed to explore the attenuating effect of SB on carbon tetrachloride (CCl4) induced hepato-toxicity by regulation of gut microbiome in ICR mice. For this purpose, CCl4 was injected intraperitoneally in different mice groups (B, C, D and E) every 4th day for a period of 47 days. Additionally, C, D, and E groups received a daily dose (50 mg/kg, 100 mg/kg, and 200 mg/kg respectively) of Ether extract of SB via gavage for the whole study period. The results of serum biochemistry analysis, ELISA, H&E staining, and sequencing of the gut microbiome, indicated that SB significantly alleviates the CCl4-induced liver damage and hepatocyte degeneration. The serum levels of alanine transaminase, aspartate aminotransferase, malondialdehyde, interleukin 1 beta and tumor necrosis factor-alpha were significantly lower in SB treated groups compared to control while levels of glutathione peroxidase were raised. Also, the sequencing data indicate that supplementation with SB could restore the microbiome and its function in CCl4-induced variations in intestinal microbiome of mice by significantly downregulating the abundances of pathogenic intestinal bacteria species including Bacteroides, Enterococcus, Eubacterium, Bifidobacterium while upregulating the levels of beneficial bacteria like Christensenella in the gut. In conclusion, we revealed that SB depicts a beneficial effect against hepatotoxicity induced by CCl4 in mice through the remission of hepatic inflammation and injury, through regulation of oxidative stress, and by restoring gut microbiota dysbiosis.

The Effect of miR-140-5p with HDAC4 towards Growth and Differentiation Signaling of Chondrocytes in Thiram-Induced Tibial Dyschondroplasia.

There is evidence to suggest that microRNA-140-5p (miR-140), which acts as a suppressor, is often elevated and has a role in various malignancies. Nevertheless, neither the function nor the mechanisms in chondrocytes linked with bone disorders, e.g., tibial dyschondroplasia (TD), have been satisfactorily established. The purpose of this study was to look into the role of microRNA-140-5p (miR-140) and its interaction with HDAC4 in chondrocytes, as well as the implications for tibial dyschondroplasia (TD), with a particular focus on the relationship between low miR-140 expression and poor pathologic characteristics, as well as its physiological effects on chondrocyte growth, differentiation, and chondrodysplasia. In this investigation, we discovered that TD had a reduced expression level of the miR-140. There was a correlation between low miR-140 expression, poor pathologic characteristics, and the short overall survival of chondrocytes. Our findings show an aberrant reduction in miR-140 expression, and HDAC4 overexpression caused disengagement in resting and proliferation zones. This further resulted in uncontrolled cell proliferation, differentiation, and chondrodysplasia. Mechanistically, HDAC4 inhibited the downstream transcription factors MEF2C and Runx2 and interacted with Col-Ⅱ, Col-X, and COMP. However, miR-140 binding to the 3'-UTR of HDAC4 resulted in the growth and differentiation of chondrocytes. Moreover, the expression of HDAC4 through LMK-235 was significantly decreased, and the expression was significantly increased under ITSA-1, referring to a positive feedback circuit of miR-140 and HDAC4 for endochondral bone ossification. Furthermore, as a prospective treatment, the flavonoids of Rhizoma drynariae (TFRD) therapy increased the expression of miR-140. Compared to the TD group, TFRD treatment increased the expression of growth-promoting and chondrocyte differentiation markers, implying that TFRD can promote chondrocyte proliferation and differentiation in the tibial growth plate. Hence, directing this circuit may represent a promising target for chondrocyte-related bone disorders and all associated pathological bone conditions.

Impact of graded levels of coated calcium butyrate on growth performance and serological indices during pre-weaning stage in Holstein calves.

The study aimed to analyze the impact of calcium butyrate supplementation in calf starter on growth performance indices associated with early rumen development to decrease the volume of milk or milk replacer feeding and enhance early starter intake in Holstein calves. For this purpose, twelve Holstein calves were randomly assigned into three treatments (n = 4/treatment); a control without coated calcium butyrate, T1, and T2 treatments supplemented with coated calcium butyrate 3 g and 6 g per day/head, respectively. Body weight was measured at days 7, 14, 21, 28, 35, 42, 49, and 56 of the trial, and the average daily weight gain and feed conversion ratio were determined. Blood samples were collected at 14, 28, 42, and 56 days of trial for serological parameters. Gut morphometry was performed at the end of trial at slaughtering by collecting duodenal samples. Furthermore, the meat was also evaluated for its quality parameters including pH and tenderness after slaughtering. The results indicated that the feed intake, average daily weight gain, feed conversion ratio, and gut morphometric parameters involving villus height and crypts depth of calves were improved in coated calcium butyrate-supplemented groups. Furthermore, the supplementation of calf starter with coated calcium butyrate significantly enhanced serum concentrations of glucose and total protein. Besides, Beta hydroxy butyrate (BHBA) levels of blood were also found to be elevated in both treatment groups. However, it was revealed that coated calcium butyrate supplementation had no significant effect on meat quality parameters. In conclusion, the supplementation of calf starter with coated calcium butyrate could improve calf performance.

Socioeconomic disparities in abdominal aortic aneurysm repair rates and survival.

BACKGROUND: Abdominal aortic aneurysm (AAA) is more prevalent in socioeconomically disadvantaged areas. This study investigated socioeconomic disparities in AAA repair rates and survival. METHODS: The study used ecological and cohort study designs, from 31 672 census areas in England (April 2006 to March 2018), the Index of Multiple Deprivation 2010 as the area-level deprivation indicator, and Poisson, logistic and Cox regression. RESULTS: Some 77 606 patients (83.4 per cent men) in four age categories (55-64, 65-74, 75-84, 85 or more years) were admitted with AAA from a population aged at least 55 years of 14.7 million. Elective open and endovascular repair rates were 41 (95 per cent c.i. 23 to 61) and 60 (36 to 89) per cent higher respectively among men aged 55-64 years in the most versus least deprived areas by quintile. This differences diminished and appeared to reverse with increasing age, with 26 (-1 to 45) and 25 (13 to 35) per cent lower rates respectively in men aged 85 years or more in the most deprived areas. Men admitted from more deprived areas were more likely to die in hospital without aneurysm repair. Among those who had aneurysm repair, this was more likely to be for a ruptured aneurysm than among men from less deprived areas. For intact aneurysm repair, they were relatively more likely to have this during an emergency admission. The mortality rate after repair was higher for men from more deprived areas, although the hazard diminished with age. Patterns were unclear for women. CONCLUSION: There were clear socioeconomic disparities in operation rates, mode of presentation, and outcome for AAA surgery. Policies are needed to address these disparities.

Enantioselective [3 + 2] annulation of 4-isothiocyanato pyrazolones and alkynyl ketones under organocatalysis.

An asymmetric [3 + 2] annulation reaction of 4-isothiocyanato pyrazolones with alkynyl ketones in the presence of an organic catalyst derived from a cinchona alkaloid under mild conditions is realized. This protocol provides unprecedented expeditious access to a wide range of optically active spiro[pyrroline-pyrazolones] with various electronic properties in high yields with good to excellent enantioselectivities.

Diastereoselective synthesis of indolenine-based spiro[pyrazolone-4,2'-pyrrolidine] scaffolds via 1,3-dipolar cycloaddition of 4-aminopyrazolones, aldehydes, and indolenines.

In this work, we report a one-pot [3 + 2] cycloaddition of 4-aminopyrazolones, indolenines, and aldehydes. The reaction utilized in situ generated azomethine ylides as 1,3-dipoles and 2-alkenylindolenines as dipolarophiles affording indolenine-derived spiro[pyrazolone-4,2'-pyrrolidine] scaffolds with four contiguous stereocenters with excellent yields (up to 95%) and diastereoselectivities (up to >20 : 1 dr) under simple conditions. The in situ generation of azomethine ylides and dipolarophiles in one pot is a unique feature of this process.

Construction of a spiro[pyrazolone-4,2'-pyridoindole] scaffold via a [3 + 3] cycloaddition of 2-indolylmethanol with a 4-aminopyrazolone-derived azomethine ylide.

This work reports a facile [3 + 3] cycloaddition sequence of two important heterocyclic pharmacophores, pyrazolone and 2-indolylmethanol, integrated into a polycyclic hybrid scaffold. In this process, an in situ generated azomethine ylide obtained from 4-aminopyrazolone and benzaldehyde reacts with 2-indolylmethanols to offer spiro[pyrazolone-pyridoindole] scaffolds in high yields with excellent diastereoselectivities. Remarkably, the reaction is carried out at room temperature without any catalyst and base.

C-4 benzofuranylation of pyrazolones by a metal-free catalyzed indirect heteroarylation strategy.

A metal-free catalyzed indirect heteroarylation of pyrazolones with 2-(3-hydroxy-3,3-diarylprop-1-yn-1-yl) phenols has been developed, and a series of novel 4-benzofuranyl substituted pyrazolone derivatives were obtained in moderate to excellent yields (up to 90%). The process has the salient features of metal-free catalysis, operational simplicity, good substrate compatibility and mild reaction conditions. In particular, the integration of the pyrazolone skeleton and benzofuran scaffold into a single molecule is expected to be of potential interest for medicinal research. In addition, the yield and efficiency are basically maintained in the gram-scale experiment, which makes the practical application of the process more prominent.

Emerging nanotechnology role in the development of innovative solutions against COVID-19 pandemic.

The COVID-19 outbreak is creating severe impressions on all facets of the global community. Despite strong measures worldwide to try and re-achieve normalcy, the ability of SARS-CoV-2 to survive sturdy ecological settings may contribute to its rapid spread. Scientists from different aspects of life are working together to develop effective treatment strategies against SARS-CoV-2. Apart from using clinical devices for patient recovery, the key focus is on developing antiviral drugs and vaccines. Given the physical size of the SARS-CoV-2 pathogen and with the vaccine delivery platform currently undergoing clinical trials, the link between nanotechnology is clear, and previous antiviral research using nanomaterials confirms this link. Nanotechnology based products can effectively suppress various pathogens, including viruses, regardless of drug resistance, biological structure, or physiology. Thus, nanotechnology is opening up new dimensions for developing new strategies for diagnosing, preventing, treating COVID-19 and other viral ailments. This article describes the application of nanotechnology against the COVID-19 virus in terms of therapeutic purposes and vaccine development through the invention of nanomaterial based substances such as sanitizers (handwashing agents and surface disinfectants), masks and gowns, amongst other personal protective equipment, diagnostic tools, and nanocarrier systems, as well as the drawbacks and challenges of nanotechnology that need to be addressed.

Par-4 activation restrains EMT-induced chemoresistance in PDAC by attenuating MDM-2.

BACKGROUND: We recently reported prostate apoptosis response 4 (Par-4), a potential tumor suppressor protein restrains epithelial-mesenchymal transition (EMT) properties and promotes mesenchymal-epithelial transition (MET) in invasive cancer cells by repressing Twist-1 promoter activity. Here, we demonstrate that genetic as well as pharmacological modulation of Par-4 by NGD16 (a small molecule antimetastatic agent), limits EMT-induced chemoresistance in aggressive cancer cells by suppressing MDM-2, a downstream effector of Twist-1. METHODS: Matrigel invasion assay, gelatin degradation assay, cell scattering assay, MTT assay and colony formation assay were used to study the proliferation and migration abilities of invasive cancer cells. Immunoblotting, immunocytochemistry, and immunoprecipitation analysis were utilized for determining protein expression and protein-protein interaction. 4T1 aggressive mouse carcinoma model was employed to evaluate tumor growth and lung metastasis. RESULTS: Treatment of gemcitabine (nucleoside analogue anticancer agent) to pancreatic cancer (Panc-1, MiaPaca-2) and breast cancer (MDA-MB-231) cells amplified MDM-2 expression along with increase in EMT properties. Conversely, NGD16 boosted expression of tumor suppressor Par-4 and inhibited invasion and migration abilities of these cells. Moreover, induction of Par-4 effectively diminished MDM-2 along with pro-EMT markers, whereas, augmented the expression of epithelial markers. Furthermore, siRNA-mediated silencing of Par-4 divulged that NGD16 exerts its EMT inhibitory effects in a Par-4-dependent manner. Mechanistically, Par-4 activation provokes p53 by disrupting MDM-2-p53 interaction, which restored epithelial characteristics in cancer cells. Additionally, partial knockdown of MDM-2 through siRNA pronounced the anti-proliferative and anti-invasive effects of NGD16. Finally, NGD16 efficiently inhibited tumor growth and lung metastasis in mouse mammary carcinoma model without showing any undesirable effects. CONCLUSION: Our findings unveil Par-4 as a key therapeutic target and NGD16 (the pharmacological modulator of Par-4) are potential tools to suppress EMT and associated chemoresistance, which could be exploited clinically for the treatment of aggressive cancers.