Autoimmune diseases: targets, biology, and drug discovery.

Autoimmune diseases (AIDs) arise from a breakdown in immunological self-tolerance, wherein the adaptive immune system mistakenly attacks healthy cells, tissues and organs. AIDs impose excessive treatment costs and currently rely on non-specific and universal immunosuppression, which only offer symptomatic relief without addressing the underlying causes. AIDs are driven by autoantigens, targeting the autoantigens holds great promise in transforming the treatment of these diseases. To achieve this goal, a comprehensive understanding of the pathogenic mechanisms underlying different AIDs and the identification of specific autoantigens are critical. In this review, we categorize AIDs based on their underlying causes and compile information on autoantigens implicated in each disease, providing a roadmap for the development of novel immunotherapy regimens. We will focus on type 1 diabetes (T1D), which is an autoimmune disease characterized by irreversible destruction of insulin-producing ß cells in the Langerhans islets of the pancreas. We will discuss insulin as possible autoantigen of T1D and its role in T1D pathogenesis. Finally, we will review current treatments of TID and propose a potentially effective immunotherapy targeting autoantigens.

Supplementing the Nuclear-Encoded PSII Subunit D1 Induces Dramatic Metabolic Reprogramming in Flag Leaves during Grain Filling in Rice.

Our previous study has demonstrated that the nuclear-origin supplementation of the PSII core subunit D1 protein stimulates growth and increases grain yields in transgenic rice plants by enhancing photosynthetic efficiency. In this study, the underlying mechanisms have been explored regarding how the enhanced photosynthetic capacity affects metabolic activities in the transgenic plants of rice harboring the integrated transgene RbcSPTP-OspsbA cDNA, cloned from rice, under control of the AtHsfA2 promoter and N-terminal fused with the plastid-transit peptide sequence (PTP) cloned from the AtRbcS. Here, a comparative metabolomic analysis was performed using LC-MS in flag leaves of the transgenic rice plants during the grain-filling stage. Critically, the dramatic reduction in the quantities of nucleotides and certain free amino acids was detected, suggesting that the increased photosynthetic assimilation and grain yield in the transgenic plants correlates with the reduced contents of free nucleotides and the amino acids such as glutamine and glutamic acid, which are cellular nitrogen sources. These results suggest that enhanced photosynthesis needs consuming more free nucleotides and nitrogen sources to support the increase in biomass and yields, as exhibited in transgenic rice plants. Unexpectedly, dramatic changes were measured in the contents of flavonoids in the flag leaves, suggesting that a tight and coordinated relationship exists between increasing photosynthetic assimilation and flavonoid biosynthesis. Consistent with the enhanced photosynthetic efficiency, the substantial increase was measured in the content of starch, which is the primary product of the Calvin-Benson cycle, in the transgenic rice plants under field growth conditions.

Regulation of Calvin-Benson cycle enzymes under high temperature stress.

The Calvin-Benson cycle (CBC) consists of three critical processes, including fixation of CO2 by Rubisco, reduction of 3-phosphoglycerate (3PGA) to triose phosphate (triose-P) with NADPH and ATP generated by the light reactions, and regeneration of ribulose 1,5-bisphosphate (RuBP) from triose-P. The activities of photosynthesis-related proteins, mainly from the CBC, were found more significantly affected and regulated in plants challenged with high temperature stress, including Rubisco, Rubisco activase (RCA) and the enzymes involved in RuBP regeneration, such as sedoheptulose-1,7-bisphosphatase (SBPase). Over the past years, the regulatory mechanism of CBC, especially for redox-regulation, has attracted major interest, because balancing flux at the various enzymatic reactions and maintaining metabolite levels in a range are of critical importance for the optimal operation of CBC under high temperature stress, providing insights into the genetic manipulation of photosynthesis. Here, we summarize recent progress regarding the identification of various layers of regulation point to the key enzymes of CBC for acclimation to environmental temperature changes along with open questions are also discussed.

Lipidomic Remodeling in Begonia grandis Under Heat Stress.

Characterization of the alterations in leaf lipidome in Begonia (Begonia grandis Dry subsp. sinensis) under heat stress will aid in understanding the mechanisms of stress adaptation to high-temperature stress often occurring during hot seasons at southern areas in China. The comparative lipidomic analysis was performed using leaves taken from Begonia plants exposed to ambient temperature or heat stress. The amounts of total lipids and major lipid classes, including monoacylglycerol (MG), diacylglycerol (DG), triacylglycerols (TG), and ethanolamine-, choline-, serine-, inositol glycerophospholipids (PE, PC, PS, PI) and the variations in the content of lipid molecular species, were analyzed and identified by tandem high-resolution mass spectrometry. Upon exposure to heat stress, a substantial increase in three different types of TG, including 18:0/16:0/16:0, 16:0/16:0/18:1, and 18:3/18:3/18:3, was detected, which marked the first stage of adaptation processes. Notably, the reduced accumulation of some phospholipids, including PI, PC, and phosphatidylglycerol (PG) was accompanied by an increased accumulation of PS, PE, and phosphatidic acid (PA) under heat stress. In contrast to the significant increase in the abundance of TG, all of the detected lysophospholipids and sphingolipids were dramatically reduced in the Begonia leaves exposed to heat stress, suggesting that a very dynamic and specified lipid remodeling process is highly coordinated and synchronized in adaptation to heat stress in Begonia plants.

Nuclear-encoded synthesis of the D1 subunit of photosystem II increases photosynthetic efficiency and crop yield.

In photosynthetic organisms, the photosystem II (PSII) complex is the primary target of thermal damage. Plants have evolved a repair process to prevent the accumulation of damaged PSII. The repair of PSII largely involves de novo synthesis of proteins, particularly the D1 subunit protein encoded by the chloroplast gene psbA. Here we report that the allotropic expression of the psbA complementary DNA driven by a heat-responsive promoter in the nuclear genome sufficiently protects PSII from severe loss of D1 protein and dramatically enhances survival rates of the transgenic plants of Arabidopsis, tobacco and rice under heat stress. Unexpectedly, we found that the nuclear origin supplementation of the D1 protein significantly stimulates transgenic plant growth by enhancing net CO2 assimilation rates with increases in biomass and grain yield. These findings represent a breakthrough in bioengineering plants to achieve efficient photosynthesis and increase crop productivity under normal and heat-stress conditions.

Metabolic Reprogramming in Chloroplasts under Heat Stress in Plants.

Increases in ambient temperatures have been a severe threat to crop production in many countries around the world under climate change. Chloroplasts serve as metabolic centers and play a key role in physiological adaptive processes to heat stress. In addition to expressing heat shock proteins that protect proteins from heat-induced damage, metabolic reprogramming occurs during adaptive physiological processes in chloroplasts. Heat stress leads to inhibition of plant photosynthetic activity by damaging key components functioning in a variety of metabolic processes, with concomitant reductions in biomass production and crop yield. In this review article, we will focus on events through extensive and transient metabolic reprogramming in response to heat stress, which included chlorophyll breakdown, generation of reactive oxygen species (ROS), antioxidant defense, protein turnover, and metabolic alterations with carbon assimilation. Such diverse metabolic reprogramming in chloroplasts is required for systemic acquired acclimation to heat stress in plants.

Identification of core subunits of photosystem II as action sites of HSP21, which is activated by the GUN5-mediated retrograde pathway in Arabidopsis.

Photosystem II (PSII) is the most thermolabile photosynthetic complex. Physiological evidence suggests that the small chloroplast heat-shock protein 21 (HSP21) is involved in plant thermotolerance, but the molecular mechanism of its action remains largely unknown. Here, we have provided genetic and biochemical evidence that HSP21 is activated by the GUN5-dependent retrograde signaling pathway, and stabilizes PSII by directly binding to its core subunits such as D1 and D2 proteins under heat stress. We further demonstrate that the constitutive expression of HSP21 sufficiently rescues the thermosensitive stability of PSII and survival defects of the gun5 mutant with dramatically improving granal stacking under heat stress, indicating that HSP21 is a key chaperone protein in maintaining the integrity of the thylakoid membrane system under heat stress. In line with our interpretation based on several lines of in vitro and in vivo protein-interaction evidence that HSP21 interacts with core subunits of PSII, the kinetics of HSP21 binding to the D1 and D2 proteins was determined by performing an analysis of microscale thermophoresis. Considering the major role of HSP21 in protecting the core subunits of PSII from thermal damage, its heat-responsive activation via the heat-shock transcription factor HsfA2 is critical for the survival of plants under heat stress. Our findings reveal an auto-adaptation loop pathway that plant cells optimize particular needs of chloroplasts in stabilizing photosynthetic complexes by relaying the GUN5-dependent plastid signal(s) to activate the heat-responsive expression of HSP21 in the nucleus during adaptation to heat stress in plants.

An intrinsic microRNA timer regulates progressive decline in shoot regenerative capacity in plants.

Plant cells are totipotent and competent to regenerate from differentiated organs. It has been shown that two phytohormones, auxin and cytokinin, play critical roles within this process. As in animals, the regenerative capacity declines with age in plants, but the molecular basis for this phenomenon remains elusive. Here, we demonstrate that an age-regulated microRNA, miR156, regulates shoot regenerative capacity. As a plant ages, the gradual increase in miR156-targeted SQUAMOSA PROMOTER BINDING PROTEIN-LIKE (SPL) transcription factors leads to the progressive decline in shoot regenerative capacity. In old plants, SPL reduces shoot regenerative capacity by attenuating the cytokinin response through binding with the B-type ARABIDOPSIS RESPONSE REGULATORs, which encode the transcriptional activators in the cytokinin signaling pathway. Consistently, the increased amount of exogenous cytokinin complements the reduced shoot regenerative capacity in old plants. Therefore, the recruitment of age cues in response to cytokinin contributes to shoot regenerative competence.

[The effect of rhubarb ethanol-extract on hyperlipidemia and liver fatty in rabbits].

AIM: To observe the effect of rhubarb ethanol-extract on hyperlipidemia and liver fatty in rabbits. METHODS: Thirty healthy male white rabbits were divided randomly into five groups, six rabbits in each group. The rabbits in control group were fed with common forage. The rabbits in model group were fed with high lipid forage. The rabbits in three different rhubarb groups were fed with high lipid forage and treated with different level rhubarb ethanol-extract (REE). In the process of experiment, periodically measured serology index of the rabbits and observed common physiology index. The rabbits were killed at the end of tenth week, liver fatty degeneration degree and liver coefficient were measured and compared. RESULTS: REE could decrease serum total cholesterol (TC) and low density lipoprotein cholesterol (LDL-C), and increase serum high density lipoprotein cholesterol (HDL-C), and reduce liver fatty de generation and protect liver cell function. And the dose-effect relation was showed among different dose REE groups. CONCLUSION: REE can significantly reduce blood lipid, prevent and treat hyperlipidemia and liver fatty.