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The Journal of Biological Chemistry May 2024Extracellular secretion is an essential mechanism for α-synuclein (α-syn) proteostasis. Although it was reported that neuronal activity affects α-syn secretion, the...
Extracellular secretion is an essential mechanism for α-synuclein (α-syn) proteostasis. Although it was reported that neuronal activity affects α-syn secretion, the underlying mechanisms remain unclear. Here, we investigated the autophagic processes that regulate the physiological release of α-syn in mouse primary cortical neurons and SH-SY5Y cells. Stimulating neuronal activity with glutamate or depolarization with high KCl enhanced α-syn secretion. This glutamate-induced α-syn secretion was blocked by a mixture of NMDA receptor antagonist AP5 and AMPA receptor antagonist NBQX, as well as by cytosolic Ca chelator BAPTA-AM. Additionally, mTOR inhibitor rapamycin increased α-syn and p62/SQSTM1 (p62) secretion, and this effect of rapamycin was reduced in primary cortical neurons deficient in the autophagy regulator beclin 1 (derived from BECN1 mice). Glutamate-induced α-syn and p62 secretion was suppressed by knockdown of ATG5, which is required for autophagosome formation. Glutamate increased LC3-II generation and decreased intracellular p62 levels, and the increase in LC3-II levels was blocked by BAPTA-AM. Moreover, glutamate promoted co-localization of α-syn with LC3-positive puncta, but not with LAMP1-positive structures in the neuronal somas. Glutamate-induced α-syn and p62 secretion was also reduced by knockdown of RAB8A, which is required for autophagosome fusion with the plasma membrane. Collectively, these findings suggest that stimulating neuronal activity mediates autophagic α-syn secretion in a cytosolic Ca-dependent manner, and autophagosomes may participate in autophagic secretion by functioning as α-syn carriers.
PubMed: 38815862
DOI: 10.1016/j.jbc.2024.107419 -
Kidney & Blood Pressure Research May 2024Background Chronic kidney disease (CKD) is a progressive systemic condition characterized by numerous complications. Among these, alterations in skeletal muscle... (Review)
Review
Background Chronic kidney disease (CKD) is a progressive systemic condition characterized by numerous complications. Among these, alterations in skeletal muscle physiology, such as sarcopenia, are particularly significant, as they are associated with poor outcomes and reduced quality of life. Summary Various interventions, including pharmacological approaches and lifestyle modifications have been investigated to slow CKD progression and prevent or treat its complications. Physical exercise, in particular, has emerged as a promising intervention with multiple beneficial effects. These include improvements in physical functioning, increased muscle mass, modulation of metabolic abnormalities, and reduced cardiovascular risk. However, the pathophysiology of physical exercise in patients with kidney disease is complex and remains only partially understood. A crucial advancement in understanding this phenomenon has been the identification of myokines-molecules expressed and released by skeletal muscle in response to physical activity. These myokines can exert both paracrine and systemic effects, influencing not only skeletal muscle physiology but also other processes such as energy metabolism and lipid regulation. Key Messages The interplay among skeletal muscle, physical activity, and myokines may act as a pivotal regulator in various physiological processes, including aging, as well as in pathological conditions like cachexia and sarcopenia, frequently observed in CKD patients at different stages, including patients on dialysis. Despite the potential importance of this relationship, only a limited number of studies have explored the relationship between exercise and myokine, and the effect of this interaction on experimental models or individuals with kidney disease. In the following sections, we review and discuss this topic.
PubMed: 38815556
DOI: 10.1159/000539489 -
Redox Biology May 2024Hypoxia-inducible factor 1 alpha (HIF-1α) is a major molecular mediator of the hypoxic response. In the endometrium, local hypoxic conditions induced by hormonal... (Review)
Review
Hypoxia-inducible factor 1 alpha (HIF-1α) is a major molecular mediator of the hypoxic response. In the endometrium, local hypoxic conditions induced by hormonal fluctuations and endometrial vascular remodeling contribute to the production of HIF-1α, which plays an indispensable role in a series of physiological activities, such as menstruation and metamorphosis. The sensitive regulation of HIF-1α maintains the cellular viability and regenerative capacity of the endometrium against cellular stresses induced by hypoxia and excess reactive oxygen species. In contrast, abnormal HIF-1α levels exacerbate the development of various endometrial pathologies. This knowledge opens important possibilities for the development of promising HIF-1α-centered strategies to ameliorate endometrial disease. Nonetheless, additional efforts are required to elucidate the regulatory network of endometrial HIF-1α and promote the applications of HIF-1α-centered strategies in the human endometrium. Here, we summarize the role of the HIF-1α-mediated pathway in endometrial physiology and pathology, highlight the latest HIF-1α-centered strategies for treating endometrial diseases, and improve endometrial receptivity.
PubMed: 38815332
DOI: 10.1016/j.redox.2024.103205 -
Journal of Medical Internet Research May 2024Remote patient monitoring (RPM) enables clinicians to maintain and adjust their patients' plan of care by using remotely gathered data, such as vital signs, to...
Remote patient monitoring (RPM) enables clinicians to maintain and adjust their patients' plan of care by using remotely gathered data, such as vital signs, to proactively make medical decisions about a patient's care. RPM interventions have been touted as a means to improve patient care and well-being while reducing costs and resource needs within the health care ecosystem. However, multiple interworking components must be successfully implemented for an RPM intervention to yield the desired outcomes, and the design and key driver of each component can vary depending on the medical context. This viewpoint and perspective paper presents a 4-component RPM infrastructure framework based on a synthesis of existing literature and practice related to RPM. Specifically, these components are identified and considered: (1) data collection, (2) data transmission and storage, (3) data analysis, and (4) information presentation. Interaction points to consider between components include transmission, interoperability, accessibility, workflow integration, and transparency. Within each of the 4 components, questions affecting research and practice emerge that can affect the outcomes of RPM interventions. This framework provides a holistic perspective of the technologies involved in RPM interventions and how these core elements interact to provide an appropriate infrastructure for deploying RPM in health systems. Further, it provides a common vocabulary to compare and contrast RPM solutions across health contexts and may stimulate new research and intervention opportunities.
Topics: Humans; Monitoring, Physiologic; Telemedicine
PubMed: 38815263
DOI: 10.2196/51234 -
American Society of Clinical Oncology... Jun 2024The management of axillary lymph nodes in breast cancer is continually evolving. Recent data now support omitting axillary lymph node dissection (ALND) in most patients... (Review)
Review
Personalizing Locoregional Therapy in Patients With Breast Cancer in 2024: Tailoring Axillary Surgery, Escalating Lymphatic Surgery, and Implementing Evidence-Based Hypofractionated Radiotherapy.
The management of axillary lymph nodes in breast cancer is continually evolving. Recent data now support omitting axillary lymph node dissection (ALND) in most patients with metastases in up to two sentinel lymph nodes (SLNs) during upfront surgery and those with residual isolated tumor cells after neoadjuvant chemotherapy (NACT). In the upfront surgery setting, ALND is still indicated, however, in patients with clinically node-positive breast cancer or more than two positive SLNs and, after NACT, in case of residual micrometastases and macrometastases. Omission of the sentinel lymph node biopsy (SLNB) can be considered in many postmenopausal patients with small luminal breast cancer, particularly when axillary ultrasound is negative. Several randomized controlled trials (RCTs) are currently aiming at eliminating the remaining indications for ALND and also establishing omission of SLNB in a broader patient population. The movement to deescalate axillary staging is in part because of the association between ALND and lymphedema, which is swelling of an extremity because of lymphatic damage and obstructed lymphatic drainage. To reduce the risk of developing this condition, patients undergoing ALND can undergo reverse mapping of the axilla and immediate reconstruction or bypass of the lymphatics from the involved extremity. Decongestion and compression are the foundation of conservative treatment for established lymphedema, while lymphovenous bypass and lymph node transfer are surgical procedures to address the physiologic dysfunction. Radiotherapy is an essential component of breast locoregional therapy: more than three decades of radiation research has optimized treatment according to patient's risk of local recurrence while substantially reducing the number of treatment visits. High-quality RCTs have shown the efficacy and safety of hypofractionation-more than 2Gy radiation dose per treatment (fraction)-significantly reducing the burden of radiotherapy treatment for many patients with breast cancer. In 2024, guidelines recommend no more than 15-16 fractions for whole-breast and nodal radiotherapy, with some recommending five fractions for whole-breast radiotherapy. In addition, simultaneous integrated boost (SIB) has been shown to be noninferior to sequential boost with regards to ipsilateral breast tumor recurrence with similar or reduced long-term side effects, also reducing overall treatment length. Further RCTs are underway investigating other indications for five fractions, including SIB and regional node irradiation, such that, in future, it may be possible for the majority of breast radiotherapy patients to be treated with a 1-week course. This manuscript serves to outline the latest updates on axillary surgical staging, lymphatic surgery, and evidence-based radiotherapy in the treatment of breast cancer.
Topics: Humans; Breast Neoplasms; Female; Axilla; Lymph Node Excision; Radiation Dose Hypofractionation; Lymphatic Metastasis; Sentinel Lymph Node Biopsy; Combined Modality Therapy; Lymph Nodes; Neoplasm Staging; Neoadjuvant Therapy
PubMed: 38815195
DOI: 10.1200/EDBK_438776 -
JCI Insight May 2024The non-physiological nutrient levels found in traditional culture media have been shown to affect numerous aspects of cancer cell physiology, including how cells...
The non-physiological nutrient levels found in traditional culture media have been shown to affect numerous aspects of cancer cell physiology, including how cells respond to certain therapeutic agents. Here, we comprehensively evaluated how physiological nutrient levels impact therapeutic response by performing drug screening in human plasma-like medium (HPLM). We observed dramatic nutrient-dependent changes in sensitivity to a variety of FDA-approved and clinically trialed compounds including rigosertib, an experimental cancer therapeutic that has recently failed in phase 3 clinical trials. Mechanistically, we found that the ability of rigosertib to destabilize microtubules is strongly inhibited by the purine metabolism end product uric acid, which is uniquely abundant in humans relative to traditional in vitro and in vivo cancer models. These results demonstrate the broad and dramatic effects nutrient levels can have on drug response, and how incorporation of human-specific physiological nutrient media might help to identify compounds whose efficacy could be impacted in humans.
PubMed: 38815134
DOI: 10.1172/jci.insight.174329 -
Arteriosclerosis, Thrombosis, and... May 2024Pericoronary epicardial adipose tissue (EAT) is a unique visceral fat depot that surrounds the adventitia of the coronary arteries without any anatomic barrier. Clinical...
BACKGROUND
Pericoronary epicardial adipose tissue (EAT) is a unique visceral fat depot that surrounds the adventitia of the coronary arteries without any anatomic barrier. Clinical studies have demonstrated the association between EAT volume and increased risks for coronary artery disease (CAD). However, the cellular and molecular mechanisms underlying the association remain elusive.
METHODS
We performed single-nucleus RNA sequencing on pericoronary EAT samples collected from 3 groups of subjects: patients undergoing coronary bypass surgery for severe CAD (n=8), patients with CAD with concomitant type 2 diabetes (n=8), and patients with valvular diseases but without concomitant CAD and type 2 diabetes as the control group (n=8). Comparative analyses were performed among groups, including cellular compositional analysis, cell type-resolved transcriptomic changes, gene coexpression network analysis, and intercellular communication analysis. Immunofluorescence staining was performed to confirm the presence of CAD-associated subclusters.
RESULTS
Unsupervised clustering of 73 386 nuclei identified 15 clusters, encompassing all known cell types in the adipose tissue. Distinct subpopulations were identified within primary cell types, including adipocytes, adipose stem and progenitor cells, and macrophages. macrophages and adipocytes were significantly expanded in CAD. In comparison to normal controls, both disease groups exhibited dysregulated pathways and altered secretome in the primary cell types. Nevertheless, minimal differences were noted between the disease groups in terms of cellular composition and transcriptome. In addition, our data highlight a potential interplay between dysregulated circadian clock and altered physiological functions in adipocytes of pericoronary EAT. ANXA1 and SEMA3B were identified as important adipokines potentially involved in functional changes of pericoronary EAT and CAD pathogenesis.
CONCLUSIONS
We built a complete single-nucleus transcriptomic atlas of human pericoronary EAT in normal and diseased conditions of CAD. Our study lays the foundation for developing novel therapeutic strategies for treating CAD by targeting and modifying pericoronary EAT functions.
PubMed: 38813696
DOI: 10.1161/ATVBAHA.124.320923 -
Advances in Physiology Education May 2024The movement of air into and out of the lungs is facilitated by changes in pressure within the thoracic cavity relative to atmospheric pressure, as well as the...
The movement of air into and out of the lungs is facilitated by changes in pressure within the thoracic cavity relative to atmospheric pressure, as well as the resistance encountered by airways. In this process, the movement of air into and out of the lungs is driven by pressure gradients established by changes in lung volume and intra-alveolar pressure. However, pressure never sucks! The concept that pressure never sucks, pressure only pushes encapsulates a fundamental principle in the behavior of gases. This concept challenges common misconceptions about pressure, shedding light on the dynamic forces that govern the movement of gases. In this Illumination, we explore the essence of this concept and its applications in pulmonary ventilation. Pressure is one of the most important concepts in physics and physiology. Atmospheric pressure at sea level is equal to 1 atmosphere, or around 101,325 Pascal [Pa (1 Pa = 1 N/m2)]. This huge pressure is pushing down on everything all the time. However, this pressure is difficult to understand because we do not often observe the power of this incredible force. We used five readily available, simple, and inexpensive demonstrations to introduce the physics and power of pressure. This extraordinarily complex physics concept was approached in a straightforward and inexpensive manner while still providing an understanding of the fundamental concepts. These simple demonstrations introduced basic concepts and addressed common misconceptions about pressure.
PubMed: 38813605
DOI: 10.1152/advan.00066.2024 -
Frontiers in Psychology 2024The confluence of physiological and psychological dynamics is fundamental to athletic performance, particularly in basketball, where physical skill and mental resilience...
INTRODUCTION
The confluence of physiological and psychological dynamics is fundamental to athletic performance, particularly in basketball, where physical skill and mental resilience are imperative. While the role of verbal encouragement (VE) as a catalyst for enhancing performance has been explored in various sports disciplines, its specific effects within the basketball have not been adequately examined. Addressing this gap, the current study zeroes in on the influence of coach-delivered VE on the physiological and psychological responses of adolescent basketball players engaged in small-sided games (SSG), providing a focused analysis of how directed encouragement can modulate performance and experience in young athletes. This study aimed to investigate the effects of coach-delivered verbal encouragement on the psychological and physiological responses of adolescent basketball players.
METHODS
Sixteen male participants (age: 16.93 ± 0.36 years; height: 176.8 ± 0.8 cm; body mass: 73.43 ± 12.57 kg; BMI: 21.70 ± 3.55) were allocated to a Verbal Encouragement Group (VEG, = 8, mean age: 16.80 ± 0.44) and a Control Group (CG, = 8, mean age: 17.06 ± 0.26). Each participant engaged in four sessions of small-sided games (SSGs) consisting of four players per side in a 14 × 10 m pitch.
RESULTS
The findings revealed significant benefits of coach-delivered verbal encouragement on both the physical and psychophysiological responses of the players ( < 0.05), including increased physical enjoyment, positive mood state, lower heart rate, and higher physical activity intensity level.
DISCUSSION
Coaches should incorporate verbal encouragement strategies during SSGs to enhance player performance and optimize both psychological and physiological adaptations.
PubMed: 38813554
DOI: 10.3389/fpsyg.2024.1392668 -
Frontiers in Behavioral Neuroscience 2024Autism spectrum disorder (ASD) is a group of diseases often characterized by poor sociability and challenges in social communication. The anterior cingulate cortex (ACC)...
INTRODUCTION
Autism spectrum disorder (ASD) is a group of diseases often characterized by poor sociability and challenges in social communication. The anterior cingulate cortex (ACC) is a core brain region for social function. Whether it contributes to the defects of social communication in ASD and whether it could be physiologically modulated to improve social communication have been poorly investigated. This study is aimed at addressing these questions.
METHODS
Fragile X mental retardation 1 (FMR1) mutant and valproic acid (VPA)-induced ASD mice were used. Male-female social interaction was adopted to elicit ultrasonic vocalization (USV). Immunohistochemistry was used to evaluate USV-activated neurons. Optogenetic and precise target transcranial magnetic stimulation (TMS) were utilized to modulate anterior cingulate cortex (ACC) neuronal activity.
RESULTS
In wild-type (WT) mice, USV elicited rapid expression of c-Fos in the excitatory neurons of the left but not the right ACC. Optogenetic inhibition of the left ACC neurons in WT mice effectively suppressed social-induced USV. In - and VPA-induced ASD mice, significantly fewer c-Fos/CaMKII-positive neurons were observed in the left ACC following USV compared to the control. Optogenetic activation of the left ACC neurons in or VPA-pretreated mice significantly increased social activity elicited by USV. Furthermore, precisely stimulating neuronal activity in the left ACC, but not the right ACC, by repeated TMS effectively rescued the USV emission in these ASD mice.
DISCUSSION
The excitatory neurons in the left ACC are responsive to socially elicited USV. Their silence mediates the deficiency of social communication in and VPA-induced ASD mice. Precisely modulating the left ACC neuronal activity by repeated TMS can promote the social communication in and VPA-pretreated mice.
PubMed: 38813469
DOI: 10.3389/fnbeh.2024.1387447