Recently, male reproductive health has attracted extensive attention, with the adverse effects of circadian disruption on male fertility gradually gaining recognition. However, the mechanism by which circadian disruption leads to damage to male reproductive system remains unclear. In this review, we first summarized the dual regulatory roles of circadian clock genes on the male reproductive system: (1) circadian regulation of testosterone synthesis via the hypothalamic-pituitary-testicular (HPT) and hypothalamic-pituitary-adrenal (HPA) axes; (2) non-circadian regulation of spermatogenesis. Next, we further listed the possible mechanisms by which circadian disruption impairs male fertility, including interference with the oscillatory function of the reproductive system, i.e., synchronization of the HPT axis, crosstalk between the HPT axis and the HPA axis, as well as direct damage to germ cells by disturbing the non-oscillatory function of the reproductive system. Future research using spatiotemporal omics, epigenomic assays, and neural circuit mapping in studying the male reproductive system may provide new clues to systematically unravel the mechanisms by which circadian disruption affects male reproductive system through circadian clock genes.
Male ; Humans ; Animals ; Circadian Clocks/physiology* ; Hypothalamo-Hypophyseal System/physiology* ; Circadian Rhythm/genetics* ; Spermatogenesis/physiology* ; Pituitary-Adrenal System/physiology* ; Testis/physiology* ; Testosterone/biosynthesis* ; CLOCK Proteins ; Infertility, Male/physiopathology*

Long-term spaceflight exposes astronauts to multiple extreme environmental factors, such as cosmic radiation, microgravity, social isolation, and circadian rhythm disruption, that markedly increase the risk of depressive symptoms, posing a direct threat to mental health and mission safety. However, the underlying biological mechanisms remain complex and incompletely understood. The potential mechanisms of spaceflight-induced depressive symptoms involve multiple domains, including alterations in brain structure and function, dysregulation of neurotransmitters and neurotrophic factors, oxidative stress, neuroinflammation, neuroendocrine system imbalance, and gut microbiota disturbances. Collectively, these changes may constitute the biological foundation of depressive in astronauts during spaceflight. Space-related stressors may increase the risk of depressive symptoms through several pathways: impairing hippocampal neuroplasticity, suppressing dopaminergic and serotonergic system function, reducing neurotrophic factor expression, triggering oxidative stress and inflammatory responses, activating the hypothalamic-pituitary-adrenal axis, and disrupting gut microbiota homeostasis. Future research should integrate advanced technologies such as brain-computer interfaces to develop individualized monitoring and intervention strategies, enabling real-time detection and effective prevention of depressive symptoms to safeguard astronauts' psychological well-being and mission safety.
Space Flight ; Humans ; Astronauts/psychology* ; Depression/physiopathology* ; Gastrointestinal Microbiome ; Weightlessness/adverse effects* ; Oxidative Stress ; Brain/physiopathology* ; Hypothalamo-Hypophyseal System ; Neuronal Plasticity ; Pituitary-Adrenal System

OBJECTIVES: To clarify the role of hippocampal glutamate system in regulating HPA axis in mediating the effect of electroacupuncture (EA) at the heart meridian for improving myocardial injury in rats with acute myocardial ischemia (AMI). METHODS: Male SD rats were randomized into sham-operated group, AMI group, EA group, and L-glutamic acid+EA group (n=9). Rat models of AMI were established by left descending coronary artery ligation, and EA was applied at the "Shenmen-Tongli" segment; the rats in L-glutamic acid+EA group were subjected to microinjection of L-glutamic acid into the bilateral hippocampus prior to AMI modeling and EA treatment. Cardiac functions of the rats were evaluated using echocardiography, and ECG and heart rate variation (HRV) were analyzed using PowerLab and LabChart. Pathological changes in the myocardial tissue was examined using HE staining, and serum levels of myocardial enzymes were detected with ELISA. Myocardial expressions of TH and GAP43 were detected with immunohistochemistry, and colocalization of VGLUT1, VGLUT2 and c-fos were observed using immunofluorescence staining; the expressions of VGLUT1, VGLUT2, NMDAR1 and NMDAR2B were detected using Western blotting. RESULTS: The rat models of AMI showed significantly decreased LVEF and LVFS and increased serum levels of myocardial enzymes in positive correlation with the HPA axis. Numerous TH- and GAP43-positive cells were observed in the hippocampus, where the expressions of NE and E, neurons colabeled with VGLUT1, VGLUT2 and c-fos, and expressions of VGLUT1, VGLUT2, NMDAR1, NMDAR2B and Glu increased significantly. All these changes were significantly improved by interventions with EA as compared with those in AMI and L-Glutamate+EA groups. CONCLUSIONS In rats with AMI, EA at the heart meridian can regulate excessive glutamate release in the hippocampus, thereby inhibiting HPA axis hyperactivity and reducing sympathetic nerve activity to protect the myocardial tissue.
Animals ; Electroacupuncture ; Male ; Rats, Sprague-Dawley ; Hippocampus/metabolism* ; Rats ; Glutamic Acid/metabolism* ; Myocardial Ischemia/physiopathology* ; Hypothalamo-Hypophyseal System/physiopathology* ; Pituitary-Adrenal System/physiopathology* ; Receptors, N-Methyl-D-Aspartate/metabolism*

OBJECTIVETo explore the rhythm regulatory mechanism of interleukin-6 (IL-6) in the process of moxibustion for rheumatoid arthritis (RA).

METHODSA total of 144 Sprague-Dawley (SD) rats were randomly divided into a blank group, a model group, a moxibustion group, a sham operation group, an operation group, an operation+moxibustion group, 24 rats in each one. Each group was divided into 4 time points (0:00 am, 6:00' am, 12:00 am, 6:00 pm), 6 rats in each time point. The Light-Dark 12 : 12 was given in all rats for light-dark cycle. Except the blank group, rats in the remaining groups were treated with intracutaneous injection of freund's complete adjuvant at right-side foot to establish the model of RA. After the model establishment, bilateral adrenal, glands were removed in the operation group and operation + moxibustion group, while those in the sham operation group were not removed with identical operation procedure. Rats in the moxibustion group and operation + moxibustion group were treated with grain-sized moxibustion from 7:00 am to 9:00 am at "Shenshu" (BL 23) and "Zusanli" (ST 36) once everyday, 6 times were taken as one session and 3 sessions were required tatclly, while rats in the remaining groups received identical fixation without moxibustion. The general health state and foot volume of rats were measured before model establishment, after establishment and after treatment. After treatment, rats were sacrificed at each time point to collect the blood sample and measure the content of IL-6 by using enzymne-immunoassay method.

RESULTSCompared with the blank group, the foot swelling in the model group was obviously increased (P<0. 05); the IL-6 maintained circadian rhythm (P<0. 05), but the peak phase had a backward trend, famplitude had an increased trend and the median was significantly lifted (P<0. 05). Compared with model group, !the foot swelling in the moxibustion group was obviously decreased (P<0. 05); the IL-6 maintained circadian. rhythm (P<0. 05), and the peak phase had a forward trend, amplitude had a decreased trend and the median was significantly reduced (P<0. 05). Compared with the moxibustion group, the foot swelling in the operation--moxibustion group was obviously increased (P < 0.05); the IL-6 maintained circadian rhythm (P < 0.5), but the peak phase moved forwrd, and the median was significantly elevated (P < 0.05).

CONCLUSIONThe IL-6 in plasma maintains significant pathological circadian rhythm in RA rats; with the complete hypothalamic-pituitary-adrenal axis, moxibustion is likely to regulate the circadian rhythm of IL-6 to play an important role of anti-inflammatory effect in RA rats.

Acupuncture Points ; Animals ; Arthritis, Rheumatoid ; metabolism ; physiopathology ; therapy ; Circadian Rhythm ; Disease Models, Animal ; Female ; Humans ; Hypothalamus ; metabolism ; Interleukin-6 ; metabolism ; Male ; Moxibustion ; Pituitary-Adrenal System ; metabolism ; Rats ; Rats, Sprague-Dawley ; Time Factors

Sini Powder (SP), a traditional Chinese herbal formula, has long been used to treat depression in patients, although the underlying mechanisms remain to be elucidated. In the present study, we found that rats treated with SP extract for 7 days showed a significant increase in swimming time and reduction in immobility time in forced swimming test in a dose-dependent manner, without changes in locomotion. These effects could be attributed to SP's modulation of the hypothalamus-pituitary-adrenal axis, because a single pretreatment of SP extract could rescue increased serum corticosterone and plasma adrenocorticotropin levels induced by acute elevated platform stress. A single pretreatment of SP extract could also elevate the mRNA expression of hippocampal glucocorticoid receptors. In conclusion, our results suggest that SP extract may act as an anti-stress medication to produce antidepressant-like effects.
Adrenocorticotropic Hormone ; blood ; Animals ; Antidepressive Agents ; administration & dosage ; Corticosterone ; blood ; Depression ; drug therapy ; genetics ; metabolism ; physiopathology ; Drugs, Chinese Herbal ; administration & dosage ; Hippocampus ; drug effects ; Humans ; Male ; Pituitary-Adrenal System ; drug effects ; metabolism ; Rats ; Rats, Sprague-Dawley ; Receptors, Glucocorticoid ; genetics ; metabolism

OBJECTIVETo observe the effect of hesperidin on behavior and hypothalamic-pituitary-adrenal (HPA) axis of ratmodel of chronic stress-induced depression.

METHODChronic unpredictable mild stress (CUMS) was used to establish the rat depression model. Sixty male SD rats were divided randomly into six groups: the normal group, the model group, the hesperidin (40, 80, 160 mg x kg(-1)) group and the positive fluoxetine (10 mg x kg(-1)) group. They were orally administered with drugs for three weeks. The sucrose preference test and the forced swimming test (FST) were assayed to detect animal behavior. The levels of corticosterone (CORT) in serum, mRNA of corticotropin release factor (CRF) in hypothalamus as well as protein expression of glucocorticoid receptor (GR) in paraventricular nucleus (PVN) were determined to clarify the anti-depression effect and mechanism of hesperidin.

RESULTCompared with the model group, rats in the hesperidin (40, 80, 160 mg x kg(-1)) treatment group showed significant increase in the sucrose consumption and decrease in the immobility time in FST to varying degrees. Meanwhile, the excessively high serum CORT and adrenal index of CUMS rats were reversed by treatment with hesperidin. In addition, hesperidin inhibited CRF mRNA expression in hypothalamus and up-regulated GR protein expression in PVN among CUMS rats.

CONCLUSIONHesperidin could effectively improve the behavior of CUMS rats and show the anti-depression effect. Its mechanisms may be related to the function of regulating HPA axis.

Administration, Oral ; Animals ; Behavior, Animal ; drug effects ; Corticosterone ; blood ; Corticotropin-Releasing Hormone ; genetics ; metabolism ; Depression ; drug therapy ; etiology ; Fluoxetine ; administration & dosage ; Gene Expression Regulation ; drug effects ; Hesperidin ; administration & dosage ; pharmacology ; Hypothalamo-Hypophyseal System ; drug effects ; physiopathology ; Hypothalamus ; metabolism ; Male ; Models, Animal ; Pituitary-Adrenal System ; drug effects ; physiopathology ; Random Allocation ; Rats ; Rats, Sprague-Dawley ; Receptors, Glucocorticoid ; metabolism ; Stress, Psychological ; complications ; drug therapy ; Sucrose ; metabolism ; Swimming ; Up-Regulation

BACKGROUNDTraumatic brain injury (TBI) is a heterogeneous condition that can lead to critical LLLness-related corticosteroid insufficiency (CIRCI) causing a high mortality and morbidity. Glucocorticoids were widely used in the clinical management of TBI, but their benefit has been challenged in some studies and their efficacy, especially for treating CIRCI in TBI patients, remains unclear.

METHODSWe conducted a meta-analysis of published data to determine if the controversy is related to clinical dosing and timing of glucocorticoids (GCs) application. We analyzed published reports in four databases (MEDLINE, EMBASE, the Cochrane Controlled Trials Register, and CBMdisc). The published data were stratified into not only low- and high-dose GCs group but also short- and long-term GCs group to compare their effectiveness in improving TBI outcomes.

RESULTSWe totally identified 16 reports. For low-dose patients, the pooled relative risks (RRs) for two clinical outcomes of death or a combination of death and severe disability were 0.95 (95% confidence interval (CI): 0.80 to 1.13) and 0.95 (95% CI: 0.83 to 1.09), respectively. The risks for infection and gastrointestinal bleeding were 0.85 (95% CI: 0.50 to 1.45) and 0.64 (95% CI: 0.15 to 2.70), respectively. For high-dose group, the pooled RR of death is 1.14 (95% CI: 1.06 to 1.21). The pooled RRs for infection and gastrointestinal bleeding for the high-dose patients were 1.04 (95% CI: 0.93 to 1.15) and 1.26 (95% CI: 0.92 to 1.75), respectively. For long-term use group, the pooled RRs for two clinical outcomes of death or a combination of death and severe disability were 0.98 (95% CI: 0.87 to 1.12) and 1.00 (95% CI: 0.90 to 1.11), respectively. The risks for infection and gastrointestinal bleeding were 0.88 (95% CI: 0.71 to 1.11) and 0.96 (95% CI: 0.35 to 2.66), respectively. For short-term use group, the pooled RR of death is 1.15 (95% CI: 1.07 to 1.23), and importantly the effects on infections were beneficial in terms of TBI patients suffering from CIRCI.

CONCLUSIONSThis meta-analysis suggests an increased risk of death for TBI patients on a high dose and short term of glucocorticoids compared with those on a low dose and long term, for whom a trend towards clinical improvement is evident. In addition, stress-does of GCs further decrease the pneumonia incidence in TBI patients suffering from CIRCI. A large-scale multicenter randomized controlled trial is warranted for testing (1) the efficacy of stress-dose GCs treatment in the sub-acute phase of TBI (4-21 days after initial trauma), when CIRCI is most likely to occur; (2) the hypothesis that stress-dose GCs could boost patients' stress function and ensure survival.

Adrenal Cortex Hormones ; deficiency ; Brain Injuries ; drug therapy ; mortality ; physiopathology ; Critical Illness ; Glucocorticoids ; therapeutic use ; Humans ; Hypothalamo-Hypophyseal System ; physiopathology ; Pituitary-Adrenal System ; physiopathology ; Time Factors

OBJECTIVETo evaluate the key indicators in the pituitary-target gland axes in the animal model of Shen-yang deficiency syndrome (SYDS).

METHODSThe 8 biological indicators [thyroid stimulating hormone (TSH), 3, 3', 5-triiodothyronine (T3), thyroxine (T4), luteinizing hormone (LH), follicle-stimulating hormone (FSH), testosterone (T), adrenocorticotropic hormone (ACTH), and cortisol (CORT)] in the pituitary-target gland axes were grouped using factor analysis. Then the sensitivity of every indicator was calculated according to the sensitivity function defined in this paper, so as to find all the most sensitive indicators in every group as key indicators of SYDS.

RESULTSThe key indicators in the early period of SYDS were T, LH, T4, and CORT. The key indicators in the middle period were LH,T, CORT, and ACTH. The key indicators in the late period were LH, T, CORT, and FSH.

CONCLUSIONST, LH, and CORT were the common key indicators of the three periods, and other different key indicator of SYDS in the early, middle and late period were T4, ACTH, and FSH respectively, which changed from the thyroid axis to the adrenal axis and then to the gonadal axis as the period changed. The key indicators in the late period were mainly in the gonadal axis, showing gonadal dysfunction in the late period.

Animals ; Disease Models, Animal ; Estradiol ; analysis ; Factor Analysis, Statistical ; Follicle Stimulating Hormone ; analysis ; Hydrocortisone ; analysis ; Luteinizing Hormone ; analysis ; Male ; Pituitary-Adrenal System ; physiopathology ; Rats ; Rats, Sprague-Dawley ; Testosterone ; analysis ; Thyrotropin ; analysis ; Thyroxine ; analysis ; Yang Deficiency ; physiopathology

Depression and insomnia are intimately related. Depressed patients usually manifest sleep discontinuity and early awakening, reduced or no slow wave sleep (SWS) and shortened latency of rapid eye movement (REM) sleep. These sleep abnormalities are very similar to those caused by over activated hypothalamic-pituitary-adrenal (HPA) axis with stress. Therefore, the animal models developed by post-traumatic stress disorder or chronic unpredictable mild stress could be used to evaluate drugs which have effects of both anti-depression and improvement of sleep quality, and to provide a more reliable platform for further studis on the mechanisms of depression and accompanied insomnia. This review mainly focuses on the typical features of sleep disturbance of depression, possible pathophysiological mechanisms, establishment of animal stress models and analysis of their abnormal sleep characteristics.
Animals ; Chronic Disease ; Depression ; physiopathology ; Depressive Disorder ; physiopathology ; Disease Models, Animal ; Humans ; Hypothalamo-Hypophyseal System ; physiopathology ; Pituitary-Adrenal System ; physiopathology ; Sleep ; physiology ; Sleep Initiation and Maintenance Disorders ; physiopathology ; Sleep, REM ; Stress Disorders, Post-Traumatic ; physiopathology ; Stress, Psychological ; physiopathology

OBJECTIVETo study the correlation between the inflammatory factors in the serum and the induced sputum and the hypothalamic-pituitary-adrenal (HPA) axis function in advanced lung adenocarcinoma patients of different syndromes.

METHODSTotally 71 patients with advanced lung adenocarcinoma were assigned to three groups according to syndrome differentiation, i.e., Shen-yang deficiency (SYD) group (28 cases), Fei-qi deficiency (FQD) group (23 cases), and yin deficiency fire excess (YDFE) group (20 cases). Another 41 healthy subjects were enrolled as the normal control group. Sputum was induced and blood samples were collected for measurement of cytokines including tumor necrosis factor alpha (TNF-alpha), transforming growth factor beta (TGF-beta), interleukin-6 (IL-6), and interferon gamma (INF-gamma). The cytokine assay was performed using Bio-Plex Pro multi assay technology. 24-h collection of urine was performed and salivary samples of the diurnal rhythm profiles [including urinary free cortisol (UFC), urinary 17-hydroxycorticosteroids (17-OH), urinary 17-ketosteroid (17-KS), and cortisol in the serum and saliva] were obtained for assessment of the HPA axis activity.

RESULTSA higher level of serum IL-6 and a lower level of 24-h UFC and 17-OH were found in the SYD group (P < 0.05). The urinary 17-KS was obviously lower in the SYD group than in the normal control group and the YDEE group (P < 0.05). Compared with the FQD group and the normal control group, a higher serum level of TNF-alpha and a lower level of IFN-gamma were found in the SYD group and the YDFE group (P < 0.05). The TNF-alpha and TGF-beta levels in the induced sputum obviously increased in the SYD group (P < 0.05). The IFN-gamma level in the induced sputum obviously decreased in the YDFE group (P < 0.05). The serum and salivary cortisol obviously decreased from 8: 00 am to 8:00 am the next morning in the SYD group (P < 0.05). The serum cortisol level was negatively correlated with serum TNF-alpha (r = -0.26, P = 0.03) and serum IL-6 (r = -0.25, P = 0.03). The salivary cortisol level was negatively correlated with IL-6 in the induced sputum (r = -0.29, P = 0.02). The serum IFN-gamma was positively correlated with urinary 17-OH (r = 0.21, P = 0.03).

CONCLUSIONSThe inflammatory factors of advanced lung adenocarcinoma patients of SYD syndrome were up-regulated, with the most obvious decreased or disarranged HPA axis functions. The levels of IL-6, TNF-alpha, and IFN-gamma were closely correlated with the HPA axis functions. The transformation from qi deficiency, yin deficiency to Shen-yang deficiency existed in lung adenocarcinoma patients. The levels of IL-6, TNF-alpha, and IFN-gamma in the serum and the induced sputum, as well as the HPA axis functions are important indices for microscopic syndrome typing of lung adenocarcinoma.

Adenocarcinoma ; blood ; physiopathology ; Adolescent ; Adult ; Aged ; Case-Control Studies ; Cytokines ; blood ; Female ; Humans ; Hypothalamo-Hypophyseal System ; metabolism ; physiopathology ; Inflammation ; Lung Neoplasms ; blood ; physiopathology ; Male ; Middle Aged ; Neoplasm Staging ; Pituitary-Adrenal System ; metabolism ; physiopathology ; Sputum ; chemistry ; Young Adult