Dendrobine Ameliorates Glucocorticoid-Induced Osteoporosis by Promoting Osteogenesis through JNK/p38 MAPK Pathway Activation and GR Nuclear Translocation Inhibition.

Glucocorticoid-induced osteoporosis (GIOP) is the common reason for secondary osteoporosis. Dendrobine (DEN) is the major biologically active component of Dendrobium officinale with anti-inflammatory and antiaging properties. Whether DEN could alleviate osteogenic inhibition in GIOP rats is still unknown. The influence on osteogenic function caused by DEN on dexamethasone-treated bone marrow mesenchymal stem cells and rats was observed. The in vitro results showed that DEN reversed the inhibition of osteogenic differentiation by dexamethasone. Moreover, DEN supplementation attenuated dexamethasone-induced bone loss in vivo. DEN activated JNK and p38 MAPK pathways and restrained GR nuclear translocation, which could be prevented by the JNK (SP600125) or p38 (SB203580) pathway inhibitor. This study verified that DEN alleviated dexamethasone-induced nuclear translocation of GR, and inhibition of osteogenesis via JNK and p38 pathways, laying the foundation for DEN as a therapeutic agent for GIOP.

All-cause and cause-specific mortality in US adults with periodontal diseases: A prospective cohort study.

AIM: This prospective cohort study investigated the association between periodontal diseases (PDs) and all-cause and cause-specific mortality. MATERIALS AND METHODS: We utilized adult participants recruited from six National Health and Nutrition Examination Survey cycles (1999-2014) and linked mortality data from the National Death Index up to December 2019. Baseline clinical periodontal examinations were performed by trained and calibrated examiners. All-cause and cause-specific mortality was modelled through multivariable Cox proportional hazards and Fine-Gray models to account for competing risks. All models were adjusted for demographic and lifestyle variables, clinical measurements and comorbidities. RESULTS: Overall, 15,030 participants were included, with a median length of follow-up of 9 years. Risk of all-cause mortality was 22% greater in people with PD than the control group (adjusted hazard ratio [HR]: 1.22, 95% confidence interval [CI]: 1.12-1.31). Risks of mortality by cardiovascular diseases (CVD), respiratory disease and diabetes were highest in participants with severe PD (CVD-sub-distribution HR [SHR]: 1.38, 95% CI: 1.16-1.64; respiratory-SHR: 1.62, 95% CI: 1.07-2.45; diabetes-SHR: 1.68, 95% CI: 1.12-2.53). CONCLUSIONS: Severe PD is associated with all-cause and cause-specific mortality among US adults after multivariable adjustment.

Astrocytes in preoptic area regulate acute nociception-induced hypothermia through adenosine receptors.

AIMS: The preoptic area (POA) of the hypothalamus, crucial in thermoregulation, has long been implicated in the pain process. However, whether nociceptive stimulation affects body temperature and its mechanism remains poorly studied. METHODS: We used capsaicin, formalin, and surgery to induce acute nociceptive stimulation and monitored rectal temperature. Optical fiber recording, chemical genetics, confocal imaging, and pharmacology assays were employed to confirm the role and interaction of POA astrocytes and extracellular adenosine. Immunofluorescence was utilized for further validation. RESULTS: Acute nociception could activate POA astrocytes and induce a decrease in body temperature. Manipulation of astrocytes allowed bidirectional control of body temperature. Furthermore, acute nociception and astrocyte activation led to increased extracellular adenosine concentration within the POA. Activation of adenosine A1 or A2A receptors contributed to decreased body temperature, while inhibition of these receptors mitigated the thermo-lowering effect of astrocytes. CONCLUSION: Our results elucidate the interplay between acute nociception and thermoregulation, specifically highlighting POA astrocyte activation. This enriches our understanding of physiological responses to painful stimuli and contributes to the analysis of the anatomical basis involved in the process.

Cerebellar Purkinje cell firing promotes conscious recovery from anesthesia state through coordinating neuronal communications with motor cortex.

Background: The neurobiological basis of gaining consciousness from unconscious state induced by anesthetics remains unknown. This study was designed to investigate the involvement of the cerebello-thalamus-motor cortical loop mediating consciousness transitions from the loss of consciousness (LOC) induced by an inhalational anesthetic sevoflurane in mice. Methods: The neural tracing and fMRI together with opto-chemogenetic manipulation were used to investigate the potential link among cerebello-thalamus-motor cortical brain regions. The fiber photometry of calcium and neurotransmitters, including glutamate (Glu), γ-aminobutyric acid (GABA) and norepinephrine (NE), were monitored from the motor cortex (M1) and the 5th lobule of the cerebellar vermis (5Cb) during unconsciousness induced by sevoflurane and gaining consciousness after sevoflurane exposure. Cerebellar Purkinje cells were optogenetically manipulated to investigate their influence on consciousness transitions during and after sevoflurane exposure. Results: Activation of 5Cb Purkinje cells increased the Ca2+ flux in the M1 CaMKIIα+ neurons, but this increment was significantly reduced by inactivation of posterior and parafascicular thalamic nucleus. The 5Cb and M1 exhibited concerted calcium flux, and glutamate and GABA release during transitions from wakefulness, loss of consciousness, burst suppression to conscious recovery. Ca2+ flux and Glu release in the M1, but not in the 5Cb, showed a strong synchronization with the EEG burst suppression, particularly, in the gamma-band range. In contrast, the Glu, GABA and NE release and Ca2+ oscillations were coherent with the EEG gamma band activity only in the 5Cb during the pre-recovery of consciousness period. The optogenetic activation of Purkinje cells during burst suppression significantly facilitated emergence from anesthesia while the optogenetic inhibition prolonged the time to gaining consciousness. Conclusions: Our data indicate that cerebellar neuronal communication integrated with motor cortex through thalamus promotes consciousness recovery from anesthesia which may likely serve as arousal regulation.

CD95 promotes stemness of colorectal cancer cells by lncRNA MALAT1.

Colorectal cancer (CRC) is the second most fatal cancer. Many studies have shown that cancer stemness contributes to resistance to conventional chemotherapy and poor prognosis. However, the mechanisms involved in maintaining cancer stemness in CRC are still obscure and few clinical drugs were used to target cancer stemness. Previous studies had reported CD95 increases the stemness of cancer cells with long-term stimulation of exogenous agonist CD95 ligand (CD95L). However, the expression of CD95L is relative low in certain human tumor tissues. In this study, we found that CD95 was highly expressed in CRC cells, and in vitro it promoted the tumorsphere formation, chemotherapy resistance and in vivo tumor growth without stimulation of exogenous CD95L. Mechanistically, the bulk and single-cell RNA-sequencing results suggested that CD95 promotes stemness of CRC cells through upregulation of long non-coding RNAs metastasis-associated lung adenocarcinoma transcript 1 (lncRNA MALAT1). MALAT1 knockdown inhibited CD95-induced tumorsphere formation and chemotherapy resistance. In summary, our findings reveal that CD95 has the capability to modulate cancer stemness via the action of the lncRNA MALAT1. Targeting CD95 may be a promising strategy to inhibit cancer stemness in CRC.

Oral diseases are associated with cognitive function in adults over 60 years old.

OBJECTIVE: To investigate the bidirectional association between oral diseases and cognitive function comprehensively. SUBJECTS AND METHODS: This cross sectional study utilized data from the National Health and Nutrition Examination Survey. Oral diseases include periodontitis, dental caries, and tooth loss (end point of oral disease resulting in tooth extraction). Cognitive function included three domains: memory, processing speed, and executive function. A global cognitive score was then derived from sum of the three cognitive domains. Oral cognition associations were examined using various statistical models: (1) Regress oral disease on cognitive function; (2) Regress cognitive function on oral disease; and (3) Structural equation modelling treating cognition and oral disease as latent variables. RESULTS: There were 2508 participants aged 60+ who had both oral and cognitive information. Associations between various oral disease and global cognitive score were observed (Odds ratio ORcog->periodontitis 0.95, 95% Confidence Interval [0.92, 0.99]; ßcog->caries -0.13, [-0.23, -0.04]; ßcog->tooth loss -0.03 [-0.04, -0.01]; ßtooth loss->cog -0.04 [-0.06, -0.02]; ßcaries->cog -0.03 [-0.06, -0.01]; ßperiodontitis->cog -0.39 [-0.69, -0.10]). Significant correlation was also found between these oral disease and cognitive function using structural equation model (r -0.22, [-0.34, -0.10]). CONCLUSIONS: This study found robust bidirectional associations between oral disease and cognitive function using various modelling approaches among the aging population.

Single cell profiling of female breast fibroadenoma reveals distinct epithelial cell compositions and therapeutic targets.

Fibroadenomas (FAs) are the most common breast tumors in women. No pharmacological agents are currently approved for FA intervention owing to its unclear mechanisms and a shortage of reproducible human models. Here, using single-cell RNA sequencing of human FAs and normal breast tissues, we observe distinct cellular composition and epithelial structural changes in FAs. Interestingly, epithelial cells exhibit hormone-responsive functional signatures and synchronous activation of estrogen-sensitive and hormone-resistant mechanisms (ERBB2, BCL2 and CCND1 pathways). We develop a human expandable FA organoid system and observe that most organoids seem to be resistant to tamoxifen. Individualized combinations of tamoxifen with ERBB2, BCL2 or CCND1 inhibitors could significantly suppress the viability of tamoxifen-resistant organoids. Thus, our study presents an overview of human FA at single-cell resolution that outlines the structural and functional differences between FA and normal breast epithelium and, in particular, provides a potential therapeutic strategy for breast FAs.

SAG treatment ameliorates memory impairment related to sleep loss by upregulating synaptic plasticity in adolescent mice.

Adequate sleep during the developmental stage can promote learning and memory functions because synaptic protein synthesis at primed synapses during sleep profoundly affects neurological function. The Sonic hedgehog (Shh) signaling pathway affects neuroplasticity in the hippocampus during the development of the central nervous system. In this study, the changes in synaptic morphology and function induced by sleep deprivation and the potential therapeutic effect of a Shh agonist (SAG) on these changes were investigated in adolescent mice. Adolescent mice were subjected to sleep deprivation for 20 hrs (2 pm to 10 am the next day) and were free to sleep for the remaining 4 hrs per day for 10 consecutive days. Sleep-deprived mice were injected with SAG (10 mg/kg body weight, i.p.) or saline (i.p.) every day 5 min before the onset of the 20 h sleep deprivation period. Chronic sleep deprivation impaired recognition and spatial memory, decreased the number of dendritic spines and mEPSCs of hippocampal CA1 pyramidal neurons, decreased the postsynaptic density, and reduced Shh and glioma-associated oncogene homolog 1 (Gli1) expression. SAG significantly protected against sleep deprivation-induced memory dysfunction, increased the CA1 pyramidal neuronal dendritic spine number and mEPSC frequency, and increased Gli1 expression. In conclusion, sleep deprivation induces memory impairment in adolescent mice, and SAG treatment prevents this impairment, probably by enhancing synaptic function in the hippocampal CA1 region.

Multiple cholesterol granulomas of the breast: A case report and review of the literature.

RATIONALE: Cholesterol granuloma of the breast is a rare disease defined as chronic reactive inflammation of cholesterol crystals and foreign body giant cells. This disease can mimic breast cancer in the clinic as painless palpable hard nodules, and imaging shows irregular hypoechoic nodules with unclear boundaries. Therefore, the uncommon lesions can be easily misdiagnosed as breast cancer. Meanwhile, it can be easily neglected by clinicians because of poor understanding. PATIENT CONCERNS: In this report, we present a rare case of multiple cholesterol granulomas of the breast, which was analyzed retrospectively and combined with all 11 relevant available studies in the last 50 years. INTERVENTIONS: The patient had undergone multiple breast imaging inspections for breast nodules and had the local resection of nodules. DIAGNOSES: The patient was confirmed to have a final diagnosis of benign cholesterol granulomas but was initially considered as breast cancer. OUTCOMES: The patient did not complain of discomfort after surgery, and ultrasound reexamination 5 months after surgery showed no recurrence. LESSONS: By retrospective analysis, dynamic contrast-enhanced magnetic resonance imaging and core needle biopsy can synergistically help clinicians distinguish it from other breast disease. To raise awareness of such a rare disease and reduce related misdiagnoses, we summarize the characteristics of cholesterol granulomas and recommend appropriate novel diagnosis and treatment regimens for patients with cholesterol granulomas.

The impact of study factors in the association of periodontal disease and cognitive disorders: systematic review and meta-analysis.

AIM: The aim was to assess study factors that impact the association of cognitive disorders in people with periodontal disease (PD). METHOD: Medline, EMBASE and Cochrane databases were searched until February 2022 using keywords and MeSH: (periodon* OR tooth loss OR missing teeth) AND (dementia OR Alzheimer's Disease OR cognitive*). Observational studies reporting prevalence or risk of cognitive decline, dementia or Alzheimer's disease (AD) in people with PD compared with healthy controls were included. Meta-analysis quantified the prevalence and risk (relative risk[RR]) of cognitive decline, dementia/AD, respectively. Meta-regression/subgroup analysis explored the impact of study factors including PD severity and classification type, and gender. RESULTS: Overall, 39 studies were eligible for meta-analysis: 13 cross-sectional and 26 longitudinal studies. PD demonstrated increased risks of cognitive disorders (cognitive decline-RR = 1.33, 95% CI = 1.13-1.55; dementia/AD-RR = 1.22, 95% CI = 1.14-1.31). Risk of cognitive decline increased with PD severity (moderate-[RR] = 1.14, 95% confidence interval [CI] = 1.07-1.22; severe-RR = 1.25, 95% CI = 1.18-1.32). For every 10% population increase in females, the risk of cognitive decline increased by 34% (RR = 1.34, 95% CI = 1.16-1.55). Self-reported PD showed a lower risk of cognitive disorders compared with clinical classification (cognitive decline-RR = 0.77, 95% CI = 0.65-0.91; dementia/AD-RR = 0.86, 95% CI = 0.77-0.96). CONCLUSION: The prevalence and risk estimates of cognitive disorders in association with PD can be influenced by gender, the disease classification of PD and its severity. Further homologous evidence taking these study factors into consideration is needed to form robust conclusions.

High FAS expression correlates with a better prognosis and efficacy of taxanes and target regents in breast cancer.

BACKGROUND: FAS can serve as both an oncogene and a suppresser in different malignancies, and the prognostic value of FAS remains controversial. METHODS: The Oncomine database, KM-Plotter and bc-GenExMiner platform were adopted to analyze the prognostic value of FAS in breast cancer. Breast cancer tissue microarrays were further used to verify these data. The Cell Miner Tool was used to predict the value of FAS mRNA expression in predicting the efficacies of clinical drugs. RESULTS: We found that both FAS mRNA and protein expression level significantly reduced in breast carcinoma. In addition, high FAS expression indicates a better metastatic relapse-free survival. Interestingly, FAS was associated with a better prognosis in different subtypes of breast cancer patients, namely, only in grade II and III, lymph nodal positive or p53 wild-type patients. The data from the Cell Miner Tool revealed that FAS mRNA expression was correlated with the efficacy of the first-line chemotherapeutic taxane agents and target drugs including olaparib and everolimus. CONCLUSIONS: FAS expression correlates with a better prognosis in breast cancer and may provide an effective clinical strategy to predict the sensitivity of taxanes and targeted drugs.

Energy metabolism in cancer stem cells.

Normal cells mainly rely on oxidative phosphorylation as an effective energy source in the presence of oxygen. In contrast, most cancer cells use less efficient glycolysis to produce ATP and essential biomolecules. Cancer cells gain the characteristics of metabolic adaptation by reprogramming their metabolic mechanisms to meet the needs of rapid tumor growth. A subset of cancer cells with stem characteristics and the ability to regenerate exist throughout the tumor and are therefore called cancer stem cells (CSCs). New evidence indicates that CSCs have different metabolic phenotypes compared with differentiated cancer cells. CSCs can dynamically transform their metabolic state to favor glycolysis or oxidative metabolism. The mechanism of the metabolic plasticity of CSCs has not been fully elucidated, and existing evidence indicates that the metabolic phenotype of cancer cells is closely related to the tumor microenvironment. Targeting CSC metabolism may provide new and effective methods for the treatment of tumors. In this review, we summarize the metabolic characteristics of cancer cells and CSCs and the mechanisms of the metabolic interplay between the tumor microenvironment and CSCs, and discuss the clinical implications of targeting CSC metabolism.

DCA for genome-wide epistasis analysis: the statistical genetics perspective.

Direct coupling analysis (DCA) is a now widely used method to leverage statistical information from many similar biological systems to draw meaningful conclusions on each system separately. DCA has been applied with great success to sequences of homologous proteins, and also more recently to whole-genome population-wide sequencing data. We here argue that the use of DCA on the genome scale is contingent on fundamental issues of population genetics. DCA can be expected to yield meaningful results when a population is in the quasi-linkage equilibrium (QLE) phase studied by Kimura and others, but not, for instance, in a phase of clonal competition. We discuss how the exponential (Potts model) distributions emerge in QLE, and compare couplings to correlations obtained in a study of about 3000 genomes of the human pathogen Streptococcus pneumoniae.