Mitochondrial stress in GABAergic neurons non-cell autonomously regulates organismal health and aging.

Mitochondrial stress within the nervous system can trigger non-cell autonomous responses in peripheral tissues. However, the specific neurons involved and their impact on organismal aging and health have remained incompletely understood. Here, we demonstrate that mitochondrial stress in γ-aminobutyric acid-producing (GABAergic) neurons in Caenorhabditis elegans ( C. elegans ) is sufficient to significantly alter organismal lifespan, stress tolerance, and reproductive capabilities. This mitochondrial stress also leads to significant changes in mitochondrial mass, energy production, and levels of reactive oxygen species (ROS). DAF-16/FoxO activity is enhanced by GABAergic neuronal mitochondrial stress and mediates the induction of these non-cell-autonomous effects. Moreover, our findings indicate that GABA signaling operates within the same pathway as mitochondrial stress in GABAergic neurons, resulting in non-cell-autonomous alterations in organismal stress tolerance and longevity. In summary, these data suggest the crucial role of GABAergic neurons in detecting mitochondrial stress and orchestrating non-cell-autonomous changes throughout the organism.

Parathyroid gland detection using an intraoperative autofluorescence handheld imager - early feasibility study.

Introduction: Parathyroid glands may be compromised during thyroid surgery which can lead to hypoparathyroidism and hypocalcemia. Identifying the parathyroid glands relies on the surgeon's experience and the only way to confirm their presence was through tissue biopsy. Near infrared autofluorescence technology offers an opportunity for real-time, non-invasive identification of the parathyroid glands. Methods: We used a new research prototype (hANDY-I) developed by Optosurgical, LLC. It offers coaxial excitation light and a dual-Red Green Blue/Near Infrared sensor that guides anatomical landmarks and can aid in identification of parathyroid glands by showing a combined autofluorescence and colored image simultaneously. Results: We tested the imager during 23 thyroid surgery cases, where initial clinical feasibility data showed that out of 75 parathyroid glands inspected, 71 showed strong autofluorescence signal and were correctly identified (95% accuracy) by the imager. Conclusions: The hANDY-I prototype demonstrated promising results in this feasibility study by aiding in real-time visualization of the parathyroid glands. However, further testing by conducting randomized clinical trials with a bigger sample size is required to study the effect on levels of hypoparathyroidism and hypocalcemia.

frpr-18, a neuropeptide receptor, regulates organismal lifespan and stress tolerance in C. elegans.

The mechanisms underlying neuropeptide signaling regulation of lifespan in Caenorhabditis elegans ( C. elegans ) remain unclear. FRPR-18 is a mammalian orexin/hypocretin-like receptor and modulates C. elegans arousal behavior by acting as a receptor for FLP-2 neuropeptide signaling, which is also associated with the systemic activation of the mitochondrial unfolded protein response (mitoUPR). Here we report our preliminary findings on the role of the frpr-18 gene in regulating lifespan and healthspan parameters, including stress resistance. Our results showed that frpr-18(ok2698) null mutants had a shorter lifespan and reduced survivability against thermal stress and paraquat treatment. On the other hand, loss of flp-2 function did not affect lifespan or paraquat tolerance but was necessary for normal thermal stress tolerance. These findings suggest that frpr-18 could play a role in regulating lifespan and stress resistance, possibly through flp-2 independent or parallel neuropeptide signaling pathways.

The beneficial role of exercise in preventing doxorubicin-induced cardiotoxicity.

Doxorubicin is a highly effective chemotherapeutic agent widely used to treat a variety of cancers. However, the clinical application of doxorubicin is limited due to its adverse effects on several tissues. One of the most serious side effects of doxorubicin is cardiotoxicity, which results in life-threatening heart damage, leading to reduced cancer treatment success and survival rate. Doxorubicin-induced cardiotoxicity results from cellular toxicity, including increased oxidative stress, apoptosis, and activated proteolytic systems. Exercise training has emerged as a non-pharmacological intervention to prevent cardiotoxicity during and after chemotherapy. Exercise training stimulates numerous physiological adaptations in the heart that promote cardioprotective effects against doxorubicin-induced cardiotoxicity. Understanding the mechanisms responsible for exercise-induced cardioprotection is important to develop therapeutic approaches for cancer patients and survivors. In this report, we review the cardiotoxic effects of doxorubicin and discuss the current understanding of exercise-induced cardioprotection in hearts from doxorubicin-treated animals.

Melatonin protects against cadmium-induced oxidative stress via mitochondrial STAT3 signaling in human prostate stromal cells.

Melatonin protects against Cadmium (Cd)-induced toxicity, a ubiquitous environmental toxicant that causes adverse health effects by increasing reactive oxygen species (ROS) production and mitochondrial dysfunction. However, the underlying mechanism remains unclear. Here, we demonstrate that Cd exposure reduces the levels of mitochondrially-localized signal transducer and activator of transcription 3 (mitoSTAT3) using human prostate stromal cells and mouse embryonic fibroblasts. Melatonin enhances mitoSTAT3 abundance following Cd exposure, which is required to attenuate ROS damage, mitochondrial dysfunction, and cell death caused by Cd exposure. Moreover, melatonin increases mitochondrial levels of GRIM-19, an electron transport chain component that mediates STAT3 import into mitochondria, which are downregulated by Cd. In vivo, melatonin reverses the reduced size of mouse prostate tissue and levels of mitoSTAT3 and GRIM-19 induced by Cd exposure. Together, these data suggest that melatonin regulates mitoSTAT3 function to prevent Cd-induced cytotoxicity and could preserve mitochondrial function during Cd-induced stress.

Iron homeostasis and organismal aging.

Iron is indispensable for normal body functions across species because of its critical roles in red blood cell function and many essential proteins and enzymes required for numerous physiological processes. Regulation of iron homeostasis is an intricate process involving multiple modulators at the systemic, cellular, and molecular levels. Interestingly, emerging evidence has demonstrated that many modulators of iron homeostasis contribute to organismal aging and longevity. On the other hand, the age-related dysregulation of iron homeostasis is often associated with multiple age-related pathologies including bone resorption and neurodegenerative diseases such as Alzheimer's disease. Thus, a thorough understanding on the interconnections between systemic and cellular iron balance and organismal aging may help decipher the etiologies of multiple age-related diseases, which could ultimately lead to developing therapeutic strategies to delay aging and treat various age-related diseases. Here we present the current understanding on the mechanisms of iron homeostasis. We also discuss the impacts of aging on iron homeostatic processes and how dysregulated iron metabolism may affect aging and organismal longevity.

Function of Mitogen-Activated Protein Kinases in Hepatic Inflammation.

The western diet and overuse of anti-inflammatory medication have caused a great deal of stress on the liver. Obesity and the associated inflammatory state in insulin-responsive tissues result in the release of pro-inflammatory cytokine that activates the stress-responsive MAPKs, p38 MAPK, and JNK. These MAPKs have figured prominently as critical effectors in physiological and pathophysiological hepatic inflammation. In contrast, evidence for a role for ERK1/2 in hepatic inflammation has been less well developed. In this review article, we describe recent insights into the physiology and pathophysiology of the role of stress-responsive MAPKs in hepatic inflammation during obesity and liver injury with a focus on macrophages, hepatocytes and hepatic stellate cells. In response to metabolic stress and liver injury, JNK activation in macrophages and hepatocytes promotes the secretion of inflammatory cytokines and macrophage and neutrophil infiltration. p38 MAPK plays an important role in contributing to the progression of hepatic inflammation in response to various hepatic cellular stresses, although the precise substrates mediating these effects in hepatocytes and hepatic stellate cells remain to be identified. Both JNK and p38 MAPK promotes profibrotic behavior in hepatic stellate cells.

Comparative toxicities of BPA, BPS, BPF, and TMBPF in the nematode Caenorhabditis elegans and mammalian fibroblast cells.

Bisphenol A (BPA) is a chemical compound commonly used in the production of plastics for daily lives and industry. As BPA is well known for its adverse health effects, several alternative materials have been developed. This study comprehensively analyzed the toxicity of BPA and its three substitutes including bisphenol S (BPS), bisphenol F (BPF), and tetramethyl bisphenol F (TMBPF) on aging, healthspan, and mitochondria using an in vivo Caenorhabditis elegans (C. elegans) model animal and cultured mammalian fibroblast cells. C. elegans treated with 1 mM BPA exhibited abnormalities in the four tested parameters related to development and growth, including delayed development, decreased body growth, reduced reproduction, and abnormal tissue morphology. Exposure to the same concentration of each alternative including TMBPF, which has been proposed as a relatively safe BPA alternative, detrimentally affected at least three of these events. Moreover, all bisphenols (except BPS) remarkably shortened the organismal lifespan and increased age-related changes in neurons. Exposure to BPA and BPF resulted in mitochondrial abnormalities, such as reduced oxygen consumption and mitochondrial membrane potential. In contrast, the ATP levels were noticeably higher after treatment with all bisphenols. In mammalian fibroblast cells, exposure to increasing concentrations of all bisphenols (ranging from 50 µM to 500 µM) caused a severe decrease in cell viability in a dose-dependent manner. BPA increased ATP levels and decreased ROS but did not affect mitochondrial permeability transition pores (mPTP). Notably, TMBPF was the only bisphenol that caused a significant increase in mitochondrial ROS and mPTP opening. These results suggest that the potentially harmful physiological effects of BPA alternatives should be considered.

A systematic review of next-generation point-of-care stroke diagnostic technologies.

OBJECTIVE: Stroke is a leading cause of morbidity and mortality. Current diagnostic modalities include CT and MRI. Over the last decade, novel technologies to facilitate stroke diagnosis, with the hope of shortening time to treatment and reducing rates of morbidity and mortality, have been developed. The authors conducted a systematic review to identify studies reporting on next-generation point-of-care stroke diagnostic technologies described within the last decade. METHODS: A systematic review was performed according to PRISMA guidelines to identify studies reporting noninvasive stroke diagnostics. The QUADAS-2 (Quality Assessment of Diagnostic Accuracy Studies-2) tool was utilized to assess risk of bias. PubMed, Web of Science, and Scopus databases were utilized. Primary outcomes assessed included accuracy and timing compared with standard imaging, potential risks or complications, potential limitations, cost of the technology, size/portability, and range/size of detection. RESULTS: Of the 2646 reviewed articles, 19 studies met the inclusion criteria and included the following modalities of noninvasive stoke detection: microwave technology (6 studies, 31.6%), electroencephalography (EEG; 4 studies, 21.1%), ultrasonography (3 studies, 15.8%), near-infrared spectroscopy (NIRS; 2 studies, 10.5%), portable MRI devices (2 studies, 10.5%), volumetric impedance phase-shift spectroscopy (VIPS; 1 study, 5.3%), and eddy current damping (1 study, 5.3%). Notable medical devices that accurately predicted stroke in this review were EEG-based diagnosis, with a maximum sensitivity of 91.7% for predicting a stroke, microwave-based diagnosis, with an area under the receiver operating characteristic curve (AUC) of 0.88 for differentiating ischemic stroke and intracerebral hemorrhage (ICH), ultrasound with an AUC of 0.92, VIPS with an AUC of 0.93, and portable MRI with a diagnostic accuracy similar to that of traditional MRI. NIRS offers significant potential for more superficially located hemorrhage but is limited in detecting deep-seated ICH (2.5-cm scanning depth). CONCLUSIONS: As technology and computational resources have advanced, several novel point-of-care medical devices show promise in facilitating rapid stroke diagnosis, with the potential for improving time to treatment and informing prehospital stroke triage.

Effects of Acute and Chronic Gamma Irradiation on the Cell Biology and Physiology of Rice Plants.

The response to gamma irradiation varies among plant species and is affected by the total irradiation dose and dose rate. In this study, we examined the immediate and ensuing responses to acute and chronic gamma irradiation in rice (Oryza sativa L.). Rice plants at the tillering stage were exposed to gamma rays for 8 h (acute irradiation) or 10 days (chronic irradiation), with a total irradiation dose of 100, 200, or 300 Gy. Plants exposed to gamma irradiation were then analyzed for DNA damage, oxidative stress indicators including free radical content and lipid peroxidation, radical scavenging, and antioxidant activity. The results showed that all stress indices increased immediately after exposure to both acute and chronic irradiation in a dose-dependent manner, and acute irradiation had a greater effect on plants than chronic irradiation. The photosynthetic efficiency and growth of plants measured at 10, 20, and 30 days post-irradiation decreased in irradiated plants, i.e., these two parameters were more severely affected by acute irradiation than by chronic irradiation. In contrast, acutely irradiated plants produced seeds with dramatically decreased fertility rate, and chronically irradiated plants failed to produce fertile seeds, i.e., reproduction was more severely affected by chronic irradiation than by acute irradiation. Overall, our findings suggest that acute gamma irradiation causes instantaneous and greater damage to plant physiology, whereas chronic gamma irradiation causes long-term damage, leading to reproductive failure.

A novel role of the mitochondrial iron-sulfur cluster assembly protein ISCU-1/ISCU in longevity and stress response.

As an ancient cellular co-factor ubiquitously present in all domains of life, nearly all iron-sulfur ([Fe-S]) clusters are assembled in the mitochondrion. Although multiple mitochondrion-derived signalings are known to be key players in longevity regulation, whether the mitochondrial [Fe-S] cluster assembly machinery modulates lifespan is previously unknown. Here, we find that ISCU-1, the C. elegans ortholog of the evolutionarily conserved iron-sulfur cluster (ISC) assembly machinery central protein ISCU, regulates longevity and stress response. Specifically, ISCU-1 accelerates aging in the intestine. Moreover, we identify the Nrf2 transcription factor SKN-1 and a nuclear hormone receptor NHR-49 as the downstream factors of ISCU-1. Lastly, a mitochondrial outer membrane protein phosphatase PGAM-5 appears to link ISCU-1 to SKN-1 and NHR-49 in lifespan regulation. Together, we have identified a novel function of mitochondrial ISC assembly machinery in longevity modulation and stress response.

Usefulness of vertebrobasilar artery radiological finding as a predictive and prognostic factor for sudden sensorineural hearing loss.

OBJECTIVE: The association between sudden sensorineural hearing loss (SSNHL) and radiological findings of the vertebrobasilar artery is not well-known and little research has been done. We hypothesized that the radiological features of the vertebrobasilar artery contribute to the incidence and prognosis of SSNHL. METHODS: We retrospectively enrolled patients diagnosed with unilateral SSNHL (SSNHL group) and those with acute vestibular neuritis (AVN; control group) in our hospital. All patients underwent magnetic resonance imaging and computed tomography. We measured the following parameters on the radiological images: basilar artery diameter, direction and distance of basilar artery deviation, direction and distance of vertebral artery deviation, and incidence of vertebral artery obstruction. Pure tone audiometry (PTA) was performed in all patients. Follow up PTA between 1 week and 1 month after treatment was performed in the SSNHL group. RESULTS: A total of 244 SSNHL patients and 62 AVN patients were included in the analysis. Age, body mass index, and basilar artery diameter were found to be significantly associated with SSNHL. In the SSNHL group, patients were divided into three subgroups based on the consistency between the basilar artery deviation site and disease site. No significant difference was noted in initial PTA, final PTA, PTA recovery, and symptom improvement among the three groups. In case of the basilar artery, when the deviation and disease sites were in the opposite direction and the basilar artery diameter was >3.5 mm, diameter of basilar artery was positively correlated with PTA recovery. CONCLUSIONS: The strength of this study is that radiological evaluation of the vertebrobasilar artery was performed. Further research on the association between SSNHL and radiological features of the vertebrobasilar artery should be conducted to emphasize the importance of vascular assessment in SSNHL.

Distinct temporal actions of different types of unfolded protein responses during aging.

Proteotoxic stress is a common challenge for all organisms. Among various mechanisms involved in defending such stress, the evolutionarily conserved unfolded protein responses (UPRs) play a key role across species. Interestingly, UPRs can occur in different subcellular compartments including the endoplasmic reticulum (UPRER ), mitochondria (UPRMITO ), and cytoplasm (UPRCYTO ) through distinct mechanisms. While previous studies have shown that the UPRs are intuitively linked to organismal aging, a systematic assay on the temporal regulation of different type of UPRs during aging is still lacking. Here, using Caenorhabditis elegans (C. elegans) as the model system, we found that the endogenous UPRs (UPRER , UPRMITO , and UPRCYTO ) elevate with age, but their inducibility exhibits an age-dependent decline. Moreover, we revealed that the temporal requirements to induce different types of UPRs are distinct. Namely, while the UPRMITO can only be induced during the larval stage, the UPRER can be induced until early adulthood and the inducibility of UPRCYTO is well maintained until mid-late stage of life. Furthermore, we showed that different tissues may exhibit distinct temporal profiles of UPR inducibility during aging. Collectively, our findings demonstrate that UPRs of different subcellular compartments may have distinct temporal mechanisms during aging.

Innovations in Geroscience to enhance mobility in older adults.

Aging is the primary risk factor for functional decline; thus, understanding and preventing disability among older adults has emerged as an important public health challenge of the 21st century. The science of gerontology - or geroscience - has the practical purpose of "adding life to the years." The overall goal of geroscience is to increase healthspan, which refers to extending the portion of the lifespan in which the individual experiences enjoyment, satisfaction, and wellness. An important facet of this goal is preserving mobility, defined as the ability to move independently. Despite this clear purpose, this has proven to be a challenging endeavor as mobility and function in later life are influenced by a complex interaction of factors across multiple domains. Moreover, findings over the past decade have highlighted the complexity of walking and how targeting multiple systems, including the brain and sensory organs, as well as the environment in which a person lives, can have a dramatic effect on an older person's mobility and function. For these reasons, behavioral interventions that incorporate complex walking tasks and other activities of daily living appear to be especially helpful for improving mobility function. Other pharmaceutical interventions, such as oxytocin, and complementary and alternative interventions, such as massage therapy, may enhance physical function both through direct effects on biological mechanisms related to mobility, as well as indirectly through modulation of cognitive and socioemotional processes. Thus, the purpose of the present review is to describe evolving interventional approaches to enhance mobility and maintain healthspan in the growing population of older adults in the United States and countries throughout the world. Such interventions are likely to be greatly assisted by technological advances and the widespread adoption of virtual communications during and after the COVID-19 era.

The stress-responsive gene GDPGP1/mcp-1 regulates neuronal glycogen metabolism and survival.

Maladaptive responses to stress might play a role in the sensitivity of neurons to stress. To identify novel cellular responses to stress, we performed transcriptional analysis in acutely stressed mouse neurons, followed by functional characterization in Caenorhabditis elegans. In both contexts, we found that the gene GDPGP1/mcp-1 is down-regulated by a variety of stresses. Functionally, the enzyme GDPGP1/mcp-1 protects against stress. Knockdown of GDPGP1 in mouse neurons leads to widespread neuronal cell death. Loss of mcp-1, the single homologue of GDPGP1 in C. elegans, leads to increased degeneration of GABA neurons as well as reduced survival of animals following environmental stress. Overexpression of mcp-1 in neurons enhances survival under hypoxia and protects against neurodegeneration in a tauopathy model. GDPGP1/mcp-1 regulates neuronal glycogen levels, indicating a key role for this metabolite in neuronal stress resistance. Together, our data indicate that down-regulation of GDPGP1/mcp-1 and consequent loss of neuronal glycogen is a maladaptive response that limits neuronal stress resistance and reduces survival.

Overexpression of rice F-box protein OsFBX322 confers increased sensitivity to gamma irradiation in Arabidopsis.

Ionizing radiation has a substantial effect on physiological and biochemical processes in plants via induction of transcriptional changes and diverse genetic alterations. Previous microarray analysis showed that rice OsFBX322, which encodes a rice F-box protein, was downregulated in response to three types of ionizing radiation: gamma irradiation, ion beams, and cosmic rays. In order to characterize the radiation-responsive genes in rice, OsFBX322 was selected for further analysis. OsFBX322 expression patterns in response to radiation were confirmed using quantitative RT-PCR. Transient expression of a GFP-OsFBX322 fusion protein in tobacco leaf epidermis indicated that OsFBX322 is localized to the nucleus. To determine the effect of OsFBX322 expression on radiation response, OsFBX322 was overexpressed in Arabidopsis. Transgenic overexpression lines were more sensitive to gamma irradiation than control plants. These results suggest that OsFBX322 plays a negative role in the defense response to radiation in plants. In addition, we obtained four co-expression genes of OsFBX322 by specific co-expression networks using the ARANCE. Quantitative RT-PCR showed that the four genes were also downregulated after exposure to the three types of radiation. These results imply that the co-expressed genes may serve as key regulators in the radiation response pathway in plants.

Circulating Tumor Cells Exhibit Metastatic Tropism and Reveal Brain Metastasis Drivers.

Hematogenous metastasis is initiated by a subset of circulating tumor cells (CTC) shed from primary or metastatic tumors into the blood circulation. Thus, CTCs provide a unique patient biopsy resource to decipher the cellular subpopulations that initiate metastasis and their molecular properties. However, one crucial question is whether CTCs derived and expanded ex vivo from patients recapitulate human metastatic disease in an animal model. Here, we show that CTC lines established from patients with breast cancer are capable of generating metastases in mice with a pattern recapitulating most major organs from corresponding patients. Genome-wide sequencing analyses of metastatic variants identified semaphorin 4D as a regulator of tumor cell transmigration through the blood-brain barrier and MYC as a crucial regulator for the adaptation of disseminated tumor cells to the activated brain microenvironment. These data provide the direct experimental evidence of the promising role of CTCs as a prognostic factor for site-specific metastasis. SIGNIFICANCE: Interests abound in gaining new knowledge of the physiopathology of brain metastasis. In a direct metastatic tropism analysis, we demonstrated that ex vivo-cultured CTCs from 4 patients with breast cancer showed organotropism, revealing molecular features that allow a subset of CTCs to enter and grow in the brain.This article is highlighted in the In This Issue feature, p. 1.