Extracellular vesicles (EVs) are cell-derived membrane-bound vesicles with heterogenous contents, including genetic materials, proteins, lipids and small metabolites. The classic EVs are exosomes, which originate from endosomal systems, and microvesicles, which are shed from the plasma membrane. Newly discovered organelle migrasome, once released from cells, adds another player to the EV realm. EVs are present in biological fluids and are important in multiple physiological and pathological processes, including immune regulation and cancer metastasis. Knowledge of EV biology is essential to promote the clinical application of EVs as potential candidates for non-invasive liquid biopsy and drug delivery vehicles. This is a fast-expanding field, but more attention should be paid to the fundamental biology of EVs in order to keep up with the explosive growth of translational needs.
Various beneficial biological activities of inorganic nitrate have been revealed in recent decades. Oral bacteria can reduce nitrate to nitrite, which is further reduced to nitric oxide (NO) in the body; this process is known as the nitrate-nitrite-NO pathway. Sialin is a mammalian membrane nitrate transporter that transports nitrate to the salivary glands and secretes it into the oral cavity through the saliva. Recent studies have indicated that nitrate has a protective effect on the salivary glands and other organs by regulating the expression of sialin and maintaining microbial homeostasis. Through the nitrate-nitrite-NO pathway, nitrate can act as a reservoir of NO in vivo and perform a variety of NO-like bioactivities, such as promoting exercise performance, protecting the digestive system, lowering blood pressure, and assisting in tumor treatment. This paper reviews the sources, functions, and possible mechanisms of inorganic nitrate, and discusses the protective role that nitrate promises to play in health and diseases.
We aimed to examine the risk of HCC associated with the long-term change patterns in HBV DNA levels.
We conducted a longitudinal study of 6,301 participants with chronic HBV infection (CHB) from October 2012 to June 2019 and measured serum levels of HBV DNA at enrollment and during follow-up. The dynamic change patterns of HBV DNA were identified by group-based trajectory models. The associations between change patterns of HBV DNA and HCC were estimated using Cox regression models.
During 35,112 person-years of follow-up, 182 participants developed HCC (518.34 per 105 person-years). Five trajectory groups of repeated measurement of HBV DNA were identified. The risk of HCC was significantly higher for the “high, fast-declined” group whose HBV DNA spontaneously decreased from > 2000 IU/mL at baseline compared with those with persistent undetected HBV DNA (reference group; 963.96 per 105 person-years, HR = 2.62, 95% CI, 1.82 to 3.77, P < 0.001). In addition, the “rebound” group whose HBV DNA level increased from undetectable level to > 20,000 IU/mL from baseline to the end of follow-up also showed an obviously higher cumulative HCC incidence rate (1193.29 per 105 person-years, HR = 4.17, 95% CI, 1.87 to 9.31, P < 0.001). The positive association remained stable after taking the potential effect of time-dependent antiviral treatment into account.
Significant variability in serum levels of HBV DNA presented during long-term follow-up. Regular monitoring of serum levels of HBV DNA and antiviral treatment are required for the clinical management of CHB patients, as well as those with undetected HBV DNA.
The pandemic of 2019 coronavirus (SARS-CoV-2) disease (COVID-19) has imposed a severe public health burden worldwide. Most patients with COVID-19 were mild. Severe patients progressed rapidly to critical condition including acute respiratory distress syndrome (ARDS), multi-organ failure and even death. This study aims to find early multi-organ injury indicators and blood glucose for predicting mortality of COVID-19.
Fasting blood glucose (FBG) ≥7.0 mmol/L for two times during hospitalization and without a history of diabetes were defined as new-onset COVID-19-related diabetes (CRD). Indicators of injuries for multiple organs, including the lung, heart, kidney and liver, and glucose homeostasis were specifically analyzed for predicting death.
A total of 120 patients with a severity equal to or greater than Moderate were hospitalized. After excluding patients with history of diabetes, chronic heart, kidney, and liver disease, 69 patients were included in the final analysis. Of the 69 patients, 23 were Moderate, 20 were Severe, and 26 were Critical (including 16 deceased patients). Univariable analysis indicated that CRD, lactate dehydrogenase (LDH), hydroxybutyrate dehydrogenase (HBDH), creatine kinase (CK) and creatinine (Cr) were associated with death. Multivariable analysis indicated that CRD was an independent predictor for death (HR = 3.75, 95% CI 1.26–11.15). Abnormal glucose homeostasis or CRD occurred earlier than other indicators for predicting poor outcomes. Indicators of multiple organ injury were in parallel with the expression patterns of ACE2 (the SARS-CoV-2 receptor) in different organs including pancreatic islet.
New-onset COVID-19-related diabetes is an early indicator of multi-organ injury and predictor for poor outcomes and death in COVID-19 patients. As it is easy to perform for clinical practices and self-monitoring, glucose testing will be helpful for predicting poor outcomes to facilitate appropriate intensive care.
Crosstalk between different signalling pathways provide deep insights for how molecules play synergistic roles in developmental and pathological conditions. RBP-Jkappa is the key effector of the canonical Notch pathway. Previously we have identified that Wnt5a, a conventional non-canonical Wnt pathway member, was under the direct transcriptional control of RBP-Jkappa in dermal papilla cells. In this study we further extended this regulation axis to the other two kind of skeletal cells: chondrocytes and osteoblasts. Mice with conditional mesenchymal deletion of RBP-Jkappa developed Rickets like symptoms. Molecular analysis suggested local defects of Wnt5a expression in chondrocytes and osteoblasts at both mRNA and protein levels, which impeded chondrocyte and osteoblast differentiation. The defects existing in the RBP-Jkappa deficient mutants could be rescued by recombinant Wnt5a treatment at both cellular level and tissue/organ level. Our results therefore provide a model of studying the connection of Notch and Wnt5a pathways with Rickets.
Dental defects and loss are common oral diseases that seriously affect the chewing efficiency of patients and thereby affect their health. With the development of tissue engineering technology, dental tissue regeneration has emerged as a promising technique. Cell type, extracellular matrix (ECM) environment, cytokines and other factors which affect odontogenic differentiation and dental tissue regeneration have aroused significant interest. The functional ECM consists of extracellular components that control the initiation and growth of crystal deposition and regulate the differentiation and regeneration of endogenous or exogenous stem cells in the defect site. At present, the function and regulatory mechanism of the functional ECM in this process remain poorly understood. Therefore, elucidating the effect of the functional ECM on odontogenic differentiation and its mechanism has great scientific significance and potential clinical application. This review explored functional ECM components involved in odontogenic differentiation and dental tissue regeneration.
Treatment options for malignant and aggressive glioma are limited. Vascular endothelial growth factor (VEGF) antibodies are angiogenesis inhibitors that prevent the growth of neoplasms by inhibiting the expansion of the vascular tissue that supports them. We designed this phase I trial to assess the safety and establish the maximum tolerable dose (MTD) of GB222, a recombinant human anti-VEGF monoclonal, for patients with recurrent malignant glioma.
Eligible patients were those who were diagnosed with WHO grade III and IV glioma and progressed after initial treatment including surgery, radiotherapy, and temozolomide. GB222 was initiated at 3 mg/kg (Cohort 1) intravenously once every four weeks (Q4W), then escalated in a 3 + 3 design at 5 mg/kg (Cohort 2, Q4W), 5 mg/kg (Cohort 3, Q2W), 7.5 mg/kg (Cohort 4, Q2W), and 10 mg/kg (Cohort 5, Q2W). The initial 28 days of each dose level cohort was the observation period for dose-limiting toxicity (DLT). After that, patients continued the treatment with the same dose of GB222 in combination of temozolomide if patients were considered to have benefited from the treatment. Our study also evaluated anti-tumor efficacy including objective response rate (ORR), progress free survival (PFS), and overall survival (OS), as well as pharmacokinetic parameters of GB222.
Sixteen patients were enrolled: 4 in Cohort 1, 3 each in Cohort 2, 3, 4, and 5. In the 28 days with GB222 alone, no DLT events were observed in all dose cohorts, and MTD was not reached. Among 16 patients, 14 (87.5%) received the combined treatment of GB222 and temozolomide after the DLT observation period. Two patients stopped the treatment after the DLT observation period due to disease progression. All patients (100%) reported experiencing at least one adverse event (AE) among patients who either received GB222 alone or the combination therapy of both GB222 and temozolomide. Four patients experienced grade 3/4 AE (one in Cohort 1, one in Cohort 2, and two in Cohort 3), including status epilepticus, herpes zoster, bone marrow failure, and hematological laboratory abnormalities. None of them was determined to be GB222 related. No death and treatment termination occurred due to AEs. Among these 16 patients, 81.3% (13/16) had treatment-related adverse events (TRAE). The common TRAE included decreased neutrophil count, decreased leukocyte count, increased alanine aminotransferase, hypertension, and rash. Pharmacokinetics (PK) studies showed drug exposure of GB222 had a linear relationship with the dose administrated. The overall objective response rate among 16 patients was 31.3% (95% CI: 11.02%, 58.66%) with 0% in Cohort 1, 66.7% in Cohort 2 (1 CR and 1 PR), 33.3% in Cohort 3 (1PR), 0% in Cohort 4, and 66.7% in Cohort 4 (2 PR). The median PFS was 4.44 months [95% confidence interval (CL) 2.76–6.60 months]. The median OS was 8.38 months (95% Cl: 4.24-not reached).
GB222 alone or combined with temozolomide had manageable safety profiles and encouraging anti-tumour activity in treating patients with recurrent HGG.
To investigate the mechanism underlying particulate matter (PM) exposure-induced oxidative stress and potential rescue strategies against pulmonary damage in this context.
A combination of omics technology and bioinformatic analysis were used to uncover mechanisms underlying cellular responses to PM exposure in human bronchial epithelia (HBE) cells and imply the potential rescue.
Our results implicated that oxidative stress, metal ion homeostasis, and apoptosis were the major cellular responses to PM exposure in HBE cells. PM exposure disrupted oxidative phosphorylation (OXPHOS)-related gene expressions in HBE cells. Rescuing the expression of these genes with supplemental coenzyme Q10 (Co Q10) inhibited reactive oxygen species (ROS) generation; however, it only partially protected HBEs against PM exposure-induced apoptosis. Further, metallothionein (MT)-encoding genes associated with metal ion homeostasis were significantly induced in HBE cells, which was transcriptionally regulated by specificity protein 1 (SP1). SP1 knock-down (KD) aggravated PM-induced apoptosis in HBE cells, suggesting it plays a role in MT induction. Subsequent studies corroborated the protective role of MT by showing that exogenous MTs supplement demonstrated effective protection against PM-induced oxidative stress and apoptosis in HBE cells. Importantly, exogenous MTs supplement was shown to reduce ROS generation and apoptosis in airway epithelia in both HBE cells and a PM-inhaled murine model.
This study demonstrates that the impact of MTs on airway epithelia by suppressing oxidative stress and maintaining metal ion homeostasis is beneficial in attenuating damage to pulmonary cells undergoing PM exposure.
Parkinson’s disease (PD) is the second most common neurodegenerative disease with mixed motor and non-motor symptoms. Dopaminergic drugs remain the mainstay of therapy for PD. However, some motor symptoms (e.g., gait problems) and a broad range of non-motor symptoms (e.g., cognitive impairment and depression) are often unresponsive to dopaminergic drugs. It is because the pathology of PD is not limited to the loss of midbrain dopamine neurons. Recent in vivo human brain imaging studies have provided novel insights into the dysfunction of multiple non-dopaminergic systems in PD. I review positron emission tomography, single photon emission computed tomography, neuromelanin-sensitive magnetic resonance imaging, and functional magnetic resonance imaging studies demonstrating the parallel alteration of noradrenergic, serotonergic, and cholinergic systems in PD. These studies shed light on the relationship between neuromodulators and vulnerable cognitive, affective, and motor functions. I finally discuss open questions in the field. More human pharmacological imaging studies are needed to reach a mechanistic understanding of the non-dopaminergic modulation of human brains.
Homeostasis is a process of dynamic balance regulated by organisms, through which they maintain an internal stability and adapt to the external environment for survival. In this paper, we propose the concept of utilizing homeostatic medicine (HM) as a strategy to explore health and disease. HM is a science that studies the maintenance of the body’s homeostasis. It is also a discipline that investigates the role of homeostasis in building health, studies the change of homeostasis in disease progression, and explores ways to restore homeostasis for the prevention, diagnosis and treatment of disease at all levels of biological organization. A new dimension in the medical system with a promising future HM focuses on how homeostasis functions in the regulation of health and disease and provides strategic directions in disease prevention and control. Nitric oxide (NO) plays an important role in the control of homeostasis in multiple systems. Nitrate is an important substance that regulates NO homeostasis through the nitrate-nitrite-NO pathway. Sialin interacts with nitrate and participates in the regulation of NO production and cell biological functions for body homeostasis. The interactions between nitrate and NO or sialin is an important mechanism by which homeostasis is regulated.
Glioma is the most common malignant brain tumor in children. Hox transcription antisense intergenic RNA (HOTAIR) has been shown to promote cancers. However, the role of genetic variation of HOTAIR gene on glioma susceptibility has not been fully elucidated. We aimed to evaluate whether HOTAIR gene single nucleotide polymorphisms (SNPs) are associated with susceptibility to glioma.
The trial included a total of 171 glioma patients and 228 non-glioma controls from Chinese children. Genotyping of HOTAIR gene was evaluated by TaqMan. The strength of the association between HOTAIR gene polymorphism (rs920778 A > G, rs4759314 A > G, rs1899663 C > A) and glioma susceptibility was assessed using odds ratios and 95% confidence intervals. Stratified analysis was further conducted.
Of the three SNPs analyzed, the rs920778 variant and the rs1899663 variant were associated with increased glioma susceptibility. In addition, the combination of two risk genotypes (OR = 1.63, P = 0.028) and one to three risk genotypes (OR = 1.58, P = 0.027) showed a significantly higher increase in glioma susceptibility than zero risk genotypes. These two SNPs (rs920778 A > G, rs1899663 C > A) were significantly associated with increased glioma susceptibility in certain subgroups in stratified analysis. Similar results were found in stratified analyses for one to three risk genotypes compared with zero risk genotypes. Splice quantitative trait loci (sQTLs) indicated rs920778 A > G and rs1899663 C > A are associated with splicing events in certain genes (HOTAIR, HOXC5, HOXC10, HOXC6, and HOXC4).
Overall, our results suggest that some HOTAIR SNPs are associated with increased glioma susceptibility.