Production Of Heat Shock Proteins Research Articles

The role of dietary fibre in intestinal heat shock protein regulation

SummaryThe gastrointestinal tract serves as a pivotal physical barrier that prevents the translocation of exogenous substances from the intestinal lumen into the systemic circulation. Dysfunction of intestinal barrier function has been implicated in the pathogenesis of several diseases, such as metabolic disorders. Heat shock proteins (HSPs) play a critical role in maintaining the resilience and viability of epithelial cells when exposed to stressors. Evidence suggests that dietary fibre (DF), a known inducer of HSP production, may be a promising candidate for strengthening the intestinal barrier. Understanding the regulation of intestinal HSPs and the protective effect of DF is critical to defending against environmental threats and preserving human health. To date, six DFs—pectin, chicory, psyllium, guar gum, partially hydrolysed guar gum, and xylooligosaccharide—have been reported to have promotive effects on intestinal HSP induction. DF promotes intestinal HSP induction through gut microbiota‐dependent and independent mechanisms. DF is fermented by gut microbiota to produce short‐chain fatty acids, specifically butyrate and propionate, to promote HSP production. Meanwhile, DF also promotes intestinal HSP induction through direct interaction with intestinal epithelial cells, independent of gut microbiota activity, although the precise mechanism is still unclear. Regulation of intestinal HSP occurs by transcriptional modulation through activation of heat shock transcription factors, primarily heat shock factor 1, or at the post‐transcriptional level by modulation of the translation process. This review highlights recent advances in understanding the role of DF in improving intestinal barrier function, with particular emphasis on the regulatory mechanisms of intestinal HSPs.

A longitudinal assessment of heat exposure and biomarkers of kidney function on heat shock protein 70 and antibodies among agricultural workers

BackgroundExposure to extreme heat impacts millions of people worldwide and outdoor workers are among the populations most affected by hot temperatures. Heat stress induces several biological responses in humans, including the production of heat shock proteins (HSP) and antibodies against HSP (anti-HSP) which may play a central role in the body’s cellular response to a hot environment.ObjectiveThis longitudinal study investigated the impact of elevated temperatures and humidity on the presence of HSP70 and anti-HSP70 and examined relationships with markers of kidney function in an at-risk workforce under conditions of extreme heat and exertion in Guatemala.MethodsWe collected ambient temperature and relative humidity data as well as biomarkers and clinical data from 40 sugarcane workers at the start and the end of a 6-month harvest. We used generalized mixed-effects models to estimate temperature effects on HSP70 and anti-HSP70 levels. In addition, we examined trends between HSP70 and anti-HSP70 levels and markers of kidney function across the harvest.ResultsAt the end of the harvest, temperatures were higher, and workers had, on average, higher levels of HSP70 and anti-HSP70 compared to the beginning of the season. We observed significant increasing trends with temperature indices, heat index, and HSP70 levels. Maximum temperature was associated with HSP70 increments after controlling for age, systolic and diastolic blood pressure (β: 0.21, 95% Confidence Interval: 0.09, 0.33). Kidney function decline across the harvest was associated with both higher levels of anti-HSP70 levels at the end of the harvest as well as greater increases in anti-HSP70 levels across the harvest.ConclusionsThese results suggest that workplace heat exposure may increase the production of HSP70 and anti-HSP70 levels and that there may be a relationship between increasing anti-HSP70 antibodies and the development of renal injury. HSP70 holds promise as a biomarker of heat stress in exposed populations.

Temperature acclimation and response to acute thermal stress in the adults of the snow crab Chionoecetes opilio Fabricius, 1788 (Decapoda: Brachyura: Oregoniidae)

ABSTRACT Ectothermic marine animals vary widely in their tolerance to temperature changes, and polar stenothermal species seem to have poor ability to compensate for a rise in water temperature. The sub-Arctic snow crab (Chionoecetes opilioFabricius, 1788) lives in the northwestern Atlantic Ocean and northern Pacific Ocean at temperatures ranging from about −1.5 °C to 4 °C. Since the metabolic costs overtake caloric intake above 7 °C, the snow crab appears to be energetically restricted to cold water. We investigated thermal stress responses in adult male crabs exposed to a sudden temperature increase to 9.5 °C for 24 hr after four weeks of acclimation at 2.5 °C or 5.5 °C. Heart-rate loggers implanted in a limited number of crabs showed 60% increase in cardiac activity during the thermal stress. Surplus oxygen supply in all crabs was inferred by the low hemolymph lactate and unchanged glucose levels, but only the crabs acclimated at 5.5 °C were still active at the elevated temperature. Low heat shock and oxidative stress responses were suggested by the missing upregulation of the genes encoding four heat shock proteins (Hsp70a, Hsc71, Hsp90a2, Hsp60) and the antioxidative enzymes superoxide dismutase and catalase. The trend towards inverse temperature-dependent on the expression of the hsp genes may be related to increased protein damage at low temperatures, or possible trade-offs between costs and benefits of producing heat shock proteins at elevated temperature. Although adult snow crabs seem to be able to cope with short-term heat stress, the tolerance to chronic elevated temperatures should be further examined using a larger number of individuals.

Molecular mechanisms of induced thermotolerance in two strains of Brachionus koreanus (Rotifera: Monogononta)

Temperature plays an important role in the occurrence and performance of organisms in aquatic ecosystems and is also one of the main environmental factors affecting species' survival and growth in aquaculture. As an important species for aquaculture sustainability, the rotifer Brachionus sp. benefits from inducible phenotypic traits that allow the organisms to cope with environmental stress. The exposure to high temperature has shown to increase production of heat shock proteins (HSPs) and histone modifications in several organisms, resulting in induced thermotolerance. This study aimed to evaluate the potential of non-lethal heat shock (NLHS) to induce thermotolerance in two strains of B. koreanus and pinpoint some of the molecular mechanisms involved in the process. Exposure of organisms to 42 °C for 30 min, with a subsequent recovery at 25 °C for 8 h demonstrated to increase thermotolerance in up to three-fold when organisms were, in a posterior phase, subjected to a lethal temperature. This study also showed that one of the strains is tendentially more thermotolerant than the other. Indeed, NLHS exposure resulted in increased mRNA expression of different Hsp genes and production of HSP70 in general, but different patterns of expression were observed between strains. However, a single NLHS showed to have no effects in epigenetic mechanisms, suggesting that the induced capacity to tolerate heat stress was transient and some more cycles of NLHS may be needed to promote a persistent effect.

Effects of HSP inducers on the gene expression of Heat Shock Proteins (HSPs) in cells extracted from sterlet sturgeon under temperature stress with antioxidant and immunity responses.

Global warming has profound effects on the living conditions and metabolism of organisms, including fish. The metabolic rate of fish increases as the temperature increases within its thermal tolerance range. Temperature changes can trigger a range of physiological reactions, including the activation of the stress axis and the production of HSPs. Under stress conditions, HSPs play a crucial role in antioxidant systems, immune responses, and enzyme activation. This study examined the effects of heat shock products (HSPs) on fish under temperature stress. Various HSP inducers (HSPis), including Pro-Tex®, amygdalin, and novel synthetic compounds derived from pirano piranazole (SZ, MZ, HN-P1, and HN-P2), were evaluated in isolated cells of sterlet sturgeon (Acipenser ruthenus) treated with temperature changes (18, 22, and 26°C). Cells from the liver, kidney, and gills were cultured in vitro in the presence and absence of temperature stress and treated with HSPi compounds. To assess HSP27, HSP70, and HSP90 expression patterns, Western blotting was used. The HSPis and HSPi + temperature stress treatments affected the antioxidant capacity and immune parameters, among other enzyme activities. The results showed that HSPi compounds increase cell survival in vitro, positively modulate HSP expression and antioxidant levels, and decrease immune parameters. HSPi can increase A. ruthenus tolerance to temperature stress. In addition, the results indicate that these compounds can reverse adverse temperature effects. Further research is needed to determine how these ecological factors affect fish species' health in vivo and in combination with other stressors.

Cytoprotective mechanism of cerebro-cognitive reserve

IntroductionConsideration of the reserve problem would be incomplete without an analysis of the cytoprotective mechanism. The predominant molecular hallmark of aging and degeneration is the accumulation of altered gene products. Moreover, several conditions, including protein, lipid, or glucose oxidation, disrupt redox homeostasis and lead to the accumulation of unfolded or misfolded proteins in the aging brain in case of AD, and other neurodegenerative diseases that have as a common denominator abnormal protein production, mitochondrial dysfunction and oxidative stress. Some authors classify aging, pathological aging, and neurodegeneration as “protein conformational diseases”.Objectivesscientific publicationsMethodsanalytical reviewResults The central nervous system has evolved a conserved unfolded protein response mechanism to cope with the accumulation of misfolded proteins. As one of the main intracellular redox systems involved in neuroprotection, the vitagene system becomes a potential neurohormetic target for novel cytoprotective interventions. Vitagens encode the cytoprotective heat shock proteins (Hsp) Hsp70 and heme oxygenase-1, as well as thioredoxin reductase and sirtuins. The cellular stress response is the ability of a cell to withstand stressful conditions, including the heat shock response. The production of heat shock proteins, including protein chaperones, is necessary for the folding and repair of damaged proteins, which promotes cell survival to avoid apoptosis.«Molecular chaperone» are proteins that function as part of an ancient defense system in our cells. They promote cell survival by sequestering damaged proteins and preventing their aggregation. Chaperone complexes are involved in the regulation of mitochondrial functions, assembly of the cytoplasmic proteolytic system of brain cells. The cellular response to stress requires the activation of survival pathways that are under the control of protective genes called vitagens. Vitagens are involved in the production of heat-shock protein molecules, glutathione, and bilirubin. They have antioxidant and anti-apoptotic activity and provide protection against oxidative stress.Conclusions Studies have shown that the heat shock response contributes to the maintenance of cellular homeostasis, the establishment of a cytoprotective state in a wide range of human diseases, including inflammation, cancer, aging, and neurodegenerative disorders. Endogenous proteins can be manipulated by food or pharmacological compounds, which represents an innovative approach to therapeutic intervention in neurodegenerative disorders, actually influencing reserve mechanisms and adaptive capacity.Disclosure of InterestNone Declared

Light-activated NIR-II imaging-guided tumor therapy with enhanced HPTT/starvation cycle

Establishing a phototheranostic platform constructed by the second near-infrared (NIR-II) region has proved a revolutionary and promising strategy for cancer treatment. However, the antitumor effectiveness is severely limited by the monotonicity of the NIR-photothermal therapy (HPTT) modality and tumor thermotolerance caused by the production of heat shock proteins (HSPs). Here, a minimalistic approach is used to construct an organic nanoplatform (IFT@PEG-GOX NPs) with the reciprocal cyclic promotion of hypothermia and starvation treatments for NIR-II imaging-guided tumor therapy. After the enhanced permeability and retention (EPR) effect causes IFT@PEG-GOX NPs to accumulate in tumors, glucose oxidase (GOx)-mediated tumor starvation may obstruct the production of adenosine triphosphate (ATP) and downregulation heat shock proteins (HSPs), thereby reducing the thermotolerance of cells. After that, sensitized HPTT was activated and GOx's catalytic activity was increased by NIR laser irradiation. Then, there would be a subsequent, intensified inhibition of HSP along with an additional amplification of the GOx-mediated tumor starvation. As a consequence, the HPTT/Starvation therapy (ST) bidirectional cycle method is initiated, leading to a bidirectional cyclic enhancing impact of HPTT and ST and significantly better tumor suppression.

Heat shock protein (HSP) and its correlation to cocaine-related death: a systematic review.

Investigating deaths related to chronic cocaine abuse can be a difficult task, particularly when they occur suddenly and without explanation. Cocaine abuse can trigger biological effects similar to physiological stressors, causing the body to produce heat-shock proteins (HSPs). However, there is still limited information on the specific levels of each HSP type. This systematic review aims to comprehensively collect and analyze all existing literature data regar-ding the relationship between HSPs and cocaine abuse to investigate whether HSPs can be utilized as forensic markers for accurately dia-gnosing cocaine-related deaths. The Authors conducted the literature search using PubMed and Scopus databases, searching for articles published between 1 January 1992 and 1 April 2024 using the text string: "heat shock protein" AND "cocaine". Twenty articles were collected, but only nine were included in the systematic review. The data gathered pertained to both human and murine species. The majority of the analyzed articles revealed an elevation in HSP25, HSP27, HSP60, HSP70, HSP72, and HSP73 levels in the brain, cerebellum, and liver, indicating cocaine-induced stress. The relationship between HSP and cocaine has been unclear over time. However, recent studies have shown that cocaine consumption leads to an increase in HSP levels, particularly in the central nervous system. This correlation can also be observed in certain types of liver cells that are capable of binding cocaine metabolites. In conclusion, HSP brain levels, along with other biomarkers, may be used to diagnose sudden, unexpected death related to cocaine abuse.

Functionalized Nanomaterials for Inhibiting ATP-Dependent Heat Shock Proteins in Cancer Photothermal/Photodynamic Therapy and Combination Therapy.

Phototherapies induced by photoactive nanomaterials have inspired and accentuated the importance of nanomedicine in cancer therapy in recent years. During these light-activated cancer therapies, a nanoagent can produce heat and cytotoxic reactive oxygen species by absorption of light energy for photothermal therapy (PTT) and photodynamic therapy (PDT). However, PTT is limited by the self-protective nature of cells, with upregulated production of heat shock proteins (HSP) under mild hyperthermia, which also influences PDT. To reduce HSP production in cancer cells and to enhance PTT/PDT, small HSP inhibitors that can competitively bind at the ATP-binding site of an HSP could be employed. Alternatively, reducing intracellular glucose concentration can also decrease ATP production from the metabolic pathways and downregulate HSP production from glucose deprivation. Other than reversing the thermal resistance of cancer cells for mild-temperature PTT, an HSP inhibitor can also be integrated into functionalized nanomaterials to alleviate tumor hypoxia and enhance the efficacy of PDT. Furthermore, the co-delivery of a small-molecule drug for direct HSP inhibition and a chemotherapeutic drug can integrate enhanced PTT/PDT with chemotherapy (CT). On the other hand, delivering a glucose-deprivation agent like glucose oxidase (GOx) can indirectly inhibit HSP and boost the efficacy of PTT/PDT while combining these therapies with cancer starvation therapy (ST). In this review, we intend to discuss different nanomaterial-based approaches that can inhibit HSP production via ATP regulation and their uses in PTT/PDT and cancer combination therapy such as CT and ST.

Heat-shock proteins, oxidative stress, and antioxidants in one-humped camels.

One-humped camels (Camelus dromedarius) exhibit remarkable adaptability to harsh desert environments through various physiological adaptations. This study aimed to assess variations and reference values of Heat-shock proteins (HSPs), physiological parameters, mineral concentrations, total antioxidant capacity (TAC), and malondialdehyde (MDA) in 90 healthy female one-humped camels from Zabol's outskirts in Iran. The objective was to understand how these camels adapt to heat stress. Blood samples were collected from camels located at five geographical regions and analyzed using standard kits and methods. Reference intervals for heat-shock protein 30 (HSP30), heat-shock protein 40 (HSP40), heat-shock protein 70 (HSP70), and heat-shock protein 90 (HSP90) were determined using the reference value advisor (RVA). The study found significant differences among different regions for HSPs (P < 0.05), MDA (P = 0.021), and TAC (P = 0.042) levels, indicating variations in adaptation mechanisms. However, no notable differences were observed for other measured parameters between these regions. There were no significant differences observed in the evaluated parameters between the age categories of > 36 months and < 36 months. The positive correlation between HSPs and MDA levels (ranging from 0.754 to 0.884) suggests that the synthesis of HSPs is triggered as a response to oxidative stress caused by an imbalance between the production of reactive oxygen species (ROS) and the body's antioxidant defenses. This oxidative stress, in turn, is a consequence of thermal stress. Additionally, the study reveals a negative association between TAC and HSP levels (ranging from - 0.660 to - 0.820), emphasizing the role of antioxidants in mitigating heat stress. The findings of this research offer compelling support for the critical role that HSPs play in protecting cells from heat-induced damage. Additionally, the presence of higher levels of HSPs in regions with more severe climate conditions serves as evidence of camels' adaptation to heat stress. These findings emphasize the substantial impact of environmental factors on HSP production and further reinforce the crucial role of HSPs in bolstering the resilience of camels. Further research is needed to explore HSP expression and mechanisms to effectively manage and enhance camel resilience in extreme temperatures.

Low-temperature exposure in early embryogenesis as a way of increasing the resistance of chicks to infectious diseases

The article is devoted to the problem of increasing the resistance of chicks from hatching to the age of 3 weeks to infectious diseases by technological methods. Dosed low-temperature exposure to the embryo during the sensitive period of early embryogenesis was proposed as an impact factor; influenza vaccine virus was used as a test virus for experimental infection of embryos. It was found that in the embryos after cooling, the titer of the virus was significantly lower by 1.5-12.0 times (p&lt;0.001) compared with the control. This fact indicates a decrease in the replicative activity of viral strains in embryos of this group. In chicken embryos of Russian Snow-White breed after cooling, there was a decrease in the infectious activity of the influenza A virus by 11.5 %, as well as a decrease in the infectious activity of the infectious bronchitis virus by 3.6-6.9 %, depending on the breed of the embryos. The level of chick resistance in the experimental group to diseases of bacterial etiology was also higher, as evidenced by the higher safety of 3-week-old chicks (0.8-1.1 % higher than in the control) and a higher bursa index in 12-day-old chicks (8.5-9.0 % higher than in the control). The hatchability of eggs of the experimental group was also 4.5 % higher than in the control. The effects obtained as a result of hypothermic exposure during this sensitive period of embryogenesis can be explained by inducing the production of heat and cold shock proteins by the embryo, which, in turn, activate innate antiviral reactions caused by major histocompatibility complex. However, this issue requires additional study with the involvement of molecular genetics methods, since the supposed mechanisms that cause an increase in resistance in response to low-temperature exposure in early ontogenesis need to be confirmed.

Lonidamine liposomes to enhance photodynamic and photothermal therapy of hepatocellular carcinoma by inhibiting glycolysis

Phototherapy, including photodynamic therapy (PDT) and photothermal therapy (PTT), has great promise in the treatment of cancer. However, there are many obstacles that can restrict the therapeutic efficacy of phototherapy. The hypoxic tumor microenvironment can restrict the production of reactive oxygen species (ROS) in PDT. As for PTT, the thermotolerance of cancer cells may lead to ineffective PTT. In this study, IR780 and glycolysis inhibitor lonidamine (LND)-encapsulated liposomes are prepared for photodynamic and photothermal therapy of hepatocellular carcinoma. IR780 can be used as a photosensitizer and photothermal agent for simultaneous PDT and PTT after being irradiated with 808 nm laser. LND can reduce the oxygen consumption of cancer cells by inhibiting glycolysis, which will relieve tumor hypoxia and produce more ROS for PDT. On the other hand, energy supply can be blocked by LND-induced glycolysis inhibition, which will inhibit the production of heat shock proteins (HSPs), reduce the thermotolerance of tumor cells, and finally enhance the therapeutic efficacy of PTT. The enhanced PTT is studied by measuring intracellular HSPs, ATP level, and mitochondrial membrane potential. The antitumor effect of IR780 and LND co-loaded liposomes is extensively investigated by in vitro and in vivo experiments. This research provides an innovative strategy to simultaneously enhance the therapeutic efficacy of PDT and PTT by inhibiting glycolysis, which is promising for future creative approaches to cancer phototherapy.

Comparative Transcriptome Analysis of Galeruca daurica Reveals Cold Tolerance Mechanisms.

Galeruca daurica (Joannis) is a pest species with serious outbreaks in the Inner Mongolian grasslands in recent years, and its larvae and eggs are extremely cold-tolerant. To gain a deeper understanding of the molecular mechanism of its cold-tolerant stress response, we performed de novo transcriptome assembly of G. daurica via RNA-Seq and compared the differentially expressed genes (DEGs) of first- and second-instar larvae grown and developed indoors and outdoors, respectively. The results show that cold tolerance in G. daurica is associated with changes in gene expression mainly involved in the glycolysis/gluconeogenesis pathway, the fatty acid biosynthesis pathway and the production of heat shock proteins (HSPs). Compared with the control group (indoor), the genes associated with gluconeogenesis, fatty acid biosynthesis and HSP production were up-regulated in the larvae grown and developed outdoors. While the changes in these genes were related to the physiological metabolism and growth of insects, it was hypothesized that the proteins encoded by these genes play an important role in cold tolerance in insects. In addition, we also investigated the expression of genes related to the metabolic pathway of HSPs, and the results show that the HSP-related genes were significantly up-regulated in the larvae of G. daurica grown and developed outdoors compared with the indoor control group. Finally, we chose to induce significant expression differences in the Hsp70 gene (Hsp70A1, Hsp70-2 and Hsp70-3) via RNAi to further illustrate the role of heat stress proteins in cold tolerance on G. daurica larvae. The results show that separate and mixed injections of dsHSP70A1, dsHsp70-2 and dsHsp70-3 significantly reduced expression levels of the target genes in G. daurica larvae. The super-cooling point (SCP) and the body fluid freezing point (FP) of the test larvae were determined after RNAi using the thermocouple method, and it was found that silencing the Hsp70 genes significantly increased the SCP and FP of G. daurica larvae, which validated the role of heat shock proteins in the cold resistance of G. daurica larvae. Our findings provide an important theoretical basis for further excavating the key genes and proteins in response to extremely cold environments and analyzing the molecular mechanism of cold adaptation in insects in harsh environments.

The Reaction of the Yeast Saccharomyces cerevisiae to Contamination of the Medium with Aflatoxins B2 and G1, Ochratoxin A and Zearalenone in Aerobic Cultures.

The mechanisms by which yeast cells respond to environmental stress include the production of heat shock proteins (HSPs) and the reduction of oxidative stress. The response of yeast exposed to aflatoxins B2+G1 (AFB2+G1), ochratoxin A (OTA), and zearalenone (ZEA) in aerobic conditions was studied. After 72 h of yeast cultivation in media contaminated with mycotoxins, the growth of yeast biomass, the level of malondialdehyde, and the activity of superoxide dismutase, glutathione S-transferase and glutathione peroxidase were examined; the expression profile of the following heat shock proteins was also determined: HSP31, HSP40, HSP60, HSP70, and HSP104. It was demonstrated that at the tested concentrations, both AFB2+G1 and ZEA inhibited yeast biomass growth. OTA at a concentration of 8.4 [µg/L] raised the MDA level. Intensified lipoperoxidation and increased activity of SOD and GPx were observed, regardless of the level of contamination with ZEA (300 µg/L or 900 µg/L). Increased contamination with AFB2+G1 and OTA caused an increase in the production of most HSPs tested (HSP31, HSP40, HSP70, HSP104). ZEA contamination in the used concentration ranges reduced the production of HSP31. The response of yeast cells to the presence of mycotoxin as a stressor resulted in the expression of certain HSPs, but the response was not systematic, which was manifested in different profiles of protein expression depending on the mycotoxin used. The tested mycotoxins influenced the induction of oxidative stress in yeast cells to varying degrees, which resulted in the activation of mainly SOD without GST mobilization or with a small involvement of GPx.

Significant influence of four highly conserved amino-acids in lipochaperon-active sHsps on the structure and functions of the Lo18 protein

To cope with environmental stresses, bacteria have developed different strategies, including the production of small heat shock proteins (sHSP). All sHSPs are described for their role as molecular chaperones. Some of them, like the Lo18 protein synthesized by Oenococcus oeni, also have the particularity of acting as a lipochaperon to maintain membrane fluidity in its optimal state following cellular stresses. Lipochaperon activity is poorly characterized and very little information is available on the domains or amino-acids key to this activity. The aim in this paper is to investigate the importance at the protein structure and function level of four highly conserved residues in sHSP exhibiting lipochaperon activity. Thus, by combining in silico, in vitro and in vivo approaches the importance of three amino-acids present in the core of the protein was shown to maintain both the structure of Lo18 and its functions.

Beat the Heat: Signaling Pathway-Mediated Strategies for Plant Thermotolerance

The frequent high temperatures caused by climate change have a very adverse impact on the growth and development of plants at different growth stages. Almost all cellular processes in plants are highly sensitive to high temperatures, but plants have their unique heat-resistant strategies. The plasma membrane usually senses temperature changes through changes in membrane fluidity. The accumulation of damaged proteins and reactive oxygen species in biofilms also helps calcium ions and thermal sensors cascade signals to transcription factors, thereby resisting high temperatures. There are also misfolded proteins in the endoplasmic reticulum and cytoplasm due to heat stress, which act as heat conduction signals. Carbohydrates commonly found in organisms can also serve as signaling molecules and participate in heat stress response. Heat shock transcription factor can effectively regulate the expression of heat-induced genes, producing heat shock proteins to maintain intracellular homeostasis.

Biomimetic Nano-Immunoactivator via Ionic Metabolic Modulation for Strengthened NIR-II Photothermal Immunotherapy.

Reprogramming the immunologically "cold" environment of solid tumors is currently becoming the mainstream strategy to elicit powerful and systemic anticancer immunity. Here, a facile and biomimetic nano-immunnoactivator (CuS/Z@M4T1 ) is detailed by engineering a Zn2+ -bonded zeolitic imidazolate framework-8 (ZIF-8) with CuS nanodots (NDs) and cancer cell membrane for amplified near-infrared-II (NIR-II) photothermal immunotherapy via Zn2+ metabolic modulation. Taking advantage of the NIR-II photothermal effect of CuS NDs and theacidic responsiveness of ZIF-8, CuS/Z@M4T1 rapidly causes intracellular Zn2+ pool overload and disturbs the metabolic flux of 4T1 cells, which effectively hamper the production of heat shock proteins and relieve the resistance of photothermal therapy (PTT). Thus, amplified immunogenic cell death is evoked and initiates the immune cascade both in vivo and in vitro as demonstrated by dendritic cells maturation and T-cell infiltration. Further combination with antiprogrammed death 1 (aPD-1) achieves escalated antitumor efficacy which eliminates the primary, distant tumor and avidly inhibits lung metastasis due to cooperation of enhanced photothermal stimulation and empowerment of cytotoxic T lymphocytes by aPD-1. Collectively, this work provides the first report of using the intrinsic modulation property of meta-organometallic ZIF-8 for enhanced cancer photoimmunotherapy together with aPD-1, thereby inspiring a novel combined paradigm of ion-rich nanomaterials for cancer treatment.

Maize and heat stress: Physiological, genetic, and molecular insights.

Global mean temperature is increasing at a rapid pace due to the rapid emission of greenhouse gases majorly from anthropogenic practices and predicted to rise up to 1.5°C above the pre-industrial level by the year 2050. The warming climate is affecting global crop production by altering biochemical, physiological, and metabolic processes resulting in poor growth, development, and reduced yield. Maize is susceptible to heat stress, particularly at the reproductive and early grain filling stages. Interestingly, heat stress impact on crops is closely regulated by associated environmental covariables such as humidity, vapor pressure deficit, soil moisture content, and solar radiation. Therefore, heat stress tolerance is considered as a complex trait, which requires multiple levels of regulations in plants. Exploring genetic diversity from landraces and wild accessions of maize is a promising approach to identify novel donors, traits, quantitative trait loci (QTLs), and genes, which can be introgressed into the elite cultivars. Indeed, genome wide association studies (GWAS) for mining of potential QTL(s) and dominant gene(s) is a major route of crop improvement. Conversely, mutation breeding is being utilized for generating variation in existing populations with narrow genetic background. Besides breeding approaches, augmented production of heat shock factors (HSFs) and heat shock proteins (HSPs) have been reported in transgenic maize to provide heat stress tolerance. Recent advancements in molecular techniques including clustered regularly interspaced short palindromic repeats (CRISPR) would expedite the process for developing thermotolerant maize genotypes.

Microwave-activated Cu-doped zirconium metal-organic framework for a highly effective combination of microwave dynamic and thermal therapy

Percutaneous microwave ablation (PMA) is a thermoablative method used as a minimally invasive treatment for liver cancer. However, the application of PMA is limited by its insufficient ROS generation efficiency and thermal effects. Herein, a new microwave-activated Cu-doped zirconium metal-organic framework (MOF) (CuZr MOF) used for enhanced PMA has a significantly improved microwave sensitizing effect. Owing to the strong inelastic collisions between ions confined in numerous micropores, CuZr MOF has strong microwave sensitivity and high thermal conversion efficiency, which can significantly improve microwave thermal therapy (MTT). Moreover, because of the existence of Cu2+ ions, a further benefit of CuZr MOF is their Fenton-like activity, in particular, microwaves used as an excitation source for microwave dynamic therapy (MDT) can improve the Fenton-like reaction to maximize the synergistic effectiveness of cancer therapy. Importantly, CuZr MOF can inhibit the production of heat shock proteins (HSPs) by producing abundant ROS to enhance tumor destruction. Mechanistically, we found that CuZr MOF + MW treatment modulates ferroptosis-mediated tumor cell death by targeting the HMOX1/GPX4 axis. In summary, this study develops a novel CuZr MOF microwave sensitizer with great potential for synergistic treatment of liver cancer by MTT and MDT.

Engineering a triple-functional magnetic gel driving mutually-synergistic mild hyperthermia-starvation therapy for osteosarcoma treatment and augmented bone regeneration

Malignant bone tumors result in high rates of disability and death and are difficult to treat in terms of killing tumors and repairing bone defects. Compared with other hyperthermia strategies, magnetic hyperthermia has become an effective therapy for treating malignant bone tumors due to its lack of depth limitations. However, tumor cells express heat shock protein (HSP) to resist hyperthermia, which reduces its curative effect. Competitive ATP consumption can reduce HSP production; fortunately, the basic principle of starvation therapy by glucose oxidase (GOx) is consuming glucose to control ATP production, thereby restricting HSP generation. We developed a triple-functional magnetic gel (Fe3O4/GOx/MgCO3@PLGA) as a magnetic bone repair hydrogels (MBRs) with liquid‒solid phase transition capability to drive magneto-thermal effects to simultaneously trigger GOx release and inhibit ATP production, reducing HSP expression and thereby achieving synergistic therapy for osteosarcoma treatment. Moreover, magnetic hyperthermia improves the effect of starvation therapy on the hypoxic microenvironment and achieves a reciprocal strengthening therapeutic effect. We further demonstrated that in situ MBRs injection effectively suppressed tumor growth in 143B osteosarcoma tumor-bearing mice and an in-situ bone tumor model in the rabbit tibial plateau. More importantly, our study also showed that liquid MBRs could effectively match bone defects and accelerate their reconstruction via magnesium ion release and enhanced osteogenic differentiation to augment the regeneration of bone defects caused by bone tumors, which generates fresh insight into malignant bone tumor treatment and the acceleration of bone defect repair.