Stress Response Proteins Research Articles

The association between neuropsychiatric effects of substance use and occurrence of endoplasmic reticulum and unfolded protein response: A systematic review

IntroductionThis systematic review aimed to assess the association between neuropsychiatric effects of substance use and occurrence of ER stress and unfolded protein response (UPR) through comprehensive electronic search of existing literature and review of their findings. MethodsA comprehensive electronic literature search was carried out on research articles published between 1950 to July 2023 through major databases, such as Scopus, Web of Science, Google Scholar, PubMed, PsycINFO, EMBASE, Medline and Cochrane Library. ResultsA total of 21 research articles were selected for review, which were comprised of sixteen animal studies, four human studies and one study on postmortem human brain samples. The selected studies revealed that alcohol, methamphetamine, cocaine, opioid and kratom exposures contributed to neuropsychiatric effects: such as decline in learning and memory function, executive dysfunction, alcohol, methamphetamine, opioid, and kratom dependence. These effects were associated with activation and persistent of ER stress and UPR with elevation of BiP and CHOP expression and the direction of ER stress is progressing towards the PERK-eIF2α-ATF4-CHOP pathway and neuronal apoptosis and neurodegeneration at various regions of the brain. In addition, regular kratom use in humans also contributed to elevation of p-JNK expression, denoting progress of ER stress towards the IRE1-ASK1-JNK-p-JNK pathway which was linked to kratom use disorder. However, treatment with certain compounds or biological agents could reverse the activation of ER stress. ConclusionsThe neuropsychiatric effects of alcohol, methamphetamine, cocaine, opioid and kratom use may be associated with persistent ER stress and UPR.

Linagliptin in combination with insulin suppresses apoptotic unfolded protein response in ovaries exposed to type 1 diabetes.

Type 1 diabetes mellitus (T1DM) is one of the main causes of ovarian atresia, but its molecular effect on the ovaries is not fully understood. Accumulating evidence suggests that T1DM causes excessive endoplasmic reticulum(ER) stress and insufficient adaptive unfolded protein response that triggers proapoptotic signaling pathways in ovarian tissue. In addition, problems such as amenorrhea and infertility, which are frequently seen in women with T1DM, continue despite the intensification of insulin therapy and improvement of metabolic control. Therefore new, and adjunctive treatments for women with T1DM need to be explored. We aimed to examine how the use of linagliptin, which has blood sugar-lowering effects and high antioxidant activity, together with insulin affects the expression levels of proteins and genes that play a role in ERstress in type 1 diabetic mouse ovaries. Eighty-four Balb/C 6-week-old female mice were randomly divided into seven groups: control, vehicle, diabetes + insulin, diabetes + linagliptin, diabetes + linagliptin + insulin, diabetes + TUDCA, and diabetes + TUDCA + insulin. TUDCA (an inhibitor of ER stress) groups are positive control groups created to compare linagliptin groups in terms of ER stress. Linagliptin and TUDCA were given by oral gavage and 1U insulin was administered subcutaneously for 2 weeks. A significant decrease was observed in the MDA and NOX1 levels and the number of atretic follicles in the ovaries of the diabetes + linagliptin + insulin group compared to the diabetes + insulin group. The use of linagliptin and insulin increased the expression of pro-survival XBP1s transmembrane protein and decreased the expression of proapoptotic ATF4, pJNK1/2, cleaved caspase 12, and cleaved caspase 3 in mouse ovaries. Our study provides new therapeutic evidence that linagliptin administered in addition to insulin induces ER stress mechanism-dependent survival in ovaries with type 1 diabetes.

Global Remodeling of Host Proteome in Response to Leishmania Infection.

The protozoan parasite Leishmania possesses an intrinsic ability to modulate a multitude of pathways in the host, toward aiding its own proliferation. In response, the host reprograms its cellular, immunological, and metabolic machinery to evade the parasite's lethal impact. Besides inducing various antioxidant signaling pathways to counter the elevated stress response proteins like heme oxygenase-1 (HO-1), Leishmania also attempts to delay host cell apoptosis by promoting anti-apoptotic proteins like Bcl-2. The downstream modulation of apoptotic proteins is regulated by effector pathways, including the PI3K/Akt survival pathway, the mitogen-activated protein kinases (MAPKs) signaling pathway, and STAT phosphorylation. In addition, Leishmania assists in its infection in a time-dependent manner by modulating the level of various proteins of autophagic machinery. Immune effector cells, such as mast cells and neutrophils, entrap and kill the pathogen by secreting various granular proteins. In contrast, the host macrophages exert their leishmanicidal effect by secreting various cytokines, such as IL-2, IL-12, etc. An interplay of various signaling pathways occurs in an organized network that is highly specific to both pathogen and host species. This Review analyzes the modulation of expression of proteins, including the cytokines, providing a realistic approach toward understanding the pathophysiology of disease and predicting some prominent markers for disease intervention and vaccine support strategies.

Alterations of protein homeostasis in Alzheimer's disease: beyond Procrustean bed of endoplasmic reticulum stress and unfolded protein response.

Alterations of protein homeostasis in Alzheimer's disease: beyond Procrustean bed of endoplasmic reticulum stress and unfolded protein response.

Comparative proteomic profiling represents an inhibition of protein synthesis to regulate osmotic stress in Nile tilapia (Oreochromis niloticus) embryos

Seawater (SW)-acclimated Nile tilapia, Oreochromis niloticus, can tolerate up to 30 g.L−1 SW but rarely produce offspring. The embryos of SW-acclimated O. niloticus survived equally well from 0- to 10-g.L−1 environment but not under 20-g. L−1. However, when the embryos were incubated under 10 g.L−1 during days 0–3, and then the salinity was suddenly shifted to and maintained at 20 g.L−1 during days 4–6, their survival rate was comparable to those incubated under 0 and 10 g.L−1. To elucidate a molecular adaptation of the embryos that survived different salinity environments, the proteomic profiles of the newly hatched embryos, or early larvae, hatched under 0 g.L−1, 10 g.L−1, and those being incubated at 10 g.L−1 during days 0–3 followed at 20 g.L−1 during days 4–6 were compared. Total proteins extracted from the samples were identified with a gel-free shot-gun proteomics approach using the Nile tilapia protein database. The early larvae from the three groups expressed 2295 proteins, and 279 proteins showed statistically different expressions among groups. Downregulation of the 182 proteins in the larvae hatched under 10 and 20 g.L−1 was found to include 22 proteins that are responsible for cellular responses to osmotic stress. This adaptation may be a crucial factor in reducing cellular metabolism and ion transport between the intra- and extra-cellular environment to stabilize cellular osmolality. In addition, some of these proteins suppress cellular damage from oxygen free radicals generated from the osmotic stress. Eighty-seven proteins significantly changed in the larvae hatched under 20 g.L−1 were clustered. Nineteen of the cellular stress response proteins, which were considered to be mortality induction, were described.

Poster Session II: Development of transparency in the human lens cells.

As the neural tube forms in the fifth week of human embryonic development, a few ectodermal cells adjacent to the neural plate in the trilaminar embryo, swell, thicken, and compress their intercellular space to form a minute lens placode. At this early stage, the embryonic cells in the lens placode resemble neuroectoderm, enriched in cytoskeletal proteins, junctions, membrane channels, and stress response proteins. With continued differentiation, intracellular organelles disappear to decrease light scattering. The expression of high concentrations of crystallin proteins increase the index of refraction, "n", for optimal optical function. In each cell, the condensed cytoplasmic proteins organize into the short-range order necessary for maximal transmission of light. Actin, intermediate filaments and microtubules provide a scaffold for the organization of connexins, and aquaporin channels in the membranes supporting a unique microcirculation for the symmetric transport of fluid, ions, and nutrients to the layers of elongating, close-packed, hexagonal cells, the basis for this unique, biological, optical element. The entire optical system is stabilized by molecular and cellular mechanisms designed to protect optical function for a lifetime. Even with the specialized protective mechanisms in lens cells, loss of transparency in cataract formation is one of the most common effects of cellular aging accounting for over 50% of vision impairment worldwide.

Genome-wide identification, characterization, and expression analysis unveil the roles of pseudouridine synthase (PUS) family proteins in rice development and stress response.

The online version contains supplementary material available at 10.1007/s12298-023-01396-4.

Effect of the res2 transcription factor gene deletion on protein secretion and stress response in the hyperproducer strain Trichoderma reesei Rut-C30

BackgroundThe fungus Trichoderma reesei is one of the most used industrial cellulase producers due to its high capacity of protein secretion. Strains of T. reesei with enhanced protein secretion capacity, such as Rut-C30, have been obtained after several rounds of random mutagenesis. The strain was shown to possess an expanded endoplasmic reticulum, but the genetic factors responsible for this phenotype remain still unidentified. Recently, three new transcription factors were described in Neurospora crassa which were demonstrated to be involved in protein secretion. One of them, RES2, was involved in upregulation of secretion-related genes. The aim of our present study was therefore to analyze the role of RES2, on protein secretion in the T. reesei Rut-C30 strain.ResultDeletion of the res2 gene in Rut-C30 resulted in slightly slower growth on all substrates tested, and lower germination rate as well as lower protein secretion compared to the parental strain Rut-C30. Transcriptomic analysis of the Rut-C30 and the Δres2 mutant strain in secretion stress conditions showed remarkably few differences : 971 genes were differentially expressed (DE) in both strains while 192 genes out of 1163 (~ 16.5%) were DE in Rut-C30 only and 693 out of 1664 genes (~ 41.6%) displayed differential expression solely in Δres2. Notably, induction of protein secretion by cultivating on lactose and addition of secretion stress inducer DTT induced many genes of the secretion pathway similarly in both strains. Among the differentially expressed genes, those coding for amino acid biosynthesis genes, transporters and genes involved in lipid metabolism were found to be enriched specifically in the Δres2 strain upon exposure to lactose or DTT. Besides, redox homeostasis and DNA repair genes were specifically upregulated in the Δres2 strain, indicating an altered stress response.ConclusionThese results indicate that in the T. reesei Rut-C30 strain, RES2 does not act as a master regulator of the secretion pathway, but it contributes to a higher protein secretion by adjusting the expression of genes involved in different steps of protein synthesis and the secretion pathway.

Insights into chickpea (Cicer arietinum L.) genotype adaptations to terminal drought stress: Evaluating water-use patterns, root growth, and stress-responsive proteins

Chickpea (Cicer arietinum L.), a rainfed crop in semi-arid regions, experiences frequent intermittent drought stress, hindering growth. This study explored morpho-physiological and molecular responses of six chickpea genotypes (ICC 4958, BG 4005, Pusa 362, BGM 10218, RSG 888, ICC 1882) under terminal drought to enhance yield and adaptability. Drought stress was imposed during early podding in a controlled glasshouse experiment. Various physiological, root growth, fertility, and yield parameters were measured. Proteomics analysis was conducted on leaf, pod, and root tissue samples, collected at ∼0.3 fraction of transpirable soil water (FTSW). Significant differences occurred for various traits, including phenologies, water relations, pollen viability and germination, flower and pod numbers, abortion rates, photosynthetic apparatus and pigments, osmotic adjustments, canopy temperatures, root length, and densities, and overall yield and biomass. FTSW dynamics can aid genotype screening during early drought. Characterizing stress-responsive proteins can provide insights into cellular processes and adaptations. Terminal drought affected leaf central shoot metabolism, reducing photosynthetic capacity, while roots and pods reconfigured enzyme abundances to promote root growth and pod development. The extensive genotypic variation in proteome data, morpho-physiological traits, and water-use patterns presents opportunities for developing drought-adapted cultivars.

Proteomics and metabolomics analyses of Streptococcus agalactiae isolates from human and animal sources

Streptococcus agalactiae (S. agalactiae), group B Streptococcus (GBS), a major cause of infection in a wide variety of diseases, have been compared in different human and animal sources. We aimed to compare the bacterial proteome and metabolome profiles of human and animal S. agalactiae strains to delineate biological interactions relevant to infection. With the innovative advancement in mass spectrometry, a comparative result between both strains provided a solid impression of different responses to the host. For instance, stress-related proteins (Asp23/Gls24 family envelope stress response protein and heat shock protein 70), which play a role in the survival of GBS under extreme environmental conditions or during treatment, are highly expressed in human and animal strains. One human strain contains ꞵ-lactamase (serine hydrolase) and biofilm regulatory protein (lytR), which are important virulence regulators and potential targets for the design of novel antimicrobials. Another human strain contains the aminoglycosides-resistance bifunctional AAC/APH (A0A0U2QMQ5) protein, which confers resistance to almost all clinically used aminoglycosides. Fifteen different metabolites were annotated between the two groups. L-aspartic acid, ureidopropionic acid, adenosine monophosphate, L-tryptophan, and guanosine monophosphate were annotated at higher levels in human strains. Butyric acid, fumaric acid, isoleucine, leucine, and hippuric acid have been found in both human and animal strains. Certain metabolites were uniquely expressed in animal strains, with fold changes greater than 2. For example, putrescine modulates biofilm formation. Overall, this study provides biological insights into the substantial possible bacterial response reflected in its macromolecular production, either at the proteomic or metabolomic level.

The Benefits of Toxicity: M. smegmatis VapBC TA Module Is Induced by Tetracycline Exposure and Promotes Survival.

Toxin-antitoxin (TA) systems are widely present in bacterial genomes. Mycolicibacterium smegmatis, a common model organism for studying Mycobacterium tuberculosis physiology, has eight TA loci, including mazEF and vapBC. This study aims to investigate the physiological significance of these TA systems. Proteomic profiling was conducted on a culture overexpressing the VapC toxin, and the involvement of VapC in M. smegmatis stress responses to heat shock and antibiotic treatment was examined. While deciphering the underlying mechanisms of the altered stress resistance, we assessed the antibiotic susceptibility of vapBC, mazEF, and double vapBC-mazEF deletion mutants. Additionally, the mRNA levels of vapC and mazF were measured following tetracycline supplementation. The results reveal changes in the abundance of metabolic enzymes and stress response proteins associated with VapC overexpression. This activation of the general stress response leads to reduced thermosensitivity in M. smegmatis, but does not affect susceptibility to ciprofloxacin and isoniazid. Under tetracycline treatment, both vapC and mazF expression levels are increased, and the fate of the cell depends on the interaction between the corresponding TA systems.

Molecular Coping Mechanisms: Reprogramming tRNAs To Regulate Codon-Biased Translation of Stress Response Proteins.

As part of the classic central dogma of molecular biology, transfer RNAs (tRNAs) are integral to protein translation as the adaptor molecules that link the genetic code in messenger RNA (mRNA) to the amino acids in the growing peptide chain. tRNA function is complicated by the existence of 61 codons to specify 20 amino acids, with most amino acids coded by two or more synonymous codons. Further, there are often fewer tRNAs with unique anticodons than there are synonymous codons for an amino acid, with a single anticodon able to decode several codons by "wobbling" of the base pairs arising between the third base of the codon and the first position on the anticodon. The complications introduced by synonymous codons and wobble base pairing began to resolve in the 1960s with the discovery of dozens of chemical modifications of the ribonucleotides in tRNA, which, by analogy to the epigenome, are now collectively referred to as the epitranscriptome for not changing the genetic code inherent to all RNA sequences. tRNA modifications were found to stabilize codon-anticodon interactions, prevent misinitiation of translation, and promote translational fidelity, among other functions, with modification deficiencies causing pathological phenotypes. This led to hypotheses that modification-dependent tRNA decoding efficiencies might play regulatory roles in cells. However, it was only with the advent of systems biology and convergent "omic" technologies that the higher level function of synonymous codons and tRNA modifications began to emerge.Here, we describe our laboratories' discovery of tRNA reprogramming and codon-biased translation as a mechanism linking tRNA modifications and synonymous codon usage to regulation of gene expression at the level of translation. Taking a historical approach, we recount how we discovered that the 8-10 modifications in each tRNA molecule undergo unique reprogramming in response to cellular stresses to promote translation of mRNA transcripts with unique codon usage patterns. These modification tunable transcripts (MoTTs) are enriched with specific codons that are differentially decoded by modified tRNAs and that fall into functional families of genes encoding proteins necessary to survive the specific stress. By developing and applying systems-level technologies, we showed that cells lacking specific tRNA modifications are sensitized to certain cellular stresses by mistranslation of proteins, disruption of mitochondrial function, and failure to translate critical stress response proteins. In essence, tRNA reprogramming serves as a cellular coping strategy, enabling rapid translation of proteins required for stress-specific cell response programs. Notably, this phenomenon has now been characterized in all organisms from viruses to humans and in response to all types of environmental changes. We also elaborate on recent findings that cancer cells hijack this mechanism to promote their own growth, metastasis, and chemotherapeutic resistance. We close by discussing how understanding of codon-biased translation in various systems can be exploited to develop new therapeutics and biomanufacturing processes.

Involvement of CONSTANS-like Proteins in Plant Flowering and Abiotic Stress Response

The process of flowering in plants is a pivotal stage in their life cycle, and the CONSTANS-like (COL) protein family, known for its photoperiod sensing ability, plays a crucial role in regulating plant flowering. Over the past two decades, homologous genes of COL have been identified in various plant species, leading to significant advancements in comprehending their involvement in the flowering pathway and response to abiotic stress. This article presents novel research progress on the structural aspects of COL proteins and their regulatory patterns within transcription complexes. Additionally, we reviewed recent information about their participation in flowering and abiotic stress response, aiming to provide a more comprehensive understanding of the functions of COL proteins.

Genome-wide identification, expression analysis, and functional study of the bZIP transcription factor family and its response to hormone treatments in pea (Pisum sativum L.)

BackgroundBasic leucine zipper (bZIP) protein is a plant-specific transcription factor involved in various biological processes, including light signaling, seed maturation, flower development, cell elongation, seed accumulation protein, and abiotic and biological stress responses. However, little is known about the pea bZIP family.ResultsIn this study, we identified 87 bZIP genes in pea, named PsbZIP1 ~ PsbZIP87, via homology analysis using Arabidopsis. The genes were divided into 12 subfamilies and distributed unevenly in 7 pea chromosomes. PsbZIPs in the same subfamily contained similar intron/exon organization and motif composition. 1 tandem repeat event and 12 segmental duplication events regulated the expansion of the PsbZIP gene family. To better understand the evolution of the PsbZIP gene family, we conducted collinearity analysis using Arabidopsis thaliana, Oryza sativa Japonica, Fagopyrum tataricum, Solanum lycopersicum, Vitis vinifera, and Brachypodium distachyon as the related species of pea. In addition, interactions between PsbZIP proteins and promoters containing hormone- and stress-responsive cis-acting elements suggest that the regulation of PsbZIP expression was complex. We also evaluated the expression patterns of bZIP genes in different tissues and at different fruit development stages, all while subjecting them to five hormonal treatments.ConclusionThese results provide a deeper understanding of PsbZIP gene family evolution and resources for the molecular breeding of pea. The findings suggested that PsbZIP genes, specifically PSbZIP49, play key roles in the development of peas and their response to various hormones.

Gypenoside XVII attenuates renal ischemia-reperfusion injury by inhibiting endoplasmic reticulum stress and NLRP3 inflammasome-triggered pyroptosis

BackgroundRenal ischemia-reperfusion (I/R) is one of the main causes of acute kidney injury (AKI), for which there is currently no effective treatment. Recently, the interaction between endoplasmic reticulum (ER) stress and pyroptosis during AKI has been investigated. AimThe purpose of this study was to investigate the protective effects of Gypenoside XVII (GP-17) against I/R-induced renal injury. MethodsIn this study, mice were divided into 6 groups, sham group, I/R group, GP-17 low-, medium-, high-dose group, and positive control 4-PBA group. The renal I/R was performed in mice by clamping the bilateral renal pedicles for 40 min, and then reperfusing for 24 h. Blood and kidney samples were collected for analysis. ResultsThe results showed that GP-17 improved renal function and alleviated renal histopathological abnormalities caused by I/R. In addition, GP-17 pretreatment significantly decreased the expression or phosphorylation of ER stress response proteins including BIP, p-PERK, and CHOP. Besides, GP-17 inhibited the expression of pyroptosis proteins including caspase-1, GSDMD, and apoptotic protein BAX. The inflammatory factor IL-1β in these GP-17 pretreatment groups was also significantly reduced. ConclusionGP-17 blocked NLRP3 inflammasome activation by inhibiting ERS, thereby inhibiting renal tubular cell pyroptosis and apoptosis, and prevented renal I/R injury.

Screening UFMylation-associated genes in heart tissues of Ufm1-transgenic mice

UFMylation is a ubiquitination-like modification that is related to endoplasmic reticulum stress and unfolded protein response. A recent study reported that Ufl1, a key enzyme of UFMylation, protects against heart failure, indicating that UFMylation may be associated with heart function regulation. In the present study, we initially constructed a Flag-6×His-tagged Ufm1ΔSC transgenic (Tg-Ufm1) mouse model that enables UFMylation studies in vivo. Tg-Ufm1 mice showed significant activation of UFMylation in hearts. By using this model, we identified 38 potential Ufm1-binding proteins in heart tissues through LC‒MS/MS methods. We found that these proteins were associated with mitochondria, metabolism and chaperone binding. By using transcriptomic screening, we identified Tnfaip2 as a novel UFMylation-associated gene. Overexpression of Ufm1 significantly upregulated the protein expression of Tnfaip2, whereas isoproterenol treatment decreased Tnfaip2 expression in Tg-Ufm1 mice. These data may provide novel clues for UFMylation in cardiac hypertrophy.

Heat shock induces HuR-dependent MKP-1 posttranslational regulation through the p38 MAPK signaling cascade

Previous studies demonstrated that phosphatases play a pivotal role in modulating inflammation-associated signal transduction, particularly in the context of heat shock, where Mitogen-Activated Protein Kinase Phosphatase-1 (MKP-1) appears to have a central role. Recently, Human Antigen R (HuR) has also been identified as a factor that enhances stress-response protein MKP-1 levels. Consequently, we have directed our interest towards elucidating the mechanisms by which heat shock induces MKP-1 mRNA stabilization, dependent on HuR via the p38 MAPK Signaling Cascade. In this study, we subjected Mouse Embryonic Fibroblast (Mef) cells to heat shock treatment, resulting in a potent stabilization MKP-1 mRNA. The RNA-binding protein HuR, known to influence mRNA, was observed to bind to the MKP-1 AU-rich 3 ´untranslated region. Transfection of p38 wild-type Mef cells with a flag-HuR plasmid resulted in a significant increase in MKP-1 mRNA stability. Interestingly, transfection of the siRNA for HuR into Mef cells resulted in diminished MKP-1 mRNA stability following heat shock, inhibition of p38 MAPK activity effectively curtailed heat shock-mediated MKP-1 mRNA stability. Immunofluorescence analyses further revealed that the translocation of HuR was contingent on p38 MAPK Signaling Cascade. Collectively, these findings underscore the regulatory role of heat shock in MKP-1 gene expression at posttranscriptional levels. The mechanisms underlying the observed increased MKP-1 mRNA stability are shown to be partially dependent on HuR through the p38 MAPK Signaling Cascade.

Deciphering the mechanisms, hormonal signaling, and potential applications of endophytic microbes to mediate stress tolerance in medicinal plants.

The global healthcare market in the post-pandemic era emphasizes a constant pursuit of therapeutic, adaptogenic, and immune booster drugs. Medicinal plants are the only natural resource to meet this by supplying an array of bioactive secondary metabolites in an economic, greener and sustainable manner. Driven by the thrust in demand for natural immunity imparting nutraceutical and life-saving plant-derived drugs, the acreage for commercial cultivation of medicinal plants has dramatically increased in recent years. Limited resources of land and water, low productivity, poor soil fertility coupled with climate change, and biotic (bacteria, fungi, insects, viruses, nematodes) and abiotic (temperature, drought, salinity, waterlogging, and metal toxicity) stress necessitate medicinal plant productivity enhancement through sustainable strategies. Plants evolved intricate physiological (membrane integrity, organelle structural changes, osmotic adjustments, cell and tissue survival, reclamation, increased root-shoot ratio, antibiosis, hypersensitivity, etc.), biochemical (phytohormones synthesis, proline, protein levels, antioxidant enzymes accumulation, ion exclusion, generation of heat-shock proteins, synthesis of allelochemicals. etc.), and cellular (sensing of stress signals, signaling pathways, modulating expression of stress-responsive genes and proteins, etc.) mechanisms to combat stresses. Endophytes, colonizing in different plant tissues, synthesize novel bioactive compounds that medicinal plants can harness to mitigate environmental cues, thus making the agroecosystems self-sufficient toward green and sustainable approaches. Medicinal plants with a host set of metabolites and endophytes with another set of secondary metabolites interact in a highly complex manner involving adaptive mechanisms, including appropriate cellular responses triggered by stimuli received from the sensors situated on the cytoplasm and transmitting signals to the transcriptional machinery in the nucleus to withstand a stressful environment effectively. Signaling pathways serve as a crucial nexus for sensing stress and establishing plants' proper molecular and cellular responses. However, the underlying mechanisms and critical signaling pathways triggered by endophytic microbes are meager. This review comprehends the diversity of endophytes in medicinal plants and endophyte-mediated plant-microbe interactions for biotic and abiotic stress tolerance in medicinal plants by understanding complex adaptive physiological mechanisms and signaling cascades involving defined molecular and cellular responses. Leveraging this knowledge, researchers can design specific microbial formulations that optimize plant health, increase nutrient uptake, boost crop yields, and support a resilient, sustainable agricultural system.

The Interconnection between Hepatic Insulin Resistance and Metabolic Dysfunction-Associated Steatotic Liver Disease-The Transition from an Adipocentric to Liver-Centric Approach.

The central mechanism involved in the pathogenesis of MAFLD is insulin resistance with hyperinsulinemia, which stimulates triglyceride synthesis and accumulation in the liver. On the other side, triglyceride and free fatty acid accumulation in hepatocytes promotes insulin resistance via oxidative stress, endoplasmic reticulum stress, lipotoxicity, and the increased secretion of hepatokines. Cytokines and adipokines cause insulin resistance, thus promoting lipolysis in adipose tissue and ectopic fat deposition in the muscles and liver. Free fatty acids along with cytokines and adipokines contribute to insulin resistance in the liver via the activation of numerous signaling pathways. The secretion of hepatokines, hormone-like proteins, primarily by hepatocytes is disturbed and impairs signaling pathways, causing metabolic dysregulation in the liver. ER stress and unfolded protein response play significant roles in insulin resistance aggravation through the activation of apoptosis, inflammatory response, and insulin signaling impairment mediated via IRE1/PERK/ATF6 signaling pathways and the upregulation of SREBP 1c. Circadian rhythm derangement and biological clock desynchronization are related to metabolic disorders, insulin resistance, and NAFLD, suggesting clock genes as a potential target for new therapeutic strategies. This review aims to summarize the mechanisms of hepatic insulin resistance involved in NAFLD development and progression.

Single-cell transcriptomic atlas throughout anti-BCMA CAR-T therapy in patients with multiple myeloma.

The emergence of chimeric antigen receptor (CAR)-T therapy targeting B cell maturation antigen (BCMA) has improved the prognosis of patients with multiple myeloma (MM); however, the majority of patients eventually experience relapse. In this study, employing the latest single-cell RNA sequencing technology, we examined 24 bone marrow or peripheral blood samples collected throughout the course of anti-BCMA CAR-T therapy, analyzing a total of 59,725 bone marrow cells and 72,479 peripheral blood cells. Our findings reveal that tumor cells in relapsed patient exhibit higher expression levels of HSP90B1 and HSPA5, and demonstrate significantly enriched pathways regarding endoplasmic reticulum stress and unfolded protein response. In the analysis of T cells, we observed that patient with impaired effector function and increased expression of immune checkpoints in endogenous T cell are more susceptible to relapse. Notably, T cells from both the bone marrow microenvironment and peripheral blood share highly similar biological characteristics. Overall, this study provides a comprehensive atlas of endogenous immune cells, particularly in the relatively long term, after CAR-T therapy. It offers clinical evidence for a deeper understanding of the internal environment post CAR-T treatment and for identifying mechanisms underlying relapse.