Upregulation Of Heat Shock Proteins Research Articles

Facile Synthesis of Fe‐Based Metal‐Quinone Networks for Mutually Enhanced Mild Photothermal Therapy and Ferroptosis

AbstractMild photothermal therapy (MPTT) has emerged as a promising therapeutic modality for attenuating thermal damage to the normal tissues surrounding tumors, while the heat‐induced upregulation of heat shock proteins (HSPs) greatly compromises the curative efficacy of MPTT by increasing cellular thermo‐tolerance. Ferroptosis has been identified to suppress the overexpression of HSPs by the accumulation of lipid peroxides and reactive oxygen species (ROS), but is greatly restricted by overexpressed glutathione (GSH) in tumor microenvironment and undesirable ROS generation efficiency. Herein, a synergistic strategy based on the mutual enhancement of MPTT and ferroptosis is proposed for cleaving HSPs to recover tumor cell sensitivity. A facile method for fabricating a series of Fe‐based metal‐quinone networks (MQNs) by coordinated assembly is proposed and the representative FTP MQNs possess high photothermal conversion efficiency (69.3 %). Upon 808 nm laser irradiation, FTP MQNs not only trigger effective MPTT to induce apoptosis but more significantly, potentiate Fenton reaction and marked GSH consumption to boost ferroptosis, and the reinforced ferroptosis effect in turn can alleviate the thermal resistance by declining the HSP70 defense and reducing ATP levels. This study provides a valuable rationale for constructing a large library of MQNs for achieving mutual enhancement of MPTT and ferroptosis.

Facile Synthesis of Fe-Based Metal-Quinone Networks for Mutually Enhanced Mild Photothermal Therapy and Ferroptosis.

Mild photothermal therapy (MPTT) has emerged as a promising therapeutic modality for attenuating thermal damage to the normal tissues surrounding tumors, while the heat-induced upregulation of heat shock proteins (HSPs) greatly compromises the curative efficacy of MPTT by increasing cellular thermo-tolerance. Ferroptosis has been identified to suppress the overexpression of HSPs by the accumulation of lipid peroxides and reactive oxygen species (ROS), but is greatly restricted by overexpressed glutathione (GSH) in tumor microenvironment and undesirable ROS generation efficiency. Herein, a synergistic strategy based on the mutual enhancement of MPTT and ferroptosis is proposed for cleaving HSPs to recover tumor cell sensitivity. A facile method for fabricating a series of Fe-based metal-quinone networks (MQNs) by coordinated assembly is proposed and the representative FTP MQNs possess high photothermal conversion efficiency (69.3 %). Upon 808 nm laser irradiation, FTP MQNs not only trigger effective MPTT to induce apoptosis but more significantly, potentiate Fenton reaction and marked GSH consumption to boost ferroptosis, and the reinforced ferroptosis effect in turn can alleviate the thermal resistance by declining the HSP70 defense and reducing ATP levels. This study provides a valuable rationale for constructing a large library of MQNs for achieving mutual enhancement of MPTT and ferroptosis.

The role of SlCHRC in carotenoid biosynthesis and plastid development in tomato fruit

Chromoplasts are specialized plastids in plants involved in carotenoid synthesis, accumulation, and stress resistance. In tomatoes (Solanum lycopersicum), the Chromoplast-associated carotenoid binding protein (CHRC) regulates chromoplast development and carotenoid accumulation, although its precise mechanisms are not yet fully understood. To investigate the role of SlCHRC in carotenoid biosynthesis, we generated transgenic tomatoes using overexpression (oe-SlCHRC) and CRISPR/Cas9-mediated gene editing (cr-SlCHRC) techniques. The results demonstrated inhibited fruit ripening and delayed onset of color break in both transgenic lines. The oe-SlCHRC lines exhibited increased carotenoid accumulation, particularly (E/Z)-phytoene, lycopene, and γ-carotene, with abundant plastoglobules and carotenoid crystals observed via TEM. In contrast, cr-SlCHRC mutants showed a greener phenotype, reduced carotenoid content, and fewer plastoglobules at the BK + 10 stage. Transcriptome analysis indicated that SlCHRC influences key genes in carotenoid biosynthesis, such as SlNCED2, as well as genes related to chloroplast development, photosynthesis, and plastoglobule formation. Additionally, SlCHRC enhances heat stress tolerance in tomato fruits by upregulating heat shock proteins (HSPs), antioxidants, and proline accumulation. These findings indicate that SlCHRC plays a crucial role in improving tomato fruit quality under heat stress conditions.

Carrier-free multifunctional nanomedicine for enhanced hyperthermic intraperitoneal chemotherapy against abdominal pelvic tumors

Hyperthermic intraperitoneal chemotherapy (HIPEC) as an innovative approach in cancer therapy can deliver heated drugs directly into the abdominal cavity. Nevertheless, HIPEC also promotes upregulation of heat shock proteins, potentially leading to resistance against hyperthermia. Herein, novel nanoparticles self-assembled from gambogic acid (GA) and metformin (Met) are prepared through multiple interactions, enabling HIPEC for the treatment of orthotopic colorectal and ovarian cancers. Briefly, mild heat (abbreviated as MH) triggers immunogenic cell death (ICD) of cancer cells, leading to the release of damage-associated molecular patterns (DMAPs) that boost the immunogenicity of tumor microenvironment. GA, a potent inhibitor of heat shock protein (HSP-90), increases the sensitivity of cancer cells to hyperthermia-induced cell death. Moreover, GA acts as a chemotherapeutic agent itself, effectively inducing apoptosis of cancer cells and amplifying the ICD induced by MH. Met, can efficiently clear the tumor extracellular matrixes to facilitate the deeper penetration of nanoparticles into tumor tissues and promotes the infiltration of cytotoxic T lymphocytes. More importantly, the synergistic combination of GA and Met during HIPEC triggers a robust anti-tumor immune response in vivo. This integrated strategy offers a promising therapeutic avenue for the management of advanced abdominal pelvic tumor, possessing the potential for broad clinical applications.

Chitosan-based hydrogel incorporated with polydopamine and protoporphyrin for photothermal-oxidation sterilization of bacteria-infected wound therapy

Phototherapy has emerged as a potential treatment strategy for bacteria-infected wounds, but the inadequate bacteria-capturing ability and excessive damage to normal tissues from single phototherapy are huge limitations. To solve the issues, herein we report the design of chitosan-based hydrogel with bacteria capturing and combined photothermal/photodynamic sterilization functions. Such hydrogel is prepared by mixing chitosan (CS) as matrix, protoporphyrin (PpIX) as photosensitizer and polydopamine (PDA) as photothermal agent and then chemically cross-linking CS with glutaraldehyde. The resulting CS-PpIX-PDA hydrogel possesses a porous architecture (average pore porosity = 60.9 %), excellent swelling capabilities (swelling ratio = 1855 %) and rheological property (G′ > G″). The hydrogel can effectively produce reactive oxygen species (ROS) under 660 nm light irradiation due to the photodynamic effect of PpIX. Owing to the presence of PDA, the hydrogel displays a photoabsorption range between 600 and 1500 nm and can generate maximal temperature of 60 °C within 10 min under 808 nm laser illumination (0.6 W/cm2) through photothermal effect. Besides, under synergetic illumination of 808/660 nm laser, CS-PpIX-PDA hydrogel can induce the death of 99.9999 % of E. coli and 99.99999 % of S. aureus. Importantly, when coated on the wound site, the hydrogel exhibits a remarkable bacteria-trapping ability due to its porous structure and the presence of amino groups on chitosan. Under the excitation of 660/808 nm, the combined photothermal and photodynamic effects can effectively eradicate bacteria. Simultaneously, the hydrogel also demonstrates anti-inflammatory properties and upregulates Heat Shock Protein 90 (HSP90) expression, thereby promoting collagen deposition and facilitating wound healing. Therefore, the study may provide some new insights into the development of multifunctional hydrogel for photothermal-oxidation sterilization of bacteria-infected wound therapy.

Graphene Oxide/Black Phosphorus Functionalized Collagen Scaffolds with Enhanced Near-Infrared Controlled In Situ Biomineralization for Promoting Infectious Bone Defect Repair through PI3K/Akt Pathway.

Infectious bone defects resulting from surgery, infection, or trauma are a prevalent clinical issue. Current treatments commonly used include systemic antibiotics and autografts or allografts. Nevertheless, therapies come with various disadvantages, including multidrug-resistant bacteria, complications arising from the donor site, and immune rejection, which makes artificial implants desirable. However, artificial implants can fail due to bacterial infections and inadequate bone fusion after implantation. Thus, the development of multifunctional bone substitutes that are biocompatible, antibacterial, osteoconductive, and osteoinductive would be of great clinical importance. This study designs and prepares 2D graphene oxide (GO) and black phosphorus (BP) reinforced porous collagen (Col) scaffolds as a viable strategy for treating infectious bone defects. The fabricated Col-GO@BP scaffold exhibited an efficient photothermal antibacterial effect under near-infrared (NIR) irradiation. A further benefit of the NIR-controlled degradation of BP was to promote biomineralization by phosphorus-driven and calcium-extracted phosphorus in situ. The abundant functional groups in GO could synergistically capture the ions and enhance the in situ biomineralization. The Col-GO@BP scaffold facilitated osteogenic differentiation of bone marrow-derived mesenchymal stem cells (BMSC) by leveraging its mild photothermal effect and biomineralization process, which upregulated heat shock proteins (HSPs) and activated PI3K/Akt pathways. Additionally, systematic in vivo experiments demonstrated that the Col-GO@BP scaffold obviously promotes infectious bone repair through admirable photothermal antibacterial performance and enhanced vascularization. As a result of this study, we provide new insights into the photothermal activity of GO@BP nanosheets, their degradation, and a new biological application for them.

Protein Misfolding Releases Human HSF1 from HSP70 Latency Control

Heat shock factor 1 (HSF1) responds to stress to mount the heat shock response (HSR), a conserved transcriptional program that allows cells to maintain proteostasis by upregulating heat shock proteins (HSPs). The homeostatic stress regulation of HSF1 plays a key role in human physiology and health but its mechanism has remained difficult to pinpoint. Recent work in the budding yeast model has implicated stress-inducible chaperones of the HSP70 family as direct negative regulators of HSF1 activity. Here, we have investigated the latency control and activation of human HSF1 by HSP70 and misfolded proteins. Purified oligomeric HSF1-HSP70 (HSPA1A) complexes exhibited basal DNA binding activity that was inhibited by increasing the levels of HSP70 and, importantly, misfolded proteins reverted the inhibitory effect. Using site-specific UV photo-crosslinking, we monitored HSP70-HSF1 complexes in HEK293T cells. While HSF1 was bound by the substrate binding domain of HSP70 in unstressed cells, activation of HSF1 by heat shock as well as by inducing the misfolding of newly synthesized proteins resulted in release of HSF1 from the chaperone. Taken our results together, we conclude that latent HSF1 populate dynamic complexes with HSP70, which are sensitive to increased levels of misfolded proteins that compete for binding to the HSP70 substrate binding domain. Thus, human HSF1 is activated by various stress conditions that all titrate available HSP70.

Ivermectin Synergizes with Modulated Electro-hyperthermia and Improves Its Anticancer Effects in a Triple-Negative Breast Cancer Mouse Model.

Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype, with limited treatment options. Modulated electro-hyperthermia (mEHT) is a novel adjuvant cancer therapy that induces selective cancer damage. However, mEHT upregulates heat shock protein beta 1 (HSPB1), a cancer-promoting stress chaperone molecule. Thus, we investigated whether ivermectin (IVM), an anthelmintic drug, may synergize with mEHT and enhance its anticancer effects by inhibiting HSPB1 phosphorylation. Isogenic 4T1 TNBC cells were inoculated into BALB/c mice and treated with mEHT, IVM, or a combination of both. IVM synergistically improved the tumor growth inhibition achieved by mEHT. Moreover, IVM downregulated mEHT-induced HSPB1 phosphorylation. Thus, the strongest cancer tissue damage was observed in the mEHT + IVM-treated tumors, coupled with the strongest apoptosis induction and proliferation inhibition. In addition, there was no significant body weight loss in mice treated with mEHT and IVM, indicating that this combination was well-tolerated. In conclusion, mEHT combined with IVM is a new, effective, and safe option for the treatment of TNBC.

Toxic Effects of Carbaryl Exposure on Juvenile Asian Seabass (Lates calcarifer).

This study examines the physiological and immunological effects of 0.5 ppm carbaryl exposure on juvenile Asian seabass (Lates calcarifer) over 12 h to 72 h. Notable results include decreased activities of liver enzymes catalase (CAT), lactate dehydrogenase (LDH), and glutathione peroxidase (GSH-PX), while superoxide dismutase (SOD) levels remained stable, with the lowest activities of CAT and GSH-PX observed at 72 h. Serum biochemistry revealed increased alkaline phosphatase (AKP) and acid phosphatase (ACP) at 24 h, with declining aspartate aminotransferase (AST) and a peak in creatinine at 48 h. Histopathological analysis showed carbaryl-induced necrosis in liver and spleen cells, and increased melanomacrophage centers in both organs. Additionally, immune gene expression analysis indicated an upregulation of heat shock proteins and consistent elevation of complement component C3 and interleukin-8 (IL-8). These findings suggest that carbaryl exposure significantly impairs organ function and modulates immune responses in L. calcarifer, underlining the need for further research on protective strategies against pesticide impacts in aquaculture.

Effects of heat shocks, heat waves, and sustained warming on solitary bees

Along with higher average temperatures, global climate change is expected to lead to more frequent and intense extreme heat events, and these different types of warming are likely to differ in their effects on bees. Although solitary bees comprise >75% of bee species, and despite their ecological and economic value as pollinators, a literature search revealed that only 8% of studies on bee responses to warming involve solitary bees. Here we review studies that have addressed how solitary bees are affected by three main types of warming that vary in magnitude and duration: heat shocks, heat waves, and sustained warming. We focus on direct physiological and behavioral effects of warming on solitary bees, rather than the underlying mechanisms. We find that heat shocks have received little attention in solitary bees both in terms of number of studies and relative to social bees, and all of those studies examine the effects of heat shocks on a single genus, Megachile. This work has shown that heat-shocked eggs, larvae, and pupae tend to upregulate heat shock protein genes, while heat shock at the adult stage can increase mortality in male bees, potentially altering population sex ratios. We find that solitary bee responses to heat waves have received even less study, but the few studies suggest that these events can increase larval mortality and slow development time, and that bees may not be able to physiologically acclimate to heat wave conditions by increasing their critical thermal maxima. Finally, sustained warming, which has been relatively well-studied in solitary bees, can speed development rate, reduce body mass, increase mortality, and alter foraging behavior. Our review reveals knowledge gaps in the effects of heat shocks and heat waves on solitary bees and, more broadly, in the responses of unmanaged solitary bees to warming. To improve our ability to anticipate the consequences of climate change for these critical pollinators, we encourage research on solitary bee thermal responses that examines short-term, extreme warming and incorporates greater ecological realism and complexity.

Impact of histone deacetylase inhibition and arimoclomol on heat shock protein expression and disease biomarkers in primary culture models of familial ALS.

Protein misfolding and mislocalization are common themes in neurodegenerative disorders, including motor neuron disease, and amyotrophic lateral sclerosis (ALS). Maintaining proteostasis is a crosscutting therapeutic target, including the upregulation of heat shock proteins (HSP) to increase chaperoning capacity. Motor neurons have a high threshold for upregulating stress-inducible HSPA1A, but constitutively express high levels of HSPA8. This study compared the expression of these HSPs in cultured motor neurons expressing three variants linked to familial ALS: TAR DNA binding protein 43kDa (TDP-43)G348C, fused in sarcoma (FUS)R521G, or superoxide dismutase I (SOD1)G93A. All variants were poor inducers of Hspa1a, and reduced levels of Hspa8 mRNA and protein, indicating multiple compromises in chaperoning capacity. To promote HSP expression, cultures were treated with the putative HSP coinducer, arimoclomol, andclass I histone deacetylase inhibitors, to promote active chromatin for transcription, and with the combination. Treatments had variable, often different effects on the expression of Hspa1a and Hspa8, depending on the ALS variant expressed, mRNA distribution (somata and dendrites), and biomarker of toxicity measured (histone acetylation, maintaining nuclear TDP-43 and the neuronal Brm/Brg-associated factor chromatin remodeling complex component Brg1, mitochondrial transport, FUS aggregation). Overall, histone deacetylase inhibition alone was effective on more measures than arimoclomol. As in the FUS model, arimoclomol failed to induce HSPA1A or preserve Hspa8 mRNA in the TDP-43 model, despite preserving nuclear TDP-43 and Brg1, indicating neuroprotective properties other than HSP induction. The data speak to the complexity of drug mechanisms against multiple biomarkers of ALS pathogenesis, as well as to the importance of HSPA8 for neuronal proteostasis in both somata and dendrites.

Short-term dietary teprenone improved thermal tolerance and mitigated liver damage caused by heat stress in juvenile largemouth bass (Micropterus salmoides)

Heat stress seriously threatens fish survival and health, demanding immediate attention. Teprenone is a gastric mucosal protective agent that can induce heat shock protein expression. This research investigated the effects of teprenone on largemouth bass (Micropterus salmoides) subjected to heat stress. Juvenile fish were assigned to different groups: group C (control group, 0 mg teprenone/kg diet), T0, T200, T400, and T800 (0, 200, 400, and 800 mg teprenone/kg diet, respectively), which were fed for 3 days, followed by a day without the diet. All groups except group C were subjected to acute heat stress (from 24 °C to 35 °C at 1 °C per hour and then maintained at 35 °C for 3 h). The results were as follows: The critical thermal maxima were significantly higher in the T200, T400, and T800 groups compared with the T0 group (P < 0.05). Heat stress caused severe damage to the tissue morphology of the liver, while teprenone significantly reduced this injury (P < 0.05). Serum cortisol concentration decreased gradually as teprenone concentration increased, and the lowest concentration was observed in the T800 group (P < 0.05). Compared with the T0 group, the serum activities of aspartate aminotransferase, alanine aminotransferase, and gamma-glutamyl transferase were significantly lower in the T200, T400, and T800 groups (P < 0.05). The liver activities of catalase, total superoxide dismutase, and peroxidase were significantly higher in the T200 group than in the T0 group (P < 0.05). Transcript levels of the heat shock proteins (hsp90, hsp70, hspa5, and hsf1) and caspase family (caspase3 and caspase9) in the liver of the T200 group were significantly higher than those of the T0 group (P < 0.05). Western blot results showed that HSP70 and HSPA5 in the liver were significantly upregulated in the T200 group compared with the T0 group (P < 0.05). In summary, dietary teprenone improved thermal tolerance, alleviated heat stress damage in the liver, enhanced antioxidant capacity, and upregulated heat shock proteins in juvenile largemouth bass. This study offers theoretical support for applying teprenone in aquaculture to reduce financial losses caused by abiotic factors.

Global warming-related response after bacterial challenge in Astroides calycularis, a Mediterranean thermophilic coral

A worldwide increase in the prevalence of coral diseases and mortality has been linked to ocean warming due to changes in coral-associated bacterial communities, pathogen virulence, and immune system function. In the Mediterranean basin, the worrying upward temperature trend has already caused recurrent mass mortality events in recent decades. To evaluate how elevated seawater temperatures affect the immune response of a thermophilic coral species, colonies of Astroides calycularis were exposed to environmental (23 °C) or elevated (28 °C) temperatures, and subsequently challenged with bacterial lipopolysaccharides (LPS). Using immunolabeling with specific antibodies, we detected the production of Toll-like receptor 4 (TLR4) and nuclear factor kappa B (NF-kB), molecules involved in coral immune responses, and heat shock protein 70 (HSP70) activity, involved in general responses to thermal stress. A histological approach allowed us to characterize the tissue sites of activation (epithelium and/or gastroderm) under different experimental conditions. The activity patterns of the examined markers after 6 h of LPS stimulation revealed an up-modulation at environmental temperature. Under warmer conditions plus LPS-challenge, TLR4-NF-kB activation was almost completely suppressed, while constituent elevated values were recorded under thermal stress only. An HSP70 up-regulation appeared in both treatments at elevated temperature, with a significantly higher activation in LPS-challenge colonies. Such an approach is useful for further understanding the molecular pathogen-defense mechanisms in corals in order to disentangle the complex interactive effects on the health of these ecologically relevant organisms related to global climate change.

A novel NIR-II FL/ PA imaging-guided synergistic photothermal-immune therapy: Biomineralizing nanosystems integrated with anti-tumor and bone repair

Advanced stages of breast cancer are frequently complicated by bone metastases, which cause significant cancer-related bone destruction and mortality. However, the early precise theranostics of bone metastasis remains a formidable challenge in clinical practice. Herein,a novel all-in-one nanotheranostic system (ABI NYs) combining NIR-II FL/PA dual-modal imaging with photothermal-immunity therapeutic functionalities in one component was designed to precisely localize bone metastasis microscopic lesions and achieve complete tumor ablation at an early stage. The surface modification of the nanosystem with ibandronate (IBN) facilitates both passive and active targeting, significantly improving the detection rate of bone metastasis and suppressing the bone resorption. Superior photothermal performance produces sufficient heat to kill tumor cells while stimulating the upregulation of heat shock proteins 70 (HSP70), which triggers the immunogenic cell death (ICD) effect and the anti-tumor immune response. These all-in-one nanosystems precisely demonstrated early lesion localization in bone metastases and total tumor ablation with a single integration via “one-component, multi-functions” technique. To sum up, ABI NYs, as novel biomineralizing nanosystems integrated with anti-tumor and bone repair, present a synergistic therapy strategy, providing insight into the theranostics of bone metastases and clinical research.

Functions and Therapeutic Use of Heat Shock Proteins in Hepatocellular Carcinoma

Heat shock proteins are intracellular proteins expressed in prokaryotes and eukaryotes that help protect the cell from stress. They play an important role in regulating cell cycle and cell death, work as molecular chaperons during the folding of newly synthesized proteins, and also in the degradation of misfolded proteins. They are not only produced under stress conditions like acidosis, energy depletion, and oxidative stress but are also continuously synthesized as a result of their housekeeping functions. There are different heat shock protein families based on their molecular weight, like HSP70, HSP90, HSP60, HSP27, HSP40, etc. Heat shock proteins are involved in many cancers, particularly hepatocellular carcinoma, the main primary tumor of the liver in adults. Their deregulations in hepatocellular carcinoma are associated with metastasis, angiogenesis, cell invasion, and cell proliferation and upregulated heat shock proteins can be used as either diagnostic or prognostic markers. Targeting heat shock proteins is a relevant strategy for the treatment of patients with liver cancer. In this review, we provide insights into heat shock proteins and heat shock protein-like proteins (clusterin) in the progression of hepatocellular carcinoma and their use as therapeutic targets.

Lack of the Histone Deacetylase SIRT1 Leads to Protection against Endoplasmic Reticulum Stress through the Upregulation of Heat Shock Proteins.

Histone deacetylase SIRT1 represses gene expression through the deacetylation of histones and transcription factors and is involved in the protective cell response to stress and aging. However, upon endoplasmic reticulum (ER) stress, SIRT1 impairs the IRE1α branch of the unfolded protein response (UPR) through the inhibition of the transcriptional activity of XBP-1 and SIRT1 deficiency is beneficial under these conditions. We hypothesized that SIRT1 deficiency may unlock the blockade of transcription factors unrelated to the UPR promoting the synthesis of chaperones and improving the stability of immature proteins or triggering the clearance of unfolded proteins. SIRT1+/+ and SIRT1-/- fibroblasts were exposed to the ER stress inducer tunicamycin and cell survival and expression of heat shock proteins were analyzed 24 h after the treatment. We observed that SIRT1 loss significantly reduced cell sensitivity to ER stress and showed that SIRT1-/- but not SIRT1+/+ cells constitutively expressed high levels of phospho-STAT3 and heat shock proteins. Hsp70 silencing in SIRT1-/- cells abolished the resistance to ER stress. Furthermore, accumulation of ubiquitinated proteins was lower in SIRT1-/- than in SIRT1+/+ cells. Our data showed that SIRT1 deficiency enabled chaperones upregulation and boosted the proteasome activity, two processes that are beneficial for coping with ER stress.

Heat shock response during the resolution of inflammation and its progressive suppression in chronic-degenerative inflammatory diseases.

The heat shock response (HSR) is a crucial biochemical pathway that orchestrates the resolution of inflammation, primarily under proteotoxic stress conditions. This process hinges on the upregulation of heat shock proteins (HSPs) and other chaperones, notably the 70 kDa family of heat shock proteins, under the command of the heat shock transcription factor-1. However, in the context of chronic degenerative disorders characterized by persistent low-grade inflammation (such as insulin resistance, obesity, type 2 diabetes, nonalcoholic fatty liver disease, and cardiovascular diseases) a gradual suppression of the HSR does occur. This work delves into the mechanisms behind this phenomenon. It explores how the Western diet and sedentary lifestyle, culminating in the endoplasmic reticulum stress within adipose tissue cells, trigger a cascade of events. This cascade includes the unfolded protein response and activation of the NOD-like receptor pyrin domain-containing protein-3 inflammasome, leading to the emergence of the senescence-associated secretory phenotype and the propagation of inflammation throughout the body. Notably, the activation of the NOD-like receptor pyrin domain-containing protein-3 inflammasome not only fuels inflammation but also sabotages the HSR by degrading human antigen R, a crucial mRNA-binding protein responsible for maintaining heat shock transcription factor-1 mRNA expression and stability on heat shock gene promoters. This paper underscores the imperative need to comprehend how chronic inflammation stifles the HSR and the clinical significance of evaluating the HSR using cost-effective and accessible tools. Such understanding is pivotal in the development of innovative strategies aimed at the prevention and treatment of these chronic inflammatory ailments, which continue to take a heavy toll on global health and well-being.

Lipid membrane remodeling and metabolic response during isobutanol and ethanol exposure in Zymomonas mobilis

BackgroundRecent engineering efforts have targeted the ethanologenic bacterium Zymomonas mobilis for isobutanol production. However, significant hurdles remain due this organism’s vulnerability to isobutanol toxicity, adversely affecting its growth and productivity. The limited understanding of the physiological impacts of isobutanol on Z. mobilis constrains our ability to overcome these production barriers.ResultsWe utilized a systems-level approach comprising LC–MS/MS-based lipidomics, metabolomics, and shotgun proteomics, to investigate how exposure to ethanol and isobutanol impact the lipid membrane composition and overall physiology of Z. mobilis. Our analysis revealed significant and distinct alterations in membrane phospholipid and fatty acid composition resulting from ethanol and isobutanol exposure. Notably, ethanol exposure increased membrane cyclopropane fatty acid content and expression of cyclopropane fatty acid (CFA) synthase. Surprisingly, isobutanol decreased cyclopropane fatty acid content despite robust upregulation of CFA synthase. Overexpression of the native Z. mobilis’ CFA synthase increased cyclopropane fatty acid content in all phospholipid classes and was associated with a significant improvement in growth rates in the presence of added ethanol and isobutanol. Heterologous expression of CFA synthase from Clostridium acetobutylicum resulted in a near complete replacement of unsaturated fatty acids with cyclopropane fatty acids, affecting all lipid classes. However, this did not translate to improved growth rates under isobutanol exposure.Correlating with its greater susceptibility to isobutanol, Z. mobilis exhibited more pronounced alterations in its proteome, metabolome, and overall cell morphology—including cell swelling and formation of intracellular protein aggregates —when exposed to isobutanol compared to ethanol. Isobutanol triggered a broad stress response marked by the upregulation of heat shock proteins, efflux transporters, DNA repair systems, and the downregulation of cell motility proteins. Isobutanol also elicited widespread dysregulation of Z. mobilis’ primary metabolism evidenced by increased levels of nucleotide degradation intermediates and the depletion of biosynthetic and glycolytic intermediates.ConclusionsThis study provides a comprehensive, systems-level evaluation of the impact of ethanol and isobutanol exposure on the lipid membrane composition and overall physiology of Z. mobilis. These findings will guide engineering of Z. mobilis towards the creation of isobutanol-tolerant strains that can serve as robust platforms for the industrial production of isobutanol from lignocellulosic sugars.

Unraveling the drought-responsive transcriptomes in nodules of two common bean genotypes during biological nitrogen fixation.

Common bean (Phaseolus vulgaris) can efficiently fix atmospheric nitrogen when associated with Rhizobia. However, drought stress impairs plant metabolic processes, especially the biological nitrogen fixation (BNF). Here, we assessed transcriptional responses in nodules of two common bean genotypes to drought stress under BNF reliance. The RNA-Seq analysis yielded a total of 81,489,262 and 72,497,478 high quality reads for Negro Argel and BAT 477 genotypes, respectively. The reads were mapped to the Phaseolus vulgaris reference genome and expression analysis identified 145 and 1451 differentially expressed genes (DEGs) for Negro Argel and BAT 477 genotypes, respectively. Although BAT 477 had more DEGs, both genotypes shared certain drought-responsive genes, including an up-regulated heat shock protein (HSP) and a down-regulated peroxidase, indicating shared pathways activated during drought in nodule tissue. Functional analysis using MapMan software highlighted the up-regulation of genes involved in abiotic stress responses, such as HSPs and specific transcription factors (TFs), in both genotypes. There was a significant down-regulation in metabolic pathways related to antioxidant protection, hormone signaling, metabolism, and transcriptional regulation. To validate these findings, we conducted RT-qPCR experiments for ten DEGs in nodules from both genotypes, for which the expression profile was confirmed, thus reinforcing their functional relevance in the nodule responses to drought stress during BNF. BAT 477 genotype exhibited more pronounced response to drought, characterized by a high number of DEGs. The strong down-regulation of DEGs leads to transcriptional disturbances in several pathways related to stress acclimation such as hormone and antioxidant metabolism. Additionally, we identified several genes that are known to play key roles in enhancing drought tolerance, such as HSPs and crucial TFs. Our results provide new insights into the transcriptional responses in root-nodules, an underexplored tissue of plants mainly under drought conditions. This research paves the way for potential improvements in plant-bacteria interactions, contributing to common bean adaptations in the face of challenging environmental conditions.

Dementia with Lewy Bodies: Genomics, Transcriptomics, and Its Future with Data Science.

Dementia with Lewy bodies (DLB) is a significant public health issue. It is the second most common neurodegenerative dementia and presents with severe neuropsychiatric symptoms. Genomic and transcriptomic analyses have provided some insight into disease pathology. Variants within SNCA, GBA, APOE, SNCB, and MAPT have been shown to be associated with DLB in repeated genomic studies. Transcriptomic analysis, conducted predominantly on candidate genes, has identified signatures of synuclein aggregation, protein degradation, amyloid deposition, neuroinflammation, mitochondrial dysfunction, and the upregulation of heat-shock proteins in DLB. Yet, the understanding of DLB molecular pathology is incomplete. This precipitates the current clinical position whereby there are no available disease-modifying treatments or blood-based diagnostic biomarkers. Data science methods have the potential to improve disease understanding, optimising therapeutic intervention and drug development, to reduce disease burden. Genomic prediction will facilitate the early identification of cases and the timely application of future disease-modifying treatments. Transcript-level analyses across the entire transcriptome and machine learning analysis of multi-omic data will uncover novel signatures that may provide clues to DLB pathology and improve drug development. This review will discuss the current genomic and transcriptomic understanding of DLB, highlight gaps in the literature, and describe data science methods that may advance the field.