Proteomic analysis reveals perturbed energy metabolism and elevated oxidative stress in hearts of rats with inborn low aerobic capacity

Selection on running capacity has created rat phenotypes of high-capacity runners (HCRs) that have enhanced cardiac function and low-capacity runners (LCRs) that exhibit risk factors of metabolic syndrome. We analysed hearts of HCRs and LCRs from generation 22 of selection using DIGE and identified proteins from MS database searches. The running capacity of HCRs was six-fold greater than LCRs. DIGE resolved 957 spots and proteins were unambiguously identified in 369 spots. Protein expression profiling detected 67 statistically significant (p<0.05; false discovery rate <10%, calculated using q-values) differences between HCRs and LCRs. Hearts of HCR rats exhibited robust increases in the abundance of each enzyme of the β-oxidation pathway. In contrast, LCR hearts were characterised by the modulation of enzymes associated with ketone body or amino acid metabolism. LCRs also exhibited enhanced expression of antioxidant enzymes such as catalase and greater phosphorylation of α B-crystallin at serine 59, which is a common point of convergence in cardiac stress signalling. Thus, proteomic analysis revealed selection on low running capacity is associated with perturbations in cardiac energy metabolism and provided the first evidence that the LCR cardiac proteome is exposed to greater oxidative stress.     

Facing the wrath of enigmatic mutations: a review on the emergence of severe acute respiratory syndrome coronavirus 2 variants amid coronavirus disease-19 pandemic

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an emerging respiratory virus responsible for the ongoing coronavirus disease 19 (COVID-19) pandemic. More than a year into this pandemic, the COVID-19 fatigue is still escalating and takes hold of the entire world population. Driven by the ongoing geographical expansion and upcoming mutations, the COVID-19 pandemic has taken a new shape in the form of emerging SARS-CoV-2 variants. These mutations in the viral spike (S) protein enhance the virulence of SARS-CoV-2 variants by improving viral infectivity, transmissibility and immune evasion abilities. Such variants have resulted in cluster outbreaks and fresh infection waves in various parts of the world with increased disease severity and poor clinical outcomes. Hence, the variants of SARS-CoV-2 pose a threat to human health and public safety. This review enlists the most recent updates regarding the presently characterized variants of SARS-CoV-2 recognized by the global regulatory health authorities (WHO, CDC). Based on the slender literature on SARS-CoV-2 variants, we collate information on the biological implications of these mutations on virus pathology. We also shed light on the efficacy of therapeutics and COVID-19 vaccines against the emerging SARS-CoV-2 variants.     

<Emphasis Type="Italic">Chenopodium</Emphasis>: a prospective plant for phytoextraction

Leaf samples were collected from 40 accessions of Chenopodium spp. and assessed for six heavy metals (Fe, Zn, Cu, Ni, Cr and Cd) accumulation to explore the use of Chenopodium for phytoextraction of heavy metals. The results suggest that Chenopodium spp. have the ability to accumulate large quantities of heavy metals in the leaf tissues even when they are present in low concentrations in the soil. C. quinoa is a better accumulator of Ni, Cr and Cd than the rest of the species, while C. album accessions are good copper accumulators. Bioconcentration factor for chromium ranged from 0.36 (C. album “Chandanbathua”) to 6.57 (C. quinoa Ames 13719) with 13 accessions of C. quinoa scoring above the mean value. High heritability coupled with high genetic advance was recorded for Ni, Cr and Cd, which indicated a major role of additive gene action in the inheritance of these characters. Zinc showed significant positive association with iron (0.351**), nickel (0.659**), chromium (0.743**) and cadmium (0.288**). Nickel was significantly and negatively associated with copper (−0.663**), while it was positively and significantly correlated with chromium (0.682**) and cadmium (0.461**). Considering the accumulation efficiency of Chenopodium spp. with respect to heavy metals, this genus should be further explored for decontamination of metal polluted soils, with plant breeding playing an important role in evolving new plant types with higher capacity of heavy metal accumulation.     

Diurnal variation in repeated sprint performance cannot be offset when rectal and muscle temperatures are at optimal levels (38.5°C)

The present study investigated whether increasing morning rectal temperatures (T_rec) to evening levels, or increasing morning and evening T_rec to an “optimal” level (38.5°C), resulting in increased muscle temperatures (T_m), would offset diurnal variation in repeated sprint (RS) performance in a causal manner. Twelve trained males underwent five sessions [age (mean ± SD) 21.0 ± 2.3 years, maximal oxygen consumption (V?O₂max) 60.0 ± 4.4 mL.kg^–1 min^–1, height 1.79 ± 0.06 m, body mass 78.2 ± 11.8 kg]. These included control morning (M, 07:30 h) and evening (E, 17:30 h) sessions (5-min warm-up), and three further sessions consisting of a warm-up morning trial (M_E, in 39–40°C water) until T_rec reached evening levels; two “optimal” trials in the morning and evening (M_38.5 and E_38.5, in 39–40°C water) respectively, until T_rec reached 38.5°C. All sessions included 3 × 3-s task-specific warm-up sprints, thereafter 10 × 3-s RS with 30-s recoveries were performed a non-motorised treadmill. T_rec and T_m measurements were taken at the start of the protocol and following the warm-up periods. Values for T_rec and T_m at rest were higher in the evening compared to morning values (0.48°C and 0.69°C, p < 0.0005). RS performance was lower (7.8–8.3%) in the M for distance covered (DC; p = 0.002), average power (AP; p = 0.029) and average velocity (AV; p = 0.002). Increasing T_rec in the morning to evening values or optimal values (38.5°C) did not increase RS performance to evening levels (p = 1.000). However, increasing T_rec in the evening to “optimal” level through a passive warm-up significantly reduced DC (p = 0.008), AP (p < 0.0005) and AV (p = 0.007) to values found in the M condition (6.0–6.9%). Diurnal variation in T_rec and T_m is not wholly accountable for time-of-day oscillations in RS performance on a non-motorised treadmill; the exact mechanism(s) for a causal link between central temperature and human performance are still unclear and require more research.     

Microemulsion Transdermal Formulation for Simultaneous Delivery of Valsartan and Nifedipine: Formulation by Design

The objective of the study was to optimize the proportion of different components for formulating oil in water microemulsion formulation meant for simultaneous transdermal delivery of two poorly soluble antihypertensive drugs. Surface response methodology of Box-Behnken design was utilized to evaluate the effect of two oils (Captex 500 - x1 and Capmul MCM - x2) and surfactant (Acrysol EL135 - x3) on response y1 (particle size), y2 (solubility of valsartan), and y3 (solubility of nifedipine). The important factors which significantly affected the responses were identified and validated using ANOVA. The model was diagnosed using normal plot of residuals and Box-Cox plot. The design revealed an inverse correlation between particle size and concentration of Capmul MCM and Acrysol EL 135. However, an increase in concentration of Captex 500 led to an increase in particle size of microemulsion. Solubility of valsartan decreased while that of nifedipine increased with increase in concentration of Captex 500. Capmul MCM played a significant role in increasing the solubility of valsartan. The effect of Acrysol EL 135 on solubility of both drugs, although significant, was only marginal as compared to that of Captex 500 and Capmul MCM. The optimized microemulsion was able to provide an enhancement ratio of 27.21 and 63.57-fold for valsartan and nifedipine, respectively, with respect to drug dispersion in aqueous surfactant system when evaluated for permeation studies. The current studies candidly suggest the scope of microemulsion systems for solubilizing as well as promoting the transport of both drugs across rat skin at an enhanced permeation rate.     

Growth factor regulation of estrogen receptor coregulator PELP1 functions via Protein Kinase A pathway

PELP1 (proline-rich, glutamic acid-rich, and leucine-rich protein-1) is a potential proto-oncogene that functions as a coregulator of estrogen receptor (ER), and its expression is deregulated during breast cancer progression. Emerging evidence suggests growth factor signaling crosstalk with ER as one possible mechanism by which breast tumors acquire resistance to therapy. In this study, we examined mechanisms by which growth factors modulate PELP1 functions, leading to activation of ER. Using in vivo labeling assays, we have found that growth factors promote phosphorylation of PELP1. Utilizing a panel of substrate-specific phosphorylated antibodies, we discovered that growth factor stimulation promotes phosphorylation of PELP1 that is recognized by a protein kinase A (PKA) substrate-specific antibody. Accordingly, growth factor-mediated PELP1 phosphorylation was effectively blocked by PKA-specific inhibitor H89. Utilizing purified PKA enzyme and in vitro kinase assays, we obtained evidence of direct PELP1 phosphorylation by PKA. Using deletion and mutational analysis, we identified PELP1 domains that are phosphorylated by PKA. Interestingly, site-directed mutagenesis of the putative PKA site in PELP1 compromised growth factor-induced activation and subnuclear localization of PELP1 and also affected PELP1-mediated transactivation function. Utilizing MCF-7 cells expressing a PELP1 mutant that cannot be phosphorylated by PKA, we provide mechanistic insights by which growth factor signaling regulates ER transactivation in a PELP1-dependent manner. Collectively, these findings suggest that growth factor signals promote phosphorylation of ER coactivator PELP1 via PKA pathway, and such modification may have functional implications in breast tumors with deregulated growth factor signaling.     

The known unknowns of antigen processing and presentation

The principal components of both MHC class I and class II antigen processing and presentation pathways are well known. In dendritic cells, these pathways are tightly regulated by Toll-like-receptor signalling and include features, such as cross-presentation, that are not seen in other cell types. However, the exact mechanisms involved in the subcellular trafficking of antigens remain poorly understood and in some cases are controversial. Recent data suggest that diverse cellular machineries, including autophagy, participate in antigen processing and presentation, although their relative contributions remain to be fully elucidated. Here, we highlight some emerging themes of antigen processing and presentation that we think merit further attention.