Potent Protection Research Articles

Microwave assisted synthesis, characterization and biological activities of ferrocenyl chalcones and their QSAR analysis: Part II

A series of ferrocenyl chalcones using acetylferrocene, with ferrocenyl group at the keto carbonyl group, and different aldehydes were synthesized and their bioefficacy evaluation was done against Sclerotium rolfsii, Alternaria solani and Meloidogyne incognita. In continuation of our quest for potent crop protection products, in the present study, a series of 18 substituted ferrocenyl chalcones were synthesized in which ferrocenyl group was attached to the aldehyde moiety, using ferrocenecarboxyaldehyde and different acetophenones by microwave method (MM) and conventional method (CM) [cf: MM 1 to 5 min; CM 12–40 h] and characterized by various techniques viz. IR, LC-HRMS, 1H-NMR and 13C-NMR. In vitro fungicidal activity showed that compound, (2E)-1-(5-Chloro-2-hydroxyphenyl)-3-ferrocenyl-prop-2-en-1-one (34) (ED50 = 21.50 mg L−1) was found to be most active against S. rolfsii and compound, (2E)-1-(4-Bromophenyl)-3-ferrocenyl-prop-2-en-1-one (21) (ED50 = 31.14 mg L−1) showed highest activity against A. solani. As regards nematicidal activity, compound (2E)-1-(3-Bromophenyl)-3-ferrocenyl-prop-2-en-1-one (29) was more potent with LC50 values of 11.95, 8.07 and 4.34 mg L−1 at 24, 48 and 72 h, respectively. QSAR study revealed that MLR for S. rolfsii (r 2 = 0.9834, q 2= 0.8975) and A. solani (r 2 = 0.9807, q 2= 0.8713) and PLS for M. incognita (r 2 = 0.9023, q 2= 0.7818) were the best models.

Anti-Inflammatory, Antioxidant, and Antifibrotic Effects of Kefir Peptides on Salt-Induced Renal Vascular Damage and Dysfunction in Aged Stroke-Prone Spontaneously Hypertensive Rats.

The increased prevalence of renal dysfunction and chronic kidney disease (CKD) and the high costs and poor outcomes of treatment are a significant health issue. The consequence of chronic high blood pressure is the increased prevalence of target organ end-stage renal disease, which has been proven to be a strong independent risk factor for adverse cardiovascular disease. A previous study showed that kefir products have anti-inflammatory and anti-hypertensive activities and immunological modulation functions. However, no data regarding the beneficial effects of kefir peptides (KPs) on salt-induced renal damage or related kidney diseases are available. In this study, KPs were orally administered to aged salt-induced stroke-prone spontaneously hypertensive (SHRSP) rats, and the effects of KPs against inflammation and oxidative stress and their ability to protect against renal dysfunction were evaluated. Fifty-five-week-old SHRSP rats under induction with 1% NaCl in drinking water for 4 weeks showed multiple renal injuries with increased renal inflammation, fibrosis, oxidative stress, tubular atrophy, and glomerulosclerosis. In contrast, oral gavage with KPs reduced the urine protein to creatinine (UPC) ratio, the fractional excretion of electrolytes (FeNa and FeCl), extracellular matrix deposition, and the interstitial fibrotic α-smooth muscle actin (α-SMA) levels in salt-induced SHRSP rats. The renal infiltration of inflammatory cells; the release of monocyte chemoattractant protein-1 (MCP-1), vascular cell adhesion molecule-1 (VCAM-1), endothelin-1 (ET-1), and the cytokine nucleotide-binding oligomerization domain (NOD)-like receptor family pyrin domain containing 3 (NLRP3) and transforming growth factor-β (TGF-β); the reactive oxygen species (ROS) levels; and histopathological lesions were also decreased in salt-induced SHRSP rats. Furthermore, KP treatment significantly increased the renal superoxide dismutase (SOD) activity and the glomerular filtration rate (GFR), which exerted potent protection against salt-induced chronic kidney disease in SHRSP rats. The results of this study suggest that KPs ameliorate salt-induced renal damage, tubular atrophy, and glomerular dysfunction through anti-inflammatory, antioxidative stress, and antifibrotic activities, and might be a promising protective agent against high salt-induced renovascular-related diseases.

Evaluation of the respiratory syncytial virus G-directed neutralizing antibody response in the human airway epithelial cell model

Human respiratory syncytial virus (RSV) is a major cause of serious respiratory tract infections in infants and the elderly. Recently it was shown that the RSV G glycoprotein mediates attachment to cells using CX3CR1 as a receptor, and that G-specific neutralizing antibodies can be detected using human airway epithelial (HAE) cell cultures. To investigate the contributions of G-specific antibodies to RSV neutralization, we performed HAE neutralization assays on sera from RSV G-immunized mice or RSV-infected infants. We confirmed that G-specific neutralization using serum from mice or humans could only be detected on HAE cultures. We also found that RSV G-specific antibodies in infants were either subgroup specific or cross-neutralizing. Altogether, our results suggest that G is an important target for generating neutralizing antibodies and would be beneficial to include in an RSV vaccine. Further, inclusion of G antigens from both RSV subgroups may enhance the vaccine cross protection potency.

Expression and Purification of Recombinant GHK Tripeptides Are Able to Protect against Acute Cardiotoxicity from Exposure to Waterborne-Copper in Zebrafish.

In this study, an alternative method is developed to replace chemical synthesis to produce glycyl-histidyl-lysine (GHK) tripeptides with a bacterial fermentation system. The target GHK tripeptides are cloned into expression plasmids carrying histidine-glutathione-S-transferase (GST) double tags and TEV (tobacco etch virus) cleavage sites at the N-terminus. After overexpression in Escherichia coli (E. coli) BL21 cells, the recombinant proteins are purified and recovered by high-pressure liquid chromatography (HPLC). UV-vis absorption spectroscopy was used to investigate the chemical and biological properties of the recombinant GHK tripeptides. The results demonstrated that one recombinant GHK tripeptide can bind one copper ion to form a GHK-Cu complex with high affinity, and the recombinant GHK peptide to copper ion ratio is 1:1. X-ray absorption near-edge spectroscopy (XANES) of the copper ions indicated that the oxidation state of copper in the recombinant GHK-Cu complexes here was Cu(II). All of the optical spectrum evidence suggests that the recombinant GHK tripeptide appears to possess the same biophysical and biochemical features as the GHK tripeptide isolated from human plasma. Due to the high binding affinity of GHK tripeptides to copper ions, we used zebrafish as an in vivo model to elucidate whether recombinant GHK tripeptides possess detoxification potential against the cardiotoxicity raised by waterborne Cu(II) exposure. Here, exposure to Cu(II) induced bradycardia and heartbeat irregularity in zebrafish larvae; however, the administration of GHK tripeptides could rescue those experiencing cardiotoxicity, even at the lowest concentration of 1 nM, where the GHK-Cu complex minimized CuSO4-induced cardiotoxicity effects at a GHK:Cu ratio of 1:10. On the other hand, copper and the combination with the GHK tripeptide did not significantly alter other cardiovascular parameters, including stroke volume, ejection fraction, and fractional shortening. Meanwhile, the heart rate and cardiac output were boosted after exposure with 1 nM of GHK peptides. In this study, recombinant GHK tripeptide expression was performed, along with purification and chemical property characterization, which revealed a potent cardiotoxicity protection function in vivo with zebrafish for the first time.

Steamed ginseng shoot extract rich in less-polar ginsenosides ameliorated the acute hepatotoxicity caused by overdose of acetaminophen in mice

• GSE exerted ability in reducing ALT and AST levels and oxidative stress and lipid peroxidation caused by overdose APAP. • GSE played vital roles in modulating excessive inflammation and apoptosis caused by APAP. • GSE with liver protective effect at lower doses had toxic effect at higher doses in mice. • GSE’s better liver protection in mice might be due to its abundant less-polar ginsenosides. The current study was conducted to comprehensively explore the potential hepatoprotective effect of steamed ginseng shoot extract (GSE) in acetaminophen (APAP)-induced liver injury model of mice. Our findings demonstrated that a single injection of APAP (250 mg/kg) increased the levels of alanine aminotransferase, aspartate aminotransferase, tumor necrosis factor-α, and interleukin-1β, which were attenuated by GSE pretreatments (50–200 mg/kg) for seven days. Depletion of glutathione, reduced expression of Bcl-2, generation of malondialdehyde and the over expressions of cytochrome P450 E1, 4-hydroxynonenal, Bax and cytochrome c caused by APAP exposure were also inhibited by the GSE pretreatments. Moreover, GSEs significantly alleviated APAP-induced apoptosis, necrosis, and inflammatory infiltration in liver tissues. Importantly, GSEs effectively attenuated APAP-induced liver injury in part via blocking caspases-3/8/9 signaling pathway. In summary, GSEs exerted potent liver protection against APAP-caused hepatotoxicity evidenced by inhibition of oxidative stress, inflammation and apoptosis.

Bacillus subtilis spore vaccines displaying protective antigen induce functional antibodies and protective potency

BackgroundBacillus anthracis is the causative agent of anthrax, a disease of both humans and various animal species, and can be used as a bioterror agent. Effective vaccines are available, but those could benefit from improvements, including increasing the immunity duration, reducing the shot frequency and adverse reactions. In addition, more sophisticated antigen delivery and potentiation systems are urgently required.The protective antigen (PA), one of three major virulence factors associated with anthrax was displayed on the surface of Bacillus subtilis spores, which is a vaccine production host and delivery vector with several advantages such as a low production cost, straightforward administration as it is safe for human consumption and the particulate adjuvanticity. Mice were immunized orally (PO), intranasally (IN), sublingually (SL) or intraperitoneally (IP) with the PA displaying probiotic spore vaccine. Clinical observation, serological analysis and challenge experiment were conducted to investigate the safety and efficacy of the vaccine.ResultsA/J mice immunized with the PA spore vaccine via PO, IN, SL, and IP were observed to have increased levels of active antibody titer, isotype profiles and toxin neutralizing antibody in sera, and IgA in saliva. The immunized mice were demonstrated to raise protective immunity against the challenge with lethal B. anthracis spores.ConclusionsIn this study, we developed a B. subtilis spore vaccine that displays the PA on its surface and showed that the PA-displaying spore vaccine was able to confer active immunity to a murine model based on the results of antibody isotype titration, mucosal antibody identification, and a lethal challenge experiment.

Mapping a Conformational Epitope of Hemagglutinin A Using Native Mass Spectrometry and Ultraviolet Photodissociation.

As the importance of effective vaccines and the role of protein therapeutics in the drug industry continue to expand, alternative strategies to characterize protein complexes are needed. Mass spectrometry (MS) in conjunction with enzymatic digestion or chemical probes has been widely used for mapping binding epitopes at the molecular level. However, advances in instrumentation and application of activation methods capable of accessing higher energy dissociation pathways have recently allowed direct analysis of protein complexes. Here we demonstrate a workflow utilizing native MS and ultraviolet photodissociation (UVPD) to map the antigenic determinants of a model antibody-antigen complex involving hemagglutinin (HA), the primary immunogenic antigen of the influenza virus, and the D1 H1-17/H3-14 antibody which has been shown to confer potent protection to lethal infection in mice despite lacking neutralization activity. Comparison of sequence coverages upon UV photoactivation of HA and of the HA·antibody complex indicates the elimination of some sequence ions that originate from backbone cleavages exclusively along the putative epitope regions of HA in the presence of the antibody. Mapping the number of sequence ions covering the HA antigen versus the HA·antibody complex highlights regions with suppressed backbone cleavage and allows elucidation of unknown epitopes. Moreover, examining the observed fragment ion types generated by UVPD demonstrates a loss in diversity exclusively along the antigenic determinants upon MS/MS of the antibody-antigen complex. UVPD-MS shows promise as a method to rapidly map epitope regions along antibody-antigen complexes as novel antibodies are discovered or developed.

Protection against UVB-Induced Photoaging by Nypa fruticans via Inhibition of MAPK/AP-1/MMP-1 Signaling.

Ultraviolet B (UVB) irradiation is major causative factor in skin aging. The aim of the present study was to investigate the protective effect of a 50% ethanol extract from Nypa fruticans (NF50E) against UVB-induced skin aging. The results indicated that NF50E exerted potent antioxidant activity (IC50 = 17.55 ± 1.63 and 10.78 ± 0.63 μg/mL for DPPH and ABTS-radical scavenging activity, respectively) in a dose-dependent manner. High-performance liquid chromatography revealed that pengxianencin A, protocatechuic acid, catechin, chlorogenic acid, epicatechin, and kaempferol were components of the extract. In addition, the extract exhibited elastase inhibitory activity (IC50 = 17.96 ± 0.39 μg/mL). NF50E protected against UVB-induced HaCaT cell death and strongly suppressed UVB-stimulated cellular reactive oxygen species generation without cellular toxicity. Moreover, topical application of NF50E mitigated UVB-induced photoaging lesions including skin erythema and skin thickness in BALB/C mice. NF50E treatment inhibited UVB-induced collagen degradation as well as MMP-1 and IL-1β expressions and significantly stimulated SIRT1 expression. Furthermore, the extract treatment markedly suppressed the activation of NF-κB and AP-1 (p-c-Jun) by deactivating the p38 and JNK proteins. Taken together, current data suggest that NF50E exhibits potent antioxidant potential and protection against photoaging by attenuating MMP-1 activity and collagen degradation possibly through the downregulation of MAPK/NF-κB/AP-1 signaling and SIRT1 activation.

ABHRAK BHASMA AND SiO2 INFLUENCED FREE RADICAL STATUS IN LIVER AND KIDNEY OF CCl4-INDUCED ACUTELY INTOXICATED MALE ALBINO RAT

Objective: The objective of the study was to study the mechanism of action of abhrak bhasma-mediated liver and kidney protection in CCl4-induced acute hepatotoxicity-induced male albino rats. Action of abhrak bhasma is compared with the action of SiO2 in similar experimental conditions to differentiate the role of silicon.
 Methods: Male albino rats (Rattus norvegicus) were used for experiments. The acute hepatotoxicity was induced by daily dose of CCl4 (3.0 ml/kg body wt for 7 days consecutive). Concurrent treatment of abhrak bhasma in graded doses (10, 20, 30, and 40 mg) was given for 7 days (PO). SiO2 (10, 20, 30, and 40 mg) in graded doses was also given in independent groups of rats as silica control. Lipid peroxidation (LPO) in liver and kidney was studied by malondialdehyde (MDA) estimations as parameter of toxicity and also to study protection.
 Results: CCl4-induced hepatotoxicity (MDA levels) is partially managed by low doses of SiO2 but not by high doses. Abhrak bhasma hepatoprotective activities were dose dependent. A 40 mg dose maintained normal levels of LPO. Abhrak bhasma also protected associated renal toxicity.
 Conclusion: Abhrak bhasma protected CCl4-induced hepatotoxicity and also associated renal toxicity. Silicon from both SiO2 and abhrak bhasma is hepatoprotective in 10 ml doses (10 and 20 mg) but silicon processed in abhrak bhasma by traditional Ayurvedic processes increased its potency and hepatoprotection and added the potency of renal protection.

Dietary Regulation of Memory T Cells.

Memory T cells are a fundamental component of immunological memory, providing rapid and potent host protection against secondary challenges. As such, memory T cells are key targets in the design of vaccination strategies and cancer immunotherapies, making it critical to understand the factors and mechanisms that regulate their biology. Diet is an environmental feature that impacts virtually all aspects of host physiology. However, the influence of specific dietary regiments and nutritional components on the immune system is only just starting to be uncovered. This article will review literature regarding the impact of diet and nutrition on memory T cell development, maintenance and function. It was recently shown that caloric restriction without undernutrition enhances memory T cell function, while diets high in fiber are also beneficial. However, memory T cell responses are dysfunctional in extreme nutritional states, such as undernutrition and diet-induced obesity. Therefore, diet and host nutritional status are major regulators of memory T cell biology and host fitness. To define the dietary balance required to promote optimal memory T cell responses could allow for the implementation of rational diet-based therapies that prevent or treat disease. Furthermore, that certain dietary regiments can enhance memory T cell function indicates the possibility of harnessing the underlying mechanisms in the design of novel vaccination strategies and cancer immunotherapies.

An SAMT-247 Microbicide Provides Potent Protection against Intravaginal Simian Immunodeficiency Virus Infection of Rhesus Macaques, whereas an Added Vaccine Component Elicits Mixed Outcomes.

Because of microbicide noncompliance and lack of a durable, highly effective vaccine, a combined approach might improve HIV prophylaxis. We tested whether a vaccine-microbicide combination would enhance protection against SIV infection in rhesus macaques. Four macaque groups included vaccine only, vaccine-microbicide, microbicide only, and controls. Vaccine groups were primed twice mucosally with replicating adenovirus type 5 host range mutant SIV env/rev, gag, and nef recombinants and boosted twice i.m. with SIV gp120 proteins in alum. Controls and the microbicide-only group received adenovirus type 5 host range mutant empty vector and alum. The microbicide was SAMT-247, a 2-mercaptobenzamide thioester that targets the viral nucleocapsid protein NCp7, causing zinc ejection and preventing RNA encapsidation. Following vaccination, macaques were challenged intravaginally with repeated weekly low doses of SIVmac251 administered 3 h after application of 0.8% SAMT-247 gel (vaccine-microbicide and microbicide groups) or placebo gel (vaccine-only and control groups). The microbicide-only group exhibited potent protection; 10 of 12 macaques remained uninfected following 15 SIV challenges. The vaccine-only group developed strong mucosal and systemic humoral and cellular immunity but did not exhibit delayed acquisition compared with adjuvant controls. However, the vaccine-microbicide group exhibited significant acquisition delay compared with both control and vaccine-only groups, indicating further exploration of the combination strategy is warranted. Impaired protection in the vaccine-microbicide group compared with the microbicide-only group was not attributed to a vaccine-induced increase in SIV target cells. Possible Ab-dependent enhancement will be further investigated. The potent protection provided by SAMT-247 encourages its movement into human clinical trials.

Development of an Inactivated Vaccine Candidate, BBIBP-CorV, with Potent Protection against SARS-CoV-2

The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) threatens global public health. The development of a vaccine is urgently needed for the prevention and control of COVID-19. Here, we report the pilot-scale production of an inactivated SARS-CoV-2 vaccine candidate (BBIBP-CorV) that induces high levels of neutralizing antibodies titers in mice, rats, guinea pigs, rabbits, and nonhuman primates (cynomolgus monkeys and rhesus macaques) to provide protection against SARS-CoV-2. Two-dose immunizations using 2 μg/dose of BBIBP-CorV provided highly efficient protection against SARS-CoV-2 intratracheal challenge in rhesus macaques, without detectable antibody-dependent enhancement of infection. In addition, BBIBP-CorV exhibits efficient productivity and good genetic stability for vaccine manufacture. These results support the further evaluation of BBIBP-CorV in a clinical trial.

Trolox is more successful than allopurinol to reduce degenerative effects of testicular ischemia/reperfusion injury in rats

Reperfusion surgery following testicular ischemia is a reproductive health threatening status and may result with organ dysfunction in men. The high level of reactive oxygen species (ROS) and cease of blood flow to the testis are the most important reasons of this testicular injury. Until today, numerous experimental studies reported that antioxidants might be efficient to alleviate oxidative stress induced organ dysfunction. For this purpose, in this study, we have investigated the protective effects of xanthine oxidase (XO) inhibitor, allopurinol, and ROS scavenger, trolox, in a comparative perspective in testicular ischemia reperfusion injury subjected rats. Twenty-eight adult male Sprague Dawley rats were divided into four groups of seven animals in each; control, ischemia/reperfusion (I/R), allopurinol and trolox. The rats in control group did not receive any application. Animals in I/R, allopurinol and trolox groups were subjected to 2h testicular reperfusion injury following 5h ischemia. Intraperitoneally (i.p.) 1ml isotonic, 200mg/kg allopurinol and 50mg/kg trolox were administered to the animals in these groups 30min prior reperfusion. At the end of experiment, all animals were sacrificed and blood serum malondialdehyde (MDA) levels were measured. Histological sections were obtained from the testis and stained with hematoxylin and eosin (H&E), proliferating cell nuclear antigen (PCNA) and cleaved caspase-3. Apoptotic index was evaluated with TUNEL Assay. Severe morphological degenerations, increased serum MDA, cleaved caspase-3 and TUNEL Assay positivity rate, but reduced PCNA positivity rate was observed in ischemia and reperfusion group. Morphological degenerations, MDA level, apoptotic index and PCNA positive cell rate were slightly alleviated in allopurinol administered animals compared with ischemia and reperfusion group. Protection with trolox was more successful and the results of the analysis were similar to the control group. Ischemia that leading to testicular torsion is a reproductive health affecting problem and current surgical treatment methods might be insufficient to recover testis. Various types of ROS generating mechanisms in cell are limiting protective potency of allopurinol, and cocktail administration of different ROS inhibitors might be more effective. However, our results indicate that free radical scavenger trolox might be a candidate drug to alleviate degenerative effects of testicular ischemia reperfusion injury. This is the first study that demonstrates antioxidant trolox was more successful than XO inhibitor allopurinol to protect testis against ischemia and reperfusion injury in rats.

BACOSIDE A, WITHANOLIDE A, AND SHATAVARIN IV ARE BENEFICIAL ULCER AND ULCER HEALING ACTIVITY BY MODULATING INFLAMMATORY MEDIATORS IN RATS

In addition to providing effective antiulcer medicines, their suboptimum safety and efficacy also stirs the search for alternative therapies. Repositioning of drugs is an attractive, convenient, and low risk strategy. The Phytoconstituents Bacoside A, Withanolide A and shatavarin IV obtained from the medicinal plants. The purpose of this analysis was to look at the mechanism of action underling the ulcer protective and ulcer healing capability of these phytoconstituents. The acute toxicity experiment was performed to look for the toxicity of the phytoconstituents, gastro protective effect determined using pylorus ligation induced ulcer model, connection of NO, SH and PGE2 were also tested. Peptic ulcer induced by acetic acid model, Western blotting assay (COX-1 and COX-2) was also performed to elucidate the mechanism of action of Phytoconstituents. No mortality was detected at given dosage in the acute toxicity study. In ulcer protective activity the phytoconstituents, Bacoside A and Shatavarin IV at the dose of 200µg/ml/kg, Withanolide A at the dose of 20µg/ml/kg appreciably reduced the ulcer index and ulcer severity in pylorus ligation induced ulcer model, the antiulcer ability involves several mechanisms like, non participation of NO and SH compounds. Improvement of PGE2 range and the up regulation of COX-2 seems to be directly related to the phytoconstituents antisecretory, ulcer-protective effects. These findings accentuate the gastro protective and gastric healing potency of the Phytoconstituents were mediated via concerted multi-pronged actions, including promotion of gastric protection, augmentation of PGE2, up regulation of COX-II.

Protective potency of ascorbic acid supplementation against cytotoxicity and DNA fragmentation induced by triphenyltin on human liver carcinoma cells.

Agrochemicals are one the most significant sources of environmental pollution. Cytotoxicity and genotoxicity are the serious side effects of fungicide. In the current study, I have evaluated acute cytotoxicity and genotoxicity of triphenyltin (TPT) on human hepatic carcinoma (HepG2) cells and the ameliorating effect of ascorbic acid for 24h. In this experiment, I have exposed HepG2 cells to ascorbic acids (50, 100, and 200μM) simultaneously and 24h prior triphenyltin (TPT, 400ng/ml) exposure for 24h to determine the protective effect of ascorbic acid by using MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) and NRU (neutral red uptake) assays. Oxidative stress, such as intracellular reactive oxygen species and glutathione levels, was measured in HepG2 cells. The intracellular reactive oxygen species was evaluated using fluorescent probe DCFDA (6-carboxy-2',7' dichloro-dihydrofluorescein diacetate). Apoptosis and genotoxicity effects of TPT in HepG2 cells were determined using flow cytometry and comet assay. The result of these experiments showed that the TPT compound (400ng/ml) induced cytotoxicity, oxidative stress and apoptosis, and DNA damage in HepG2 cells.Ascorbic acid reduced cytotoxicity, oxidative stress, apoptosis, and genotoxicity induced by TPT. Thus, ascorbic acid is a potent antioxidant, and it showed a significant protective effect against toxicity induced by TPT in HepG2 cells.

Identification and optimization of piperine analogues as neuroprotective agents for the treatment of Parkinson’s disease via the activation of Nrf2/keap1 pathway

Parkinson’s disease (PD) is a slowly progressive and complex neurodegenerative disorder. Up to date, there are no approved drugs that could slow or reverse the neurodegenerative process of PD. Here, we reported the synthesis of series of piperine analogues and the evaluation of their neuroprotective effects against hydrogen peroxide (H2O2) induced damage in the neuron-like PC12 cells. Among these analogues, 3b exhibited the most potent protection effect and its underlying mechanism was further investigated. Further results indicated that the ROS scavenging and cytoprotection effect of 3b might be related to the Nrf2 activation and upregulation of related phase II antioxidant enzymes, such as HO-1 and NQO1. In in vivo study, oral administration (100 mg/kg) of 3b significantly attenuated PD-associated behavioral deficits in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model of PD and protected tyrosine hydroxylase-immunopositive dopaminergic neurons. Our results provided evidence that 3b might be a promising candidate for Parkinson’s disease treatment.

Food safety and COVID-19: Limitations of HACCP and the way forward

Food is a basic need for existence and thus the food industry can never be shut even at the time of a pandemic. The COVID-19 pandemic has exposed the lapses in the current food system and it is understood that HACCP based food systems are not effective as desired in reducing the risk associated with unidentified hazards. While HACCP deals with food safety only, in the present scenario there is a need for tools which address all four elements of food protection i.e. food safety, food quality, food defense and food fraud. These elements can be defined and understood as separate concepts yet overlapping interactions are observed. Tools which encompasses various elements of food protection are proposed in recent literature which may be used in combination to develop a more potent and bespoke food protection system for the food industry or organizations. Further, in addition to the use of technological advancement for food protection, utilization of behavioral sciences especially in food safety execution and communication systems process is necessary.

CD8 T cell fate is programmed by a miRNA-mediated mechanism

Abstract CD8 T cells are the cytotoxic effectors of the adaptive immune response, clearing virally infected and cancerous cells within the host. CD8 T cells acquire their cytotoxic function by differentiating into cytotoxic T lymphocytes (CTLs). Once the CTLs have cleared the antigen, the majority of responding cells will die during contraction, while a small population of the antigen-specific responders will remain, differentiating into long-lived memory cells that provide potent protection to the host upon re-encounter with the antigen. However, during chronic infection and cancer, CD8 T cells are often diverted into the so-called exhausted state, in which CTLs are losing their function. As such, the ability to program the differentiation of CD8 T cells into a particular lineage is an important therapeutic strategy. We have identified a global post-transcriptional mechanism that directs the fate of differentiating CD8 T cells. Specifically, we have found that let-7 miRNAs are downregulated upon T cell activation, allowing T cells to differentiate into CTLs. Moreover, we have found that prolonged expression of these miRNAs programs CD8 T cells to become memory cells, while complete loss induces exhaustion. Thus, these findings may have important implications for the improvement of current immunotherapies targeting CD8 T cell fate.

Expression of MuRF1 or MuRF2 is essential for the induction of skeletal muscle atrophy and dysfunction in a murine pulmonary hypertension model

BackgroundPulmonary hypertension leads to right ventricular heart failure and ultimately to cardiac cachexia. Cardiac cachexia induces skeletal muscles atrophy and contractile dysfunction. MAFbx and MuRF1 are two key proteins that have been implicated in chronic muscle atrophy of several wasting states.MethodsMonocrotaline (MCT) was injected over eight weeks into mice to establish pulmonary hypertension as a murine model for cardiac cachexia. The effects on skeletal muscle atrophy, myofiber force, and selected muscle proteins were evaluated in wild-type (WT), MuRF1, and MuRF2-KO mice by determining muscle weights, in vitro muscle force and enzyme activities in soleus and tibialis anterior (TA) muscle.ResultsIn WT, MCT treatment induced wasting of soleus and TA mass, loss of myofiber force, and depletion of citrate synthase (CS), creatine kinase (CK), and malate dehydrogenase (MDH) (all key metabolic enzymes). This suggests that the murine MCT model is useful to mimic peripheral myopathies as found in human cardiac cachexia. In MuRF1 and MuRF2-KO mice, soleus and TA muscles were protected from atrophy, contractile dysfunction, while metabolic enzymes were not lowered in MuRF1 or MuRF2-KO mice. Furthermore, MuRF2 expression was lower in MuRF1KO mice when compared to C57BL/6 mice.ConclusionsIn addition to MuRF1, inactivation of MuRF2 also provides a potent protection from peripheral myopathy in cardiac cachexia. The protection of metabolic enzymes in both MuRF1KO and MuRF2KO mice as well as the dependence of MuRF2 expression on MuRF1 suggests intimate relationships between MuRF1 and MuRF2 during muscle atrophy signaling.

Progress in development of neutralizing monoclonal antibody (McAb) against MERS-CoV

The rapid spread and outbreak of Middle East respiratory syndrome coronavirus (MERS-CoV) in the regions of Middle East in 2012 have been a great concern for researchers worldwide. Thus, efficient preventative and therapeutic countermeasures are urgently needed. Clinical studies have confirmed that high titers of neutralizing antibodies (Abs) against MERS-CoV in patients during convalescence have protective potency, which indicates that neutralizing Abs are safe and effective for the treatment of MERS-CoV infection. Spike (S) protein is a key structural protein that mediates MERS-CoV infection and currently a critical protein for studying MERS-CoV neutralizing monoclonal antibodies. This review summarizes recent advances in identifying neutralizing McAbs against MERS-CoV through describing the structural characteristics of MERS-CoV S protein, different kinds of MERS-CoV vaccines and methods for mAbs screening. Furthermore, we propose the prospects for future research on MERS-CoV neutralizing McAbs according to the current research progress. Key words: MERS-CoV; McAb; Neutralization; Spike protein; RBD