Hyperthermic Response Research Articles

Injectable Magnetic Hydrogel Incorporated with Anti-Inflammatory Peptide for Efficient Magnetothermal Treatment of Endometriosis.

Endometriosis is a prevalent gynecological condition characterized by chronic pelvic pain, dysmenorrhea, and infertility, affecting ≈176 million women of reproductive age worldwide. Current treatments, including pharmacological and surgical interventions, are often associated with significant side effects and high recurrence rates. Consequently, there is an urgent need for innovative and safer therapeutic approaches. In this study, an injectable magnetic hydrogel nanosystem is developed designed for the dual-purpose magnetothermal and anti-inflammatory treatment of endometriosis. This hydrogel incorporates Fe3O4 nanoparticles alongside an anti-inflammatory peptide. Upon magnetic activation, the Fe3O4 nanoparticles induce a localized hyperthermic response, raising the temperature of endometriotic lesions to 63.3°C, effectively destroying endometriotic cells. Concurrently, the thermally responsive hydrogel facilitates the controlled release of the anti-inflammatory peptide, thus modulating the inflammatory milieu. The biocompatibility and complete in vivo degradability of the hydrogel further enhance its therapeutic potential. The in vivo studies demonstrated that this injectable magnetic hydrogel system achieved a 90% reduction in the volume of endometriotic lesions and significantly decreased inflammatory markers, offering a promising non-invasive treatment modality for endometriosis. By integrating precise lesion ablation with the modulation of the inflammatory microenvironment, this system represents a novel approach to the clinical management of endometriosis.

Behavioural Responses of Beef Cattle to Hot Conditions.

Cattle are increasingly exposed to hot temperatures as a result of climate change, and a better understanding of behavioural responses could be beneficial for the diagnosis of heat loads. The changes in the positioning of key body parts, feeding behaviour, body maintenance, and respiratory dynamics were assessed in 24 Black Angus steers individually exposed to hot conditions and fed a finisher diet based on cereal grain or a substituted diet (8% of the grain replaced by an isoenergetic amount of lucerne hay). Increased respiration rate during the heat load period, compared to the recovery period, was associated with increased stepping, especially by left limbs. Cattle also reduced eating, grooming, and scratching during the heat load period. The lowered head, backward ear, vertical or raised tail, and increased respiration rate and panting persisted in cattle during the heat load period. Cattle on the cereal grain diet stood for longer and were more likely to hold their ears backward and tail vertical than those on the substituted diet. We conclude that these behaviours could be used to detect animals that are most affected and that changing from a cereal-based diet to a substituted diet containing a higher amount of fibre, such as lucerne hay, can reduce hyperthermic behavioural responses to a heat load.

Bile acids and the gut microbiome are involved in the hyperthermia mediated by 3,4-methylenedioxymethamphetamine (MDMA)

Hyperthermia induced by phenethylamines, such as 3,4–methylenedioxymethamphetamine (MDMA), can lead to life-threatening complications and death. Activation of the sympathetic nervous system and subsequent release of norepinephrine and activation of uncoupling proteins have been demonstrated to be the key mediators of phenethylamine-induced hyperthermia (PIH). Recently, the gut microbiome was shown to also play a contributing role in PIH. Here, the hypothesis that bile acids (BAs) produced by the gut microbiome are essential to PIH was tested. Changes in the serum concentrations of unconjugated primary BAs cholic acid (CA) and chenodeoxycholic acid (CDCA) and secondary BA deoxycholic acid (DCA) were measured following MDMA (20 mg/kg, sc) treatment in antibiotic treated and control rats. MDMA-induced a significant hyperthermic response and reduced the serum concentrations of three BAs 60 min post-treatment. Pretreatment with antibiotics (vancomycin, bacitracin and neomycin) in the drinking water for five days resulted in the depletion of BAs and a hypothermic response to MDMA. Gut bacterial communities in the antibiotic-treated group were distinct from the MDMA or saline treatment groups, with decreased microbiome diversity and alteration in taxa. Metagenomic functions inferred using the bioinformatic tool PICRUSt2 on 16S rRNA gene sequences indicated that bacterial genes associated to BA metabolism are less abundant in the antibiotic-MDMA treated group. Overall, these findings suggest that gut bacterial produced BAs might play an important role in MDMA-induced hyperthermia.

Auto tunable hyperthermic response of temperature sensitive magnetic fluid in agarose gel containing Mn1−xZnxFe2O4 nanoparticles

The present study reports the synthesis and physico-chemical characterization of Mn1−xZnxFe2O4 (x = 0.5, 0.4, 0.3, 0.2, 0.1) nanoparticles-based magnetic fluids with reference to magnetic fluid hyperthermia. The properties of these fluids are studied using XRD, FTIR, TGA, VSM and the induction heating equipment operated at 330 kHz. The heating response of the fluids is investigated within the safety limit of H·f (4.8 *108 A/m-s). The study is also extended to simulate it for the agarose gel phantom system. The power absorption by these samples in distilled water and in agarose gel is calculated to compare with the experimentally observed value. To the best of the author’s knowledge, no study of temperature sensitive magnetic fluid is reported on agarose gel, which simulates or phantom an in vivo condition. Results analysis show that the control of hyperthermia temperature is possible at lower fields and frequencies for the A91 sample with the smallest possible concentration, which can be acceptable for in vitro study.

Body temperature and thermoregulatory behaviour in the Endangered African Penguin Spheniscus demersus

Summary Heat stress from high temperatures has been recognised as a threat to several bird species and one that is likely to increase in severity and frequency as a result of global environmental change. Many seabirds are particularly vulnerable as their adaptations to forage in cold water can make it hard for them to resist heat gain while on land. The African Penguin Spheniscus demersus forages in cool water (10–20°C) but breeds and moults on land where temperatures can exceed 30°C. Little is known about its thermal physiology and when heat stress will occur. Here, we provide the first account of changes in body temperature and behaviour in African Penguins in response to an experimental increase in ambient temperature from 20°C to 35°C. Surprisingly, the highest body temperature observed (39.2°C) was recorded at the start of the study. Presumably, this response in body temperature was due to the stress of transport and handling. Penguins returned to normal body temperature (37.3°C) after 3.5 hours and maintained normothermia for roughly an hour. We then observed the onset of heat storage at an ambient temperature of 29°C, whereafter body temperature increased steadily at a rate of ca.0.2°C per 1°C increase in ambient temperature. Panting commenced at an ambient temperature of 31.4°C, when body temperature was 37.8°C. In addition to panting, penguins changed their posture to facilitate heat dissipation by standing, raising their heads, and extending their flippers. Our results corroborate field observations and support the argument that African Penguins are highly vulnerable to heat stress in the near future as extreme heat events become more severe and frequent due to climate change. Our results also confirm that penguins are sensitive to handling, which elicits a hyperthermic response. Given the general sensitivity of penguins to disturbance, from a conservation perspective, we advise that cautionary measures be implemented at colonies during critical life-history stages.

Effect of light and feeding regimes on the daily rhythm of thermal preference in Nile tilapia (Oreochromis niloticus)

Fish thermal preference varies throughout the day by allowing them to develop their biological processes under the most suitable thermal conditions. This study aimed to determine the effect of light and feeding regimes on the daily rhythm of thermal preference in Nile tilapia (Oreochromis niloticus). For this purpose, fish were allowed to freely choose their preferred temperature with different lighting conditions (experiment 1) and feeding schedules (experiment 2) using a multichamber tank with a thermal gradient from 26 °C to 34 °C or at a constant temperature of 30 °C (control). Fish were exposed to three different photoperiod combination [Light:Dark (LD) cycle, inverted LD cycle (DL) and constant darkness conditions (DD)] and four different feeding schedules [random (RD), feeding in the mid-light phase (mid-light, ML) or the mid-dark phase (mid-dark, MD), and fasting (FT)] . Regardless of the feeding/fasting protocol, a daily rhythm of temperature preference was observed, which suggests the role of LD cycles as the main synchronizer. In all the experimental phases, tilapia chose higher temperatures at dusk and cooler temperatures at dawn. Persistence of the rhythm for DD and FT indicated that an endogenous pacemaker may drive this rhythm. In both experiments, when fish were placed in the experimental tank on a thermal gradient for the first time, fish exhibited a stress-induced hyperthermia (SIH) response, characterized by the selection of higher temperatures. Conversely, the fish fed at MD selected cooler temperatures at night than the fish fed at ML or RD. Finally, FT resulted in selecting temperatures below the thermal optimum. These findings provide new insights into ecological and evolutionary aspects of fish thermoregulation, and might be useful for designing feeding protocols, which could impact fish welfare and, therefore, optimize fish production.

Biosynthesized gold nanoparticles that activate Toll-like receptors and elicit localized light-converting hyperthermia for pleiotropic tumor immunoregulation

Manipulating the tumor immune contexture towards a more active state can result in better therapeutic outcomes. Here we describe an easily accessible bacterial biomineralization-generated immunomodulator, which we name Ausome (Au + [exo]some). Ausome comprises a gold nanoparticle core covered by bacterial components; the former affords an inducible hyperthermia effect, while the latter mobilizes diverse immune responses. Multiple pattern recognition receptors actively participate in Ausome-initiated immune responses, which lead to the release of a broad spectrum of pro-inflammatory cytokines and the activation of effector immune cells. Upon laser irradiation, tumor-accumulated Ausome elicits a hyperthermic response, which improves tissue blood perfusion and contributes to enhanced infiltration of immunostimulatory modules, including cytokines and effector lymphocytes. This immune-modulating strategy mediated by Ausome ultimately brings about a comprehensive immune reaction and selectively amplifies the effects of local antitumor immunity, enhancing the efficacy of well-established chemo- or immuno-therapies in preclinical cancer models in female mice.

Preparation of Selenium-Based Drug-Modified Polymeric Ligand-Functionalised Fe3O4 Nanoparticles as Multimodal Drug Carrier and Magnetic Hyperthermia Inductor.

In recent years, much effort has been invested into developing multifunctional drug delivery systems to overcome the drawbacks of conventional carriers. Magnetic nanoparticles are not generally used as carriers but can be functionalised with several different biomolecules and their size can be tailored to present a hyperthermia response, allowing for the design of multifunctional systems which can be active in therapies. In this work, we have designed a drug carrier nanosystem based on Fe3O4 nanoparticles with large heating power and 4-amino-2-pentylselenoquinazoline as an attached drug that exhibits oxidative properties and high selectivity against a variety of cancer malignant cells. For this propose, two samples composed of homogeneous Fe3O4 nanoparticles (NPs) with different sizes, shapes, and magnetic properties have been synthesised and characterised. The surface modification of the prepared Fe3O4 nanoparticles has been developed using copolymers composed of poly(ethylene-alt-maleic anhydride), dodecylamine, polyethylene glycol and the drug 4-amino-2-pentylselenoquinazoline. The obtained nanosystems were properly characterised. Their in vitro efficacy in colon cancer cells and as magnetic hyperthermia inductors was analysed, thereby leaving the door open for their potential application as multimodal agents.

Putative malignant hyperthermia mutation CaV1.1-R174W is insufficient to trigger a fulminant response to halothane or confer heat stress intolerance

Malignant hyperthermia susceptibility (MHS) is an autosomal dominant pharmacogenetic disorder that manifests as a hypermetabolic state when carriers are exposed to halogenated volatile anesthetics or depolarizing muscle relaxants. In animals, heat stress intolerance is also observed. MHS is linked to over 40 variants in RYR1 that are classified as pathogenic for diagnostic purposes. More recently, a few rare variants linked to the MHS phenotype have been reported in CACNA1S, which encodes the voltage-activated Ca2+ channel CaV1.1 that conformationally couples to RyR1 in skeletal muscle. Here, we describe a knock-in mouse line that expresses one of these putative variants, CaV1.1-R174W. Heterozygous (HET) and homozygous (HOM) CaV1.1-R174W mice survive to adulthood without overt phenotype but fail to trigger with fulminant malignant hyperthermia when exposed to halothane or moderate heat stress. All three genotypes (WT, HET, and HOM) express similar levels of CaV1.1 by quantitative PCR, Western blot, [3H]PN200-110 receptor binding and immobilization-resistant charge movement densities in flexor digitorum brevis fibers. Although HOM fibers have negligible CaV1.1 current amplitudes, HET fibers have similar amplitudes to WT, suggesting a preferential accumulation of the CaV1.1-WT protein at triad junctions in HET animals. Never-the-less both HET and HOM have slightly elevated resting free Ca2+ and Na+ measured with double barreled microelectrode in vastus lateralis that is disproportional to upregulation of transient receptor potential canonical (TRPC) 3 and TRPC6 in skeletal muscle. CaV1.1-R174W and upregulation of TRPC3/6 alone are insufficient to trigger fulminant malignant hyperthermia response to halothane and/or heat stress in HET and HOM mice.

Optimization of magnetic fluid hyperthermia protocols for the elimination of breast cancer cells MCF7 using Mn-Zn ferrite ferrofluid

The present study aimed to optimize magnetic fluid hyperthermia (MFH) protocols by standardizing MF incubation time, hyperthermic duration, magnetic field, and MFH sessions to achieve a better hyperthermic response for the profuse killing of human breast cancer cell cells MCF7. Magnetic nanoparticles and MF were characterized using XRD, VSM, and DLS. Induction heating was performed for 30 min at field strengths of 12.5 and 13.3 kA/m at a fixed frequency of 330 kHz with varying concentrations and incubation duration on MCF7 cells. Single and multiple sessions hyperthermia protocols were used to kill MCF7 cells and the cytotoxicity effect was analyzed using MTT assay. Single and multiple sessions MFH protocols were established to kill breast cancer cells utilizing 0.2 mg/mL MF at 13.3 kA/m field and 330 kHz frequency and maintaining the hyperthermic temperature of 43–45 °C for 30 min. The single session MFH revealed severe toxicity of MF leading to more than 75% of cell death after 24 h of MF incubation. Multiple sessions hyperthermia resulted in more than 90% killing of MCF7 cells after two consequent 3 h MF incubation with 3 h gap. Each 3 h of MF incubation was followed by 30 min of induction heating. Multiple sessions hyperthermia was effective in killing a larger cell population compared to the single session protocol. The results may help in optimizing protocols for the profuse killing of cancer cells of multiple origins, and aid in deciding futuristic in vivo MFH-based therapeutic strategies against breast cancer.Graphical Variation in MCF7 cells’ viability due to HT, MF, and MF + HT in multiple sessions.

Influence of adrenalectomy on the gut microbiome and MDMA-induced hyperthermia

The increased use of the stimulant drug, 3,4-methylenedioxymethamphetamine (MDMA), more commonly known as Ecstasy, Molly or X, has been linked to the development of life-threatening hyperthermia in human and animal models. The current study aimed to investigate the role of the gut-adrenal axis in MDMA-induced hyperthermia by assessing the influence of the acute exogenous supplementation with norepinephrine (NE) or corticosterone (CORT) to adrenalectomized (ADX) rats following MDMA administration. MDMA (10 mg/kg, sc) resulted in significant increase of body temperature in SHAM animals compared to ADX animals at 30-, 60- and 90-min timepoints post-MDMA treatment. The attenuated MDMA-mediated hyperthermic response seen in ADX animals was partially restored by the exogenous administration of NE (3 mg/kg, ip) or CORT (3 mg/kg, ip) 30 min after MDMA treatment. Additionally, 16 S rRNA analysis revealed distinct changes in the gut microbiome composition and diversity notable by the higher abundance of minor phyla Actinobacteria, Verrucomicrobia and Proteobacteria in ADX rats compared to control and SHAM rats. Furthermore, MDMA administration resulted in marked changes in the dominant phyla Firmicutes and Bacteroidetes and minor phyla Actinobacteria, Verrucomicrobia and Proteobacteria in ADX animals. The most notable changes in the gut microbiome upon CORT treatment were reported with increase in Bacteroidetes and decrease in Firmicutes phyla whereas NE treatment resulted in increase in Firmicutes and decrease in Bacteroidetes and Proteobacteria post treatment. These results suggest a correlation between the sympathoadrenal axis, gut microbiome structure and diversity and MDMA-mediated hyperthermia.

The hyperthermic response to intra-preoptic area administration of agmatine in male rats

Agmatine is an endogenous biogenic amine that exerts various effects on the central nervous system. The hypothalamic preoptic area (POA, thermoregulatory command center) has high agmatine immunoreactivity. In this study, in conscious and anesthetized male rats, agmatine microinjection into the POA induced hyperthermic responses associated with increased heat production and locomotor activity. Intra-POA administration of agmatine increased the locomotor activity, the brown adipose tissue temperature and rectum temperature, and induced shivering as demonstrated by increased neck muscle electromyographic activity. However, intra-POA administration of agmatine almost had no impact on the tail temperature of anesthetized rats. Furthermore, there were regional differences in the response to agmatine in the POA. The most effective sites for the microinjection of agmatine to elicit hyperthermic responses were localized in the medial preoptic area (MPA). Agmatine microinjection into the median preoptic nucleus (MnPO) and lateral preoptic nucleus (LPO) had a minimal effect on the mean core temperature. Analysis of the in vitro discharge activity of POA neurons in brain slices when perfused with agmatine showed that agmatine inhibited most warm-sensitive but not temperature-insensitive neurons in the MPA. However, regardless of thermosensitivity, the majority of MnPO and LPO neurons were not responsive to agmatine. The results demonstrated that agmatine injection into the POA of male rats, especially the MPA, induced hyperthermic responses, which may be associated with increased BAT thermogenesis, shivering and locomotor activity by inhibiting warm-sensitive neurons.

Selection of preferred thermal environment and cold-avoidance responses in rats rely on signals transduced by the dorsal portion of the lateral funiculus of the spinal cord

ABSTRACT Thermoregulatory behaviors are powerful effectors for core body temperature (Tc) regulation. We evaluated the involvement of afferent fibers ascending through the dorsal portion of the lateral funiculus (DLF) of the spinal cord in “spontaneous” thermal preference and thermoregulatory behaviors induced by thermal and pharmacological stimuli in a thermogradient apparatus. In adult Wistar rats, the DLF was surgically severed at the first cervical vertebra bilaterally. The functional effectiveness of funiculotomy was verified by the increased latency of tail-flick responses to noxious cold (−18°C) and heat (50°C). In the thermogradient apparatus, funiculotomized rats showed a higher variability of their preferred ambient temperature(Tpr) and, consequently, increased Tc fluctuations, as compared to sham-operated rats. The cold-avoidance (warmth-seeking) response to moderate cold (whole-body exposure to ~17°C) or epidermal menthol (an agonist of the cold-sensitive TRPM8 channel) was attenuated in funiculotomized rats, as compared to sham-operated rats, and so was the Tc (hyperthermic) response to menthol. In contrast, the warmth-avoidance (cold-seeking) and Tc responses of funiculotomized rats to mild heat (exposure to ~28°C) or intravenous RN-1747 (an agonist of the warmth-sensitive TRPV4; 100 μg/kg) were unaffected. We conclude that DLF-mediated signals contribute to driving spontaneous thermal preference, and that attenuation of these signals is associated with decreased precision of Tc regulation. We further conclude that thermally and pharmacologically induced changes in thermal preference rely on neural, presumably afferent, signals that travel in the spinal cord within the DLF. Signals conveyed by the DLF are important for cold-avoidance behaviors but make little contribution to heat-avoidance responses.

The neural pathway of the hyperthermic response to antagonists of the transient receptor potential vanilloid-1 channel

ABSTRACT We identified the neural pathway of the hyperthermic response to TRPV1 antagonists. We showed that hyperthermia induced by i.v. AMG0347, AMG 517, or AMG8163 did not occur in rats with abdominal sensory nerves desensitized by pretreatment with a low i.p. dose of resiniferatoxin (RTX, TRPV1 agonist). However, neither bilateral vagotomy nor bilateral transection of the greater splanchnic nerve attenuated AMG0347-induced hyperthermia. Yet, this hyperthermia was attenuated by bilateral high cervical transection of the spinal dorsolateral funiculus (DLF). To explain the extra-splanchnic, spinal mediation of TRPV1 antagonist-induced hyperthermia, we proposed that abdominal signals that drive this hyperthermia originate in skeletal muscles – not viscera. If so, in order to prevent TRPV1 antagonist-induced hyperthermia, the desensitization caused by i.p. RTX should spread into the abdominal-wall muscles. Indeed, we found that the local hypoperfusion response to capsaicin (TRPV1 agonist) in the abdominal-wall muscles was absent in i.p. RTX-desensitized rats. We then showed that the most upstream (lateral parabrachial, LPB) and the most downstream (rostral raphe pallidus) nuclei of the intrabrain pathway that controls autonomic cold defenses are also required for the hyperthermic response to i.v. AMG0347. Injection of muscimol (inhibitor of neuronal activity) into the LPB or injection of glycine (inhibitory neurotransmitter) into the raphe blocked the hyperthermic response to i.v. AMG0347, whereas i.v. AMG0347 increased the number of c-Fos cells in the raphe. We conclude that the neural pathway of TRPV1 antagonist-induced hyperthermia involves TRPV1-expressing sensory nerves in trunk muscles, the DLF, and the same LPB-raphe pathway that controls autonomic cold defenses.

Modulation of hyperthermic and relaxometric responses of magnetic iron oxide nanoparticles through ligand exchange provides design criteria for dual-functionality

Changes in hyperthermic and MRI efficacies of magnetic nanoparticle suspensions following ligand exchange/phase transfer and in the gel phase reveals how the responses are determined by moment dynamics and particle and solvent diffusion.

Varying intensity of simulated infection partially affects the magnitude of the acute-phase immune response in the subterranean rodent Ctenomys talarum.

The acute phase response (APR), coordinated by a complex network of components of the immune and neuroendocrine systems, plays a key role in early immune defense. This response can be elicited by a wide variety of pathogens at different intensities (frequencies and doses), hence experimental immune challenges with antigen gradients makes it possible to evaluate sickness progression with a better representation of what occurs in natural systems. However, how infection intensity could shape the APR magnitude in wild species is still poorly understood. Here, the immune response was activated in the subterranean rodent Ctenomys talarum with a gradient of lipopolysaccharide (LPS) doses (0.5, 1, 1.5, and 2 mg/kg of body mass). Changes in body temperature, body mass, and energetic costs were evaluated over time. We also assessed cortisol levels, white blood cells counts and neutrophil: lymphocyte ratios, before and after injection. Results indicated that during the APR, C. talarum shows a hyperthermic response, which is maintained for 6 h, with slight differences among antigen doses in the pattern of thermal response and body mass change. A maximum increase in body temperature of 0.83°C to 1.63°C was observed during the first hour, associated with a metabolic cost that ranged from 1.25 to 1.41 ml O2 /gh. Although no clear effects of treatment were detected on leukocyte abundance, we found increments in neutrophil: lymphocyte ratios and gradual increases in cortisol levels corresponding to the intensity of simulated infection, which may indicate redistribution of immune cells and enhancement of immune function. An evident sickness syndrome was observed even at the lowest LPS dose that was characterized by an increase in body temperature, energy expenditure, and N: L ratio, as well as a dose-dependent increase in cortisol levels. Although in nature, other constraints and challenges could affect the magnitude and costs of immune responses, C. talarum mounts an effective APR with a low increase in their daily energy expenditure, regardless of LPS dose.

Acute heat stress-indued apoptosis in mouse skeletal muscle is not associated with alteration of glutamine homeostasis.

We previously demonstrated that exposing mice to heat causes functional and ultrastructural mitochondrial alterations and apoptosis in skeletal muscle. Emerging evidence indicates that glutamine (Gln) deprivation may increase cell susceptibility to apoptosis whereas Gln supplementation may protect cells against heat stress. In this study, we investigated the effect of short-term Gln treatment on heat-induced changes in mouse skeletal muscle. Male mice received vehicle, low-dose Gln (100 mg/kg/d) or high-dose Gln (300 mg/kg/d) through daily gavage for 10 days before a heat exposure test. During heat exposure, mice displayed a hyperthermic response and no significant differences in peak core body temperature were noted across the three groups. Neither heat exposure nor pretreatment with low-dose or high-dose Gln significantly affected Gln concentrations in plasma and gastrocnemius muscles. Heat-exposed mice had significantly higher caspase 3/7 levels in gastrocnemius muscle compared to unexposed controls. Heat exposure significantly increased ROS production and mitochondrial fragmentation and decreased mitochondrial membrane potential in flexor digitorum brevis muscle. These changes were not affected by low- or high-dose Gln pretreatment. Together, acute heat stress did not disrupt Gln homeostasis in mouse skeletal muscle and Gln supplementation did not protect mouse skeletal muscle against heat-induced injury. The results of this study do not support a role of Gln in heat-induced skeletal muscle apoptosis.

Tuning of Magnetic Hyperthermia Response in the Systems Containing Magnetosomes.

A number of materials are studied in the field of magnetic hyperthermia. In general, the most promising ones appear to be iron oxide particle nanosystems. This is also indicated in some clinical trial studies where iron-based oxides were used. On the other hand, the type of material itself provides a number of variations on how to tune hyperthermia indicators. In this paper, magnetite nanoparticles in various forms were analyzed. The nanoparticles differed in the core size as well as in the form of their arrangement. The arrangement was determined by the nature of the surfactant. The individual particles were covered chemically by dextran; in the case of chain-like particles, they were encapsulated naturally in a lipid bilayer. It was shown that in the case of chain-like nanoparticles, except for relaxation, a contribution from magnetic hysteresis to the heating process also appears. The influence of the chosen methodology of magnetic field generation was also analyzed. In addition, the influence of the chosen methodology of magnetic field generation was analyzed. The application of a rotating magnetic field was shown to be more efficient in generating heat than the application of an alternating magnetic field. However, the degree of efficiency depended on the arrangement of the magnetite nanoparticles. The difference in the efficiency of the rotating magnetic field versus the alternating magnetic field was much more pronounced for individual nanoparticles (in the form of a magnetic fluid) than for systems containing chain nanoparticles (magnetosomes and a mix of magnetic fluid with magnetosomes in a ratio 1:1).

Reversal of temperature responses to methylone mediated through bi-directional fecal microbiota transplantation between hyperthermic tolerant and naïve rats

ABSTRACT The synthetic cathinone (“bath salt”) methylone induces a hyperthermia response and with chronic administration tolerance to this hyperthermia has been reported. The microbiome-gut-brain axis has been implicated in multiple bodily systems and pathologies, and intentional manipulation of the gut-microbiome has yielded clinically significant results. Here, we examined the effects of bi-directional Fecal Microbiota Transplantation (FMT) between methylone-induced hyperthermic tolerant (MHT) and methylone-naïve (MN) rats. Rats treated with methylone once per week developed tolerance to methylone-induced hyperthermia by the fourth week. Once tolerant, daily bi-directional FMT between the two groups were performed for seven days prior to the next methylone treatment. The FMT abated the developed tolerance in the MHT group. When treated with methylone for the first time following FMT, recipient MN rats displayed significant tolerance to hyperthermia despite it being their initial drug treatment. Post-FMT, MHT rats displayed elevations in norepinephrine and expression of UCP1, UCP3 and TGR5 in brown adipose tissue, with reductions in expression of TGR5 and UCP3 in skeletal muscle. The pre- and post-FMT methylone tolerance phenotypes of transplant recipients are concurrent with changes in the relative abundance of several classes of Proteobacteria, most evident for Gammaproteobacteria and Alphaproteobacteria. MHT recipients demonstrated a marked increase in the relative proportion of the Firmicutes class Erysipelotrichia. These findings suggest that transplantation of gut-microbiomes can confer phenotypic responses to a drug and that the microbiome may be playing a major role in sympathomimetic-mediated hyperthermia. Abbreviations: 3,4-methylenedioxymethamphetamine (MDMA); methylone-induced hyperthermic tolerant (MHT); methylone-naïve (MN); fecal microbiota transplantation (FMT); uncoupling protein (UCP); subcutaneous (sc); intraperitoneal (ip); brown adipose tissue (BAT); skeletal muscle (SKM); sympathetic nervous system (SNS); norepinephrine (NE); quantitative PCR (qRT-PCR); quantification cycle (Cq); High Performance Liquid Chromatography-Electrochemical Detection (HPLC-EC); amplicon sequence variants (ASVs); principal coordinates analysis (PCoA); permutational multivariate analysis (PERMANOVA)

Hyperthermia inhibits growth of nasopharyngeal carcinoma through degradation of c-Myc

Background Hyperthermia is a widely used adjunct treatment for different cancers including nasopharyngeal carcinoma (NPC). The protooncogene c-Myc is up-regulated in NPC and its expression is associated with poor prognosis. Objective We hypothesized that c-Myc constitutes an important hyperthermia treatment target, and we investigated its contribution to hyperthermia responses in NPC. Methods The growth of the human NPC cell lines CNE1 and CNE2 was analyzed using CCK-8 and clonogenicity assays after 43 °C hyperthermia, knockdown or overexpression of c-Myc. Flow cytometry measurements assessed cell cycle parameters and apoptosis, while levels of c-Myc together with key transcriptional targets were determined using qPCR and Western blotting. Parallel experiments were undertaken using NPC xenografts in nude mice and lastly, global transcriptomic changes were determined using ‘RNAseq’. Results Hyperthermia increased the ubiquitination and proteasomal destruction of c-Myc, causing a rapid decline in c-Myc protein levels in NPC cells. Similar to c-Myc knockdown, NPC cells treated with hyperthermia showed growth inhibition associated with the downregulation of c-Myc target genes. Moreover, low levels of c-Myc could be sustainably repressed in NPC cells through repeated hyperthermia treatments. Importantly, the key findings of growth inhibition and decreased c-Myc protein levels were reproduced in NPC tumor xenografts. Bioinformatic analyses showed that downregulation of c-Myc constituted a central node in the hyperthermia response of NPC cells. Conclusion Our study reveals that hyperthermia can readily destabilize c-Myc levels in NPC cells and inhibit tumor growth. This proposes new strategies for implementing hyperthermia to target c-Myc-driven cancers to improve therapeutic efficacy.