Now showing items 1-20 of 841

    • Responding to preconditioned cues is devaluation sensitive and requires orbitofrontal cortex during cue-cue learning

      Hart, Evan E; Sharpe, Melissa J; Gardner, Matthew Ph; Schoenbaum, Geoffrey (eLife Sciences Publications, 2020-08-24)
      The orbitofrontal cortex (OFC) is necessary for inferring value in tests of model-based reasoning, including in sensory preconditioning. This involvement could be accounted for by representation of value or by representation of broader associative structure. We recently reported neural correlates of such broader associative structure in OFC during the initial phase of sensory preconditioning (Sadacca et al., 2018). Here, we used optogenetic inhibition of OFC to test whether these correlates might be necessary for value inference during later probe testing. We found that inhibition of OFC during cue-cue learning abolished value inference during the probe test, inference subsequently shown in control rats to be sensitive to devaluation of the expected reward. These results demonstrate that OFC must be online during cue-cue learning, consistent with the argument that the correlates previously observed are not simply downstream readouts of sensory processing and instead contribute to building the associative model supporting later behavior.
    • Cardioembolic stroke in a young male with cor triatriatum sinister: a case report

      Amara, Richard S; Lalla, Rakhee; Jeudy, Jean; Hong, Susie Nam (Oxford University Press (OUP), 2020-06)
      Background: Cor triatriatum sinister (CTS) is a rare congenital cardiac anomaly defined by a fibromuscular membrane which bisects the left atrium. Cor triatriatum sinister has been associated with cardioembolic stroke through mechanisms including stagnation of blood flow within the left atrium, an association with atrial fibrillation (AF), and/or an accompanying atrial septal defect (ASD) or patent foramen ovale. We describe a case highlighting the role that CTS may play in cardioembolic stroke, provide high-quality computed tomography angiography and two- and three-dimensional echocardiography of the CTS membrane, and outline management strategies for this uncommon clinical scenario. Case summary: A 35-year-old man with no prior medical history presented with acute onset weakness and aphasia. He was found to have an embolic stroke with left M1 and A1 occlusions and received tissue plasminogen activator followed by mechanical thrombectomy with successful recanalization. A thorough stroke workup revealed CTS with an associated ASD as well as potential protein C deficiency. He was managed with indefinite anticoagulation with apixaban. Discussion: This is the 13th reported case of CTS associated with stroke. In most previous cases evidence of blood stasis or frank thrombus was associated with the CTS membrane, and/or existing AF was noted. In this case, none of these were identified, particularly highlighting the surreptitious risk of CTS. In addition, the presence of potential protein C deficiency in this case compounded the risk for thromboembolism and factored into multidisciplinary management decisions.
    • Extensive coil embolization of a giant coronary artery aneurysm in an octogenarian: A case report

      Ahmed, Talha; Chahal, Diljon; Shkullaku, Melsjan; Gupta, Anuj (Oxford University Press, 2020-06-01)
      Background: Coronary artery aneurysms (CAA) are often diagnosed incidentally on coronary angiography or imaging modalities done for other reasons. 'Giant' CAA by definition exceeds 20 mm in diameter or four times the diameter of normal coronary artery. The management of patients with CAAs is challenging due to poorly understood mechanism, variable presentation, and lack of clear-cut societal recommendations. Though conservative management is preferred in asymptomatic patients, massive size or interval growth may make intervention necessary. Case summary: We describe a case of successful coil embolization of a giant coronary aneurysm in an elderly 84-year-old male. Patient, who presented for a follow-up computed tomography angiography to evaluate a previously repaired abdominal aortic aneurysm 2 years back, was found to have interval growth of right coronary artery aneurysm from 4 cm in diameter to 7 x 8 cm in its greatest dimensions. The rationale for treatment was to prevent sudden death from continued growth and eventual rupture of aneurysm in addition to potential risk of thromboembolism and compression of adjacent structures. Discussion: This case demonstrates the safe and successful use of extensive coil embolization technique to treat a 'giant' CAA in an elderly patient when surgical risks were prohibitive.
    • Brain-Selective Estrogen Therapy Prevents Androgen Deprivation-Associated Hot Flushes in a Rat Model

      Merchenthaler, Istvan; Lane, Malcolm; Stennett, Christina; Zhan, Min; Nguyen, Vien; Prokai-Tatrai, Katalin; Prokai, Laszlo (MDPI AG, 2020-06-10)
      Hot flushes are best-known for affecting menopausal women, but men who undergo life-saving castration due to androgen-sensitive prostate cancer also suffer from these vasomotor symptoms. Estrogen deficiency in these patients is a direct consequence of androgen deprivation, because estrogens (notably 17β-estradiol, E2) are produced from testosterone. Although estrogens alleviate hot flushes in these patients, they also cause adverse systemic side effects. Because only estrogens can provide mitigation of hot flushes on the basis of current clinical practices, there is an unmet need for an effective and safe pharmacotherapeutic intervention that would also greatly enhance patient adherence. To this end, we evaluated treatment of orchidectomized (ORDX) rats with 10β, 17β-dihydroxyestra-1,4-dien-3-one (DHED), a brain-selective bioprecursor prodrug of E2. A pilot pharmacokinetic study using oral administration of DHED to these animals revealed the formation of E2 in the brain without the appearance of the hormone in the circulation. Therefore, DHED treatment alleviated androgen deprivation-associated hot flushes without peripheral impact in the ORDX rat model. Concomitantly, we showed that DHED-derived E2 induced progesterone receptor gene expression in the hypothalamus without stimulating galanin expression in the anterior pituitary, further indicating the lack of systemic estrogen exposure upon oral treatment with DHED.
    • Revisiting the Protein C Pathway: An Opportunity for Adjunctive Intervention in COVID-19?

      Mazzeffi, Michael; Chow, Jonathan H; Amoroso, Anthony; Tanaka, Kenichi (Wolters Kluwer Health, 2020-09-01)
    • In Response

      Chow, Jonathan H; Mazzeffi, Michael A; Tanaka, Kenichi A (Wolters Kluwer Health, 2020-09-01)
    • Secreted Chaperones in Neurodegeneration

      Chaplot, Kriti; Jarvela, Timothy S.; Lindberg, Iris (Frontiers Media S.A., 2020-08-27)
      Protein homeostasis, or proteostasis, is a combination of cellular processes that govern protein quality control, namely, protein translation, folding, processing, and degradation. Disruptions in these processes can lead to protein misfolding and aggregation. Proteostatic disruption can lead to cellular changes such as endoplasmic reticulum or oxidative stress; organelle dysfunction; and, if continued, to cell death. A majority of neurodegenerative diseases involve the pathologic aggregation of proteins that subverts normal neuronal function. While prior reviews of neuronal proteostasis in neurodegenerative processes have focused on cytoplasmic chaperones, there is increasing evidence that chaperones secreted both by neurons and other brain cells in the extracellular – including transsynaptic – space play important roles in neuronal proteostasis. In this review, we will introduce various secreted chaperones involved in neurodegeneration. We begin with clusterin and discuss its identification in various protein aggregates, and the use of increased cerebrospinal fluid (CSF) clusterin as a potential biomarker and as a potential therapeutic. Our next secreted chaperone is progranulin; polymorphisms in this gene represent a known genetic risk factor for frontotemporal lobar degeneration, and progranulin overexpression has been found to be effective in reducing Alzheimer’s- and Parkinson’s-like neurodegenerative phenotypes in mouse models. We move on to BRICHOS domain-containing proteins, a family of proteins containing highly potent anti-amyloidogenic activity; we summarize studies describing the biochemical mechanisms by which recombinant BRICHOS protein might serve as a therapeutic agent. The next section of the review is devoted to the secreted chaperones 7B2 and proSAAS, small neuronal proteins which are packaged together with neuropeptides and released during synaptic activity. Since proteins can be secreted by both classical secretory and non-classical mechanisms, we also review the small heat shock proteins (sHsps) that can be secreted from the cytoplasm to the extracellular environment and provide evidence for their involvement in extracellular proteostasis and neuroprotection. Our goal in this review focusing on extracellular chaperones in neurodegenerative disease is to summarize the most recent literature relating to neurodegeneration for each secreted chaperone; to identify any common mechanisms; and to point out areas of similarity as well as differences between the secreted chaperones identified to date.
    • Mass Drug Administration of Azithromycin to Reduce Child Mortality: Only for High-Mortality Settings?

      Tickell, Kirkby D; Deichsel, Emily L; Walson, Judd L (American Society of Tropical Medicine and Hygiene, 2020-09-01)
    • Minimizing pharmacotherapy-related healthcare worker exposure to SARS-CoV-2

      Barlow, Brooke; Barlow, Ashley; Thompson Bastin, Melissa L; Berger, Karen; Dixit, Deepali; Heavner, Mojdeh S (American Society of Health-System Pharmacists, 2020-09-04)
    • The Role of Eicosanoids in Gynecological Malignancies

      Smith, Paige G.; Roque, Dana; Ching, Mc Millan; Fulton, Amy; Rao, Gautam; Reader, Jocelyn C. (Frontiers Media S.A., 2020-08-26)
      Eicosanoids, bio-active lipid molecules, evoke a multitude of biological effects that directly affect cancer cells and indirectly affect tumor microenvironment. An emerging role has been shown for eicosanoids in the pathogenesis of gynecological malignancies which include cancers of the vulva, vagina, cervix, uterine, and ovary. Eicosanoid biosynthesis pathways start at the metabolism of phospholipids by phospholipase A2 then proceeding to one of three pathways: the cyclooxygenase (COX), lipoxygenase (LOX), or P450 epoxygenase pathways. The most studied eicosanoid pathways include COX and LOX; however, more evidence is appearing to support further study of the P450 epoxygenase pathway in gynecologic cancers. In this review, we present the current knowledge of the role of COX, LOX and P450 pathways in the pathogenesis of gynecologic malignancies. Vulvar and vaginal cancer, the rarest subtypes, there is association of COX-2 expression with poor disease specific survival in vulvar cancer and, in vaginal cancer, COX-2 expression has been found to play a role in mucosal inflammation leading to disease susceptibility and transmission. Cervical cancer is associated with COX-2 levels 7.4 times higher than in healthy tissues. Additionally, HPV elevates COX-2 levels through the EGFR pathway and HIV promotes elevated COX-2 levels in cervical tissue as well as increases PGE2 levels eliciting inflammation and progression of cancer. Evidence supports significant roles for both the LOX and COX pathways in uterine cancer. In endometrial cancer, there is increased expression of 5-LOX which is associated with adverse outcomes. Prostanoids in the COX pathway PGE2 and PGF2α have been shown to play a significant role in uterine cancer including alteration of proliferation, adhesion, migration, invasion, angiogenesis, and the inflammatory microenvironment. The most studied gynecological malignancy in regard to the potential role of eicosanoids in tumorigenesis is ovarian cancer in which all three pathways have shown to be associated or play a role in ovarian tumorigenesis directly on the tumor cell or through modulation of the tumor microenvironment. By identifying the gaps in knowledge, additional pathways and targets could be identified in order to obtain a better understanding of eicosanoid signaling in gynecological malignancies and identify potential new therapeutic approaches.
    • Intratumoral generation of photothermal gold nanoparticles through a vectorized biomineralization of ionic gold

      Schwartz-Duval, Aaron S; Konopka, Christian J; Moitra, Parikshit; Daza, Enrique A; Srivastava, Indrajit; Johnson, Elyse V; Kampert, Taylor L; Fayn, Stanley; Haran, Anand; Dobrucki, Lawrence W; et al. (Springer Nature, 2020-09-10)
      Various cancer cells have been demonstrated to have the capacity to form plasmonic gold nanoparticles when chloroauric acid is introduced to their cellular microenvironment. But their biomedical applications are limited, particularly considering the millimolar concentrations and longer incubation period of ionic gold. Here, we describe a simplistic method of intracellular biomineralization to produce plasmonic gold nanoparticles at micromolar concentrations within 30 min of application utilizing polyethylene glycol as delivery vector for ionic gold. We have characterized this process for intracellular gold nanoparticle formation, which progressively accumulates proteins as the ionic gold clusters migrate to the nucleus. This nano-vectorized application of ionic gold emphasizes its potential biomedical opportunities while reducing the quantity of ionic gold and required incubation time. To demonstrate its biomedical potential, we further induce in-situ biosynthesis of gold nanoparticles within MCF7 tumor mouse xenografts which is followed by its photothermal remediation. © 2020, The Author(s).
    • Computed Tomography-Based Radiomics Signature for the Preoperative Differentiation of Pancreatic Adenosquamous Carcinoma From Pancreatic Ductal Adenocarcinoma

      Ren, Shuai; Zhao, Rui; Cui, Wenjing; Qiu, Wenli; Guo, Kai; Cao, Yingying; Duan, Shaofeng; Wang, Zhongqiu; Chen, Rong (Frontiers Media S.A., 2020-08-25)
      Purpose: The purpose was to assess the predictive ability of computed tomography (CT)-based radiomics signature in differential diagnosis between pancreatic adenosquamous carcinoma (PASC) and pancreatic ductal adenocarcinoma (PDAC). Materials and Methods: Eighty-one patients (63.6 ± 8.8 years old) with PDAC and 31 patients (64.7 ± 11.1 years old) with PASC who underwent preoperative CE-CT were included. A total of 792 radiomics features were extracted from the late arterial phase (n = 396) and portal venous phase (n = 396) for each case. Significantly different features were selected using Mann–Whitney U test, univariate logistic regression analysis, and minimum redundancy and maximum relevance method. A radiomics signature was constructed using random forest method, the robustness and the reliability of which was validated using 10-times leave group out cross-validation (LGOCV) method. Results: Seven radiomics features from late arterial phase images and three from portal venous phase images were finally selected. The radiomics signature performed well in differential diagnosis between PASC and PDAC, with 94.5% accuracy, 98.3% sensitivity, 90.1% specificity, 91.9% positive predictive value (PPV), and 97.8% negative predictive value (NPV). Moreover, the radiomics signature was proved to be robust and reliable using the LGOCV method, with 76.4% accuracy, 91.1% sensitivity, 70.8% specificity, 56.7% PPV, and 96.2% NPV. Conclusion: CT-based radiomics signature may serve as a promising non-invasive method in differential diagnosis between PASC and PDAC.
    • Host and Parasite Transcriptomic Changes upon Successive Plasmodium falciparum Infections in Early Childhood

      Bradwell, Katie R; Coulibaly, Drissa; Koné, Abdoulaye K; Laurens, Matthew B; Dembélé, Ahmadou; Tolo, Youssouf; Traoré, Karim; Niangaly, Amadou; Berry, Andrea A; Kouriba, Bourema; et al. (American Society for Microbiology, 2020-08)
      Children are highly susceptible to clinical malaria, and in regions where malaria is endemic, their immune systems must face successive encounters with Plasmodium falciparum parasites before they develop immunity, first against severe disease and later against uncomplicated malaria. Understanding cellular and molecular interactions between host and parasites during an infection could provide insights into the processes underlying this gradual acquisition of immunity, as well as to how parasites adapt to infect hosts that are successively more malaria experienced. Here, we describe methods to analyze the host and parasite gene expression profiles generated simultaneously from blood samples collected from five consecutive symptomatic P. falciparum infections in three Malian children. We show that the data generated enable statistical assessment of the proportions of (i) each white blood cell subset and (ii) the parasite developmental stages, as well as investigations of host-parasite gene coexpression. We also use the sequences generated to analyze allelic variations in transcribed regions and determine the complexity of each infection. While limited by the modest sample size, our analyses suggest that host gene expression profiles primarily clustered by individual, while the parasite gene expression profiles seemed to differentiate early from late infections. Overall, this study provides a solid framework to examine the mechanisms underlying acquisition of immunity to malaria infections using whole-blood transcriptome sequencing (RNA-seq).IMPORTANCE We show that dual RNA-seq from patient blood samples allows characterization of host/parasite interactions during malaria infections and can provide a solid framework to study the acquisition of antimalarial immunity, as well as the adaptations of P. falciparum to malaria-experienced hosts.
    • Role of fever and ambient temperature in COVID-19

      Gul, Muhammad Hamdan; Htun, Zin Mar; Inayat, Asad (Taylor and Francis Inc., 2020-09-09)
    • Virtual grand rounds as a novel means for applicants and programs to connect in the era of COVID-19

      Xu, Linhan; Ambinder, David; Kang, Juhye; Faris, Sarah; Scarpato, Kristen; Moy, Lou; Kobashi, Kathleen; Lemack, Gary; Malik, Rena (Elsevier Ltd., 2020-09-02)
      Background: COVID-19 has disrupted the 2020–2021 residency application cycle with the cancellation of away rotations and in-person interviews. This study seeks to investigate the feasibility and utility of video conferencing technology (VCT) as an opportunity for applicants to interact with faculty from outside programs. Methods: 18 prospective urology applicants were randomized to 6 urology programs to give a virtual grand rounds (VGR) talk. Presentations were recorded and analyzed to determine audience engagement. Students were surveyed regarding perceived utility of VGR. Faculty were surveyed to determine system usability of VCT and ability to evaluate the applicant. Results: 17 students completed the survey, reporting a 100% satisfaction rate with VGR. A majority felt this was a useful way to learn about outside programs. 85 physicians completed the faculty survey, with nearly half feeling confident in their ability to evaluate the applicant. Video transcription data shows sessions were interactive with minimal distractions. Conclusions: VGR can be a useful means for medical students to express interest in programs as well as an additional marker for faculty to evaluate applicants.
    • Coagulopathy and Thrombosis as a Result of Severe COVID-19 Infection: A Microvascular Focus

      Katneni, Upendra K; Alexaki, Aikaterini; Hunt, Ryan C; Schiller, Tal; DiCuccio, Michael; Buehler, Paul W; Ibla, Juan C; Kimchi-Sarfaty, Chava (Thieme, 2020-08-24)
      Coronavirus disease of 2019 (COVID-19) is the clinical manifestation of the respiratory infection caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). While primarily recognized as a respiratory disease, it is clear that COVID-19 is systemic illness impacting multiple organ systems. One defining clinical feature of COVID-19 has been the high incidence of thrombotic events. The underlying processes and risk factors for the occurrence of thrombotic events in COVID-19 remain inadequately understood. While severe bacterial, viral, or fungal infections are well recognized to activate the coagulation system, COVID-19-associated coagulopathy is likely to have unique mechanistic features. Inflammatory-driven processes are likely primary drivers of coagulopathy in COVID-19, but the exact mechanisms linking inflammation to dysregulated hemostasis and thrombosis are yet to be delineated. Cumulative findings of microvascular thrombosis has raised question if the endothelium and microvasculature should be a point of investigative focus. von Willebrand factor (VWF) and its protease, a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS-13), play important role in the maintenance of microvascular hemostasis. In inflammatory conditions, imbalanced VWF-ADAMTS-13 characterized by elevated VWF levels and inhibited and/or reduced activity of ADAMTS-13 has been reported. Also, an imbalance between ADAMTS-13 activity and VWF antigen is associated with organ dysfunction and death in patients with systemic inflammation. A thorough understanding of VWF-ADAMTS-13 interactions during early and advanced phases of COVID-19 could help better define the pathophysiology, guide thromboprophylaxis and treatment, and improve clinical prognosis.
    • Climate and season are associated with prevalence and distribution of trans-hemispheric blue crab reovirus (Callinectes sapidus reovirus 1)

      Zhao, Mingli; Behringer, Donald C.; Bojko, Jamie; Kough, Andrew S.; Plough, Louis; dos Santos Tavares, Camila Prestes; Aguilar-Perera, Alfonso; Reynoso, Omar Shamir; Seepersad, Govind; Maharaj, Omardath; et al. (Inter-Research Science Publishing, 2020-08-13)
      Among the many Callinectes spp. across the western Atlantic, the blue crab C. sapidus has the broadest latitudinal distribution, encompassing both tropical and temperate climates. Its life history varies latitudinally, from extended overwintering at high latitudes to year-round activity in tropical locations. Callinectes sapidus reovirus 1 (CsRV1) is a pathogenic virus first described in North Atlantic C. sapidus and has recently been detected in southern Brazil. Little information exists about CsRV1 prevalence at intervening latitudes or in overwintering blue crabs. Using a quantitative reverse transcription PCR (RT-qPCR) method, this study investigated CsRV1 prevalence in C. sapidus across latitudinal differences in temperature and crab life history, as well as in additional Callinectes spp. and within overwintering C. sapidus. CsRV1 prevalence in C. sapidus was significantly correlated with high water temperature and blue crab winter dormancy. Prevalence of CsRV1 in C. sapidus on the mid-Atlantic coast was significantly lower in winter than in summer. CsRV1 infections were not detected in other Callinectes spp. These findings revealed that CsRV1 is present in C. sapidus across their range, but not in other Callinectes species, with prevalence associated with temperature and host life history. Such information helps us to better understand the underlying mechanisms that drive marine virus dynamics under changing environmental conditions. © The authors 2020.
    • A clickable probe for versatile characterization of S-nitrosothiols

      Clements, Jenna L.; Pohl, Franziska; Muthupandi, Pandi; Rogers, Stephen C.; Mao, Jack; Doctor, Allan; Birman, Vladimir B.; Held, Jason M. (Elsevier BV, 2020-10)
      S-nitrosation of cysteine thiols (SNOs), commonly referred to as S-nitrosylation, is a cysteine oxoform that plays an important role in cellular signaling and impacts protein function and stability. Direct labeling of SNOs in cells with the flexibility to perform a wide range of cellular and biochemical assays remains a bottleneck as all SNO-targeted probes to date employ a single analytical modality such as biotin or a specific fluorophore. We therefore developed a clickable, alkyne-containing SNO probe ‘PBZyn’ based on the o-phosphino-benzoyl group warhead that enables multi-modal analysis via click conjugation. We demonstrate the utility of PBZyn to assay SNOs using in situ cellular imaging, protein blotting and affinity purification, as well as mass spectrometry. The flexible PBZyn probe will greatly facilitate investigation into the regulation of SNOs.
    • A Meta-Analysis of Transcriptomics Reveals a Stage-Specific Transcriptional Response Shared Across Different Hosts

      Chung, Matthew; Basting, Preston J; Patkus, Rayanna S; Grote, Alexandra; Luck, Ashley N; Ghedin, Elodie; Slatko, Barton E; Michalski, Michelle; Foster, Jeremy M; Bergman, Casey M; et al. (Genetics Society of America, 2020-09-02)
      Wolbachia is a genus containing obligate, intracellular endosymbionts with arthropod and nematode hosts. Numerous studies have identified differentially expressed transcripts in Wolbachia endosymbionts that potentially inform the biological interplay between these endosymbionts and their hosts, albeit with discordant results. Here, we re-analyze previously published Wolbachia RNA-Seq transcriptomics data sets using a single workflow consisting of the most up-to-date algorithms and techniques, with the aim of identifying trends or patterns in the pan-Wolbachia transcriptional response. We find that data from one of the early studies in filarial nematodes did not allow for robust conclusions about Wolbachia differential expression with these methods, suggesting the original interpretations should be reconsidered. Across datasets analyzed with this unified workflow, there is a general lack of global gene regulation with the exception of a weak transcriptional response resulting in the upregulation of ribosomal proteins in early larval stages. This weak response is observed across diverse Wolbachia strains from both nematode and insect hosts suggesting a potential pan-Wolbachia transcriptional response during host development that diverged more than 700 million years ago.
    • Curcumin Ameliorates Heat-Induced Injury through NADPH Oxidase-Dependent Redox Signaling and Mitochondrial Preservation in C2C12 Myoblasts and Mouse Skeletal Muscle

      Yu, Tianzheng; Dohl, Jacob; Wang, Li; Chen, Yifan; Gasier, Heath G; Deuster, Patricia A (American Society for Nutritional Sciences, 2020-09-01)
      BACKGROUND: Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and the mitochondrial electron transport chain are the primary sources of reactive oxygen species (ROS). Previous studies have shown that severe heat exposure damages mitochondria and causes excessive mitochondrial ROS production that contributes to the pathogenesis of heat-related illnesses. OBJECTIVES: We tested whether the antioxidant curcumin could protect against heat-induced mitochondrial dysfunction and skeletal muscle injury, and characterized the possible mechanism. METHODS: Mouse C2C12 myoblasts and rat flexor digitorum brevis (FDB) myofibers were treated with 5 μM curcumin; adult male C57BL/6J mice received daily curcumin (15, 50, or 100 mg/kg body weight) by gavage for 10 consecutive days. We compared ROS levels and mitochondrial morphology and function between treatment and nontreatment groups under unheated or heat conditions, and investigated the upstream mechanism and the downstream effect of curcumin-regulated ROS production. RESULTS: In C2C12 myoblasts, curcumin prevented heat-induced mitochondrial fragmentation, ROS overproduction, and apoptosis (all P < 0.05). Curcumin treatment for 2 and 4 h at 37°C induced increases in ROS levels by 42% and 59% (dihydroethidium-derived fluorescence), accompanied by increases in NADPH oxidase protein expression by 24% and 32%, respectively (all P < 0.01). In curcumin-treated cells, chemical inhibition and genetic knockdown of NADPH oxidase restored ROS to levels similar to those of controls, indicating NADPH oxidase mediates curcumin-stimulated ROS production. Moreover, curcumin induced ROS-dependent shifting of the mitochondrial fission-fusion balance toward fusion, and increases in mitochondrial mass by 143% and membrane potential by 30% (both P < 0.01). In rat FDB myofibers and mouse gastrocnemius muscles, curcumin preserved mitochondrial morphology and function during heat stress, and prevented heat-induced mitochondrial ROS overproduction and tissue injury (all P < 0.05). CONCLUSIONS: Curcumin regulates ROS hormesis favoring mitochondrial fusion/elongation, biogenesis, and improved function in rodent skeletal muscle. Curcumin may be an effective therapeutic target for heat-related illness and other mitochondrial diseases.