Potential Active Marine Peptides as Anti-Aging Drugs or Drug Candidates.

Aging is an irreversible physiological process in the human body, and the aging characteristics of the body that accompany this process also lead to many other chronic diseases, such as neurodegenerative diseases represented by Alzheimer's disease and Parkinson's disease, cardiovascular diseases, hypertension, obesity, cancer, and so on. The marine environment is highly biodiverse, the natural active products of these organisms constitute a vast treasure trove of marine drugs or drug candidates that play an essential role in disease prevention and treatment, and the active peptide products among them have received special attention because of their unique chemical properties. Therefore, the development of marine peptide compounds as anti-aging drugs is emerging as an important research area. This review highlights the currently available data on marine bioactive peptides with anti-aging potential from 2000 to 2022 by analyzing the prevalent aging mechanisms, critical aging metabolic pathways and well-established multi-omics aging characteristics, as well as grouping different bioactive and biological species lines of peptides from marine organisms and discussing their research modalities and functional characteristics. Active marine peptides is a promising topic to explore and to develop their potential as anti-aging drugs or drug candidates. We expect this review to be instructive for future marine drug development and to reveal new directions for future biopharmaceuticals.

Predictors of delayed reocclusion after successful recanalization in acute basilar artery occlusion patients.

Background: Delayed reocclusion (DR) after successful recanalization in acute basilar artery occlusion (BAO) patients, which is associated with clinical deterioration and poor outcome, has not been well studied. The current study is aimed to predict DR after successful endovascular therapy in acute BAO patients. Method: 187 consecutive patients presenting with acute BAO and undergoing endovascular treatment (EVT) were selected in Beijing Tiantan Hospital from January 2012 to July 2018. Computed tomographic angiography (CTA) or magnetic resonance angiography (MRA) within 7 days of the thrombectomy was used to identify reocclusion of the target vessel. Multivariable logistic regression analysis was used to evaluate associated factors and clinical impact. Results: DR was observed in 17 of 169 successfully reperfused patients (10.1%). Patients with DR had higher frequency of intracranial atherosclerotic stenosis (ICAS) (94.1% vs. 61.8%; P = 0.01), higher frequency of intracranial angioplasty during EVT (88.2% vs. 57.2%; P = 0.02), lower frequency of stent-retriever use during EVT (52.9% vs. 78.9%; P = 0.03) and a lower proportion of modified Thrombolysis In Cerebral Infarction (mTICI) 3 reperfusion (41.2% vs. 78.3%; P < 0.01). Suggestive predictors were mTICI3 reperfusion (aOR, 0.205; 95% CI, 0.061-0.686) and stent-retriever using (aOR, 0.29; 95% CI, 0.086-0.980). DR was an independent predictor of unfavorable outcome at 90 days (aOR for mTICI ≤3, 5.205; 95% CI, 1.129-24.005). Conclusions: DR within 7 days after successful mechanical thrombectomy in acute BAO patients is rare but associated with poor outcome. Patients without mTICI3 reperfusion and stent-retriever using are at high risk for DR.

Two patients with congenital myasthenic syndrome caused by COLQ gene mutations and the consequent ColQ protein defect.

Objective: To report two cases of congenital myasthenic syndromes (CMS) in a Chinese family with mutations in the COLQ gene and to prove the consequence defect of the ColQ protein. Method: Clinical characteristics of the two children from the same family were described. Next-generation sequencing (NGS) and sanger sequencing was performed on the proband and family members. The consequence of the mutation was predicted by 3D protein structure prediction using I-TASSER. The wild type and mutant were transfected to 293T cells, and ColQ protein was detected by Western Blot. Results: The diagnosis of CMS was based on a symptom combination of fatigable muscle weakness, ptosis, scoliosis, and hypotonia, aggravation of muscle weakness after the neostigmine test, and a 46% decrement in repetitive nerve stimulation. A muscle biopsy was performed on the proband, revealing mild variation in the myofiber size. NGS data revealed two compound heterozygous mutations at c.173delC (p.Pro58Hisfs*22) and c.C706T (p.R236X) in the COLQ gene, where the former was a novel mutation. A 3D structure prediction showed two truncated ColQ proteins with 78aa and 235aa, respectively. The truncated ColQ protein was proved in 293T cells transfected with c.173delC or c.C706T mutants by Western Blot. Conclusions: The mutations of c.173delC and c.C706T in the COLQ gene led to truncated ColQ protein and contributed to the pathogenesis of CMS in this Chinese family.

Effects of Butylphthalide Sodium Chloride Injection Combined with Edaravone Dexborneol on Neurological Function and Serum Inflammatory Factor Levels in Sufferers Having Acute Ischemic Stroke.

For investigating an influence on butylphthalide sodium chloride injection combined with edaravone dexborneol on neurological function and serum inflammatory factor levels in sufferers having acute ischemic stroke, 120 sufferers having acute ischemic stroke from September 2020 to September 2021 are chosen for the study subjects. In line with the diverse therapies, they took part in a control group and the study group, with 60 examples in each group. The control group is treated with edaravone dexborneol, and the study group is treated with butylphthalide sodium chloride injection, based on the control group. The posttreatment curative efficacy on the two groups is recorded, and treatment of both the two groups is compared. Before and after neurological function indexes (NIHSS and mRS), inflammatory factor indexes (IL-6, CRP, and TNF-α), life quality index (Barthel index), hemorheological indexes (plasma-specific viscosity), and neurological levels of NSE are logged and contrasted between the two groups of adverse reactions during therapy. Postcure, the overall response rate and Barthel index of the study group obviously overtop those of the control group (p < 0.05). IL-6, CRP, TNF-α, NSE, plasma specific viscosity, and NIHSS and mRS scores obviously hypodown those of the control group (p < 0.05), and untoward effects on the two groups during curing are lower, and the discrepancy is not obvious(p > 0.05). Butylphthalide sodium chloride injection combined with edaravone dexborneol can enhance curative efficacy on sufferers having acute ischemic stroke, improve neurological function, blood rheology, and quality of life, and decrease the secretion of cytokine, having a better effect and high medication safety.

In silico, synthesis and anticancer evaluation of benzamide tryptamine derivatives as novel eEF2K inhibitors.

Eukaryotic elongation factor 2 kinase (eEF2K), a member of the atypical α-kinase family, is highly expressed in a variety of tumor tissues. Inhibition of eEF2K function can effectively kill cancer cells without affecting the function of normal cells. Therefore, eEF2K is a promising new target for cancer therapy. In this study, a series of benzamide tryptamine derivatives were designed and synthesized as novel eEF2K inhibitors. The druggability properties of the synthesized compounds were predicted in silico and performed well. The MTT assay indicated that most of these compounds displayed good antiproliferative activity against human leukemia CCRF-CEM and K562 cell lines. The structure-activity relationship (SAR) revealed that substituents with different electronic effects on the C5 position of indole ring or C2', C4' positions of benzene ring have a great influence on the anti-proliferative activity. Among them, 5j demonstrated the highest anti-proliferative activity with IC50 value of 1.63-3.54 µM. this compound displayed an effective eEF2K inhibition by down-regulated the level of phosphorylated eEF2 in CCRF-CEM cells. Additionally, the western blot analysis further revealed that 5j also significantly affected eEF2K-related signaling pathways. Anticancer mechanism studies have shown that 5j arrested the cell cycle in G0/G1 and induced CCRF-CEM cells apoptosis. Furthermore, 5j activated cleaved caspase-9, 8, 3 and cleaved PARP in a time-dependent manner, which suggesting that 5j induced cancer cells apoptosis through both intrinsic and extrinsic pathways. In summary, benzamide tryptamine derivative 5j represents a novel and promising lead structure for the development of eEF2K inhibitors in cancer therapy.

8a, a New Acridine Antiproliferative and Pro-Apoptotic Agent Targeting HDAC1/DNMT1.

Epigenetic therapy using histone deacetylase (HDAC) inhibitors has become an attractive project in new drug development. However, DNA methylation and histone acetylation are important epigenetic ways to regulate the occurrence and development of leukemia. Given previous studies, N-(2-aminophenyl)benzamide acridine (8a), as a histone deacetylase 1 (HDAC1) inhibitor, induces apoptosis and shows significant anti-proliferative activity against histiocytic lymphoma U937 cells. HDAC1 plays a role in the nucleus, which we confirmed by finding that 8a entered the nucleus. Subsequently, we verified that 8a mainly passes through the endogenous (mitochondrial) pathway to induce cell apoptosis. From the protein interaction data, we found that 8a also affected the expression of DNA methyltransferase 1 (DNMT1). Therefore, an experiment was performed to assess the binding of 8a to DNMT1 at the molecular and cellular levels. We found that the binding strength of 8a to DNMT1 enhanced in a dose-dependent manner. Additionally, 8a inhibits the expression of DNMT1 mRNA and its protein. These findings suggested that the anti-proliferative and pro-apoptotic activities of 8a against leukemia cells were achieved by targeting HDAC1 and DNMT1.

Recent Advances in Small Peptides of Marine Origin in Cancer Therapy.

Cancer is one of the leading causes of death in the world, and antineoplastic drug research continues to be a major field in medicine development. The marine milieu has thousands of biological species that are a valuable source of novel functional proteins and peptides, which have been used in the treatment of many diseases, including cancer. In contrast with proteins and polypeptides, small peptides (with a molecular weight of less than 1000 Da) have overwhelming advantages, such as preferential and fast absorption, which can decrease the burden on human gastrointestinal function. Besides, these peptides are only connected by a few peptide bonds, and their small molecular weight makes it easy to modify and synthesize them. Specifically, small peptides can deliver nutrients and drugs to cells and tissues in the body. These characteristics make them stand out in relation to targeted drug therapy. Nowadays, the anticancer mechanisms of the small marine peptides are still largely not well understood; however, several marine peptides have been applied in preclinical treatment. This paper highlights the anticancer linear and cyclic small peptides in marine resources and presents a review of peptides and the derivatives and their mechanisms.

Progress in the Development of Eukaryotic Elongation Factor 2 Kinase (eEF2K) Natural Product and Synthetic Small Molecule Inhibitors for Cancer Chemotherapy.

Eukaryotic elongation factor 2 kinase (eEF2K or Ca2+/calmodulin-dependent protein kinase, CAMKIII) is a new member of an atypical α-kinase family different from conventional protein kinases that is now considered as a potential target for the treatment of cancer. This protein regulates the phosphorylation of eukaryotic elongation factor 2 (eEF2) to restrain activity and inhibit the elongation stage of protein synthesis. Mounting evidence shows that eEF2K regulates the cell cycle, autophagy, apoptosis, angiogenesis, invasion, and metastasis in several types of cancers. The expression of eEF2K promotes survival of cancer cells, and the level of this protein is increased in many cancer cells to adapt them to the microenvironment conditions including hypoxia, nutrient depletion, and acidosis. The physiological function of eEF2K and its role in the development and progression of cancer are here reviewed in detail. In addition, a summary of progress for in vitro eEF2K inhibitors from anti-cancer drug discovery research in recent years, along with their structure-activity relationships (SARs) and synthetic routes or natural sources, is also described. Special attention is given to those inhibitors that have been already validated in vivo, with the overall aim to provide reference context for the further development of new first-in-class anti-cancer drugs that target eEF2K.

Research Progresses of Targeted Therapy and Immunotherapy for Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors worldwide, with nearly one million new cases and deaths every year. Owing to the complex pathogenesis, hidden early symptoms, rapidly developing processes, and poor prognosis, the morbidity and mortality of HCC are increasing yearly. With the progress being made in modern medicine, the treatment of HCC is no longer limited to traditional methods. Targeted therapy and immunotherapy have emerged to treat advanced and metastatic HCC in recent years. Since Sorafenib is the first molecular targeting drug against angiogenesis, targeted drugs for HCC are continually emerging. Moreover, immunotherapy plays a vital role in clinical trials. In particular, the application of immune checkpoint inhibitors, which have received increasing attention in the field of cancer treatment, is a possible research path. Interestingly, these two therapies generally complement each other at some stages of HCC, bringing new hope for patients with advanced HCC. In this paper, we discuss the research progress of targeted therapy and immunotherapy for HCC in recent years, which will provide a reference for the further development of drugs for HCC.

Blood Pressure Variability during Angiography in Patients with Ischemic Stroke and Intracranial Artery Stenosis.

Our aim was to investigate factors predicting blood pressure (BP) variability during diagnostic cerebral angiography and associations between BP variability and clinical outcomes in patients with acute and subacute ischemic stroke and intracranial artery stenosis. 114 patients with ischemic stroke and intracranial artery stenosis (stenosis rate >50%) were recruited. Patients who underwent cerebral angiography within 3 days and 3-14 days of disease onset are referred to be Group A and Group S, respectively. BP variability in Group A was defined as the coefficient of variance (CV) of BP. Univariate and multivariate regression analyses were used to identify predictors of CV of BP and associations between CV of BP and clinical outcomes at discharge. In Group A patients, advanced age was associated with increased CV of SBP and diastolic blood pressure (DBP), and antihypertensive use was associated with lower CV of SBP. Male was associated with lower CV of DBP. In Group S, higher CV of SBP was associated with hypertension and antihypertensive use. Males had lower CV of SBP than females. The calcium channel blocker was associated with lower CV of DBP. Higher scores of the Stroke Scale at admission were significantly associated with poor clinical outcomes for both groups, while BP variability was not. Factors associated with BP variability are significantly different between stroke patients undergoing angiography within 3 days vs. 3-14 days after disease onset. BP variability is not significantly associated with clinical outcomes at discharge.

The Posterior Insula Shows Disrupted Brain Functional Connectivity in Female Migraineurs Without Aura Based on Brainnetome Atlas.

Long-term headache attacks may cause human brain network reorganization in patients with migraine. In the current study, we calculated the topologic properties of functional networks based on the Brainnetome atlas using graph theory analysis in 29 female migraineurs without aura (MWoA) and in 29 female age-matched healthy controls. Compared with controls, female MWoA exhibited that the network properties altered, and the nodal centralities decreased/increased in some brain areas. In particular, the right posterior insula and the left medial superior occipital gyrus of patients exhibited significantly decreased nodal centrality compared with healthy controls. Furthermore, female MWoA exhibited a disrupted functional network, and notably, the two sub-regions of the right posterior insula exhibited decreased functional connectivity with many other brain regions. The topological metrics of functional networks in female MWoA included alterations in the nodal centrality of brain regions and disrupted connections between pair regions primarily involved in the discrimination of sensory features of pain, pain modulation or processing and sensory integration processing. In addition, the posterior insula decreased the nodal centrality, and exhibited disrupted connectivity with many other brain areas in female migraineurs, which suggests that the posterior insula plays an important role in female migraine pathology.

Assessment of gray and white matter structural alterations in migraineurs without aura.

BACKGROUND: Migraine constitute a disorder characterized by recurrent headaches, and have a high prevalence, a high socio-economic burden and severe effects on quality of life. Our previous fMRI study demonstrated that some brain regions are functional alterations in migraineurs. As the function of the human brain is related to its structure, we further investigated white and gray matter structural alterations in migraineurs. METHODS: In current study, we used surface-based morphometry, voxel-based morphometry and diffusion tensor imaging analyses to detect structural alterations of the white matter and gray matter in 32 migraineurs without aura compared with 32 age- and gender-matched healthy controls. RESULTS: We found that migraineurs without aura exhibited significantly increased gray matter volume in the bilateral cerebellar culmen, increased cortical thickness in the lateral occipital-temporal cortex, decreased cortical thickness in the right insula, increased gyrification index in left postcentral gyrus, superior parietal lobule and right lateral occipital cortex, and decreased gyrification index in the left rostral middle frontal gyrus compared with controls. No significant change in white matter microstructure was found in DTI analyses. CONCLUSION: The significantly altered gray matter brain regions were known to be associated with sensory discrimination of pain, multi-sensory integration and nociceptive information processing and were consistent with our previous fMRI study, and may be involved in the pathological mechanism of migraine without aura.

The sensorimotor network dysfunction in migraineurs without aura: a resting-state fMRI study.

Migraine is a common recurrent neurological disorder combining nausea, vomiting, and hypersensitivities to visual, auditory, olfactory and somatosensory stimuli. However, the dysfunction of the sensorimotor network in migraineurs has not been well clarified. In the present study, we evaluated the dysfunction of the sensorimotor network in 30 migraineurs without aura and in 31 controls by combining regional homogeneity (ReHo), amplitudes of low-frequency fluctuation (ALFF) and degree centrality (DC) analysis methods based on resting-state fMRI. A seed-based functional connectivity (FC) analysis was used to investigate whether the dysfunctional areas within the sensorimotor network exhibited abnormal FC with other brain areas. Compared to the controls, the migraineurs without aura exhibited significantly smaller ReHo, ALFF and DC values in the primary somatosensory cortex (S1) and right premotor cortex (PMC). The migraineurs showed weaker FC between the S1 and brain areas within the pain intensity and spatial discrimination pathways and trigemino-thalamo-cortical nociceptive pathway. We proposed that the dysfunction of the S1 and PMC and the decreased FC between the S1 and brain areas in migraineurs without aura may disrupt the discrimination of sensory features of pain and affect nociception pathways, and would be involved in the dysfunctional mechanism in migraine.

Visual cortex and cerebellum hyperactivation during negative emotion picture stimuli in migraine patients.

Migraines are a common and undertreated disease and often have psychiatric comorbidities; however, the abnormal mechanism of emotional processing in migraine patients has not been well clarified. This study sought to investigate the different brain functional activation to neutral, positive and negative emotional stimuli between migraine and healthy subjects. Twenty-six adults with migraines and 26 healthy adults, group-matched for sex and age, participated in this experiment. Although there were no significant differences between two groups during the viewing of positive affective pictures vs. neutral affective pictures, there were different activation patterns during the viewing of negative to neutral affective pictures in the two groups; the control group showed both increased and decreased activation patterns, while the migraine subjects showed only increased activation. Negative affective pictures elicited stronger activation than neutral affective pictures in migraineurs, which included the bilateral cerebellum anterior lobe/culmen, the bilateral lingual gyri, the bilateral precuneus and the left cuneus. Our data indicated that migraine patients were hypersensitive to negative stimuli, which might provide clues to aid in the understanding of the pathophysiology and psychiatric comorbidities of migraines.

Increased default mode network connectivity and increased regional homogeneity in migraineurs without aura.

BACKGROUND: The precuneus/posterior cingulate cortex, which has been associated with pain sensitivity, plays a pivotal role in the default mode network. However, information regarding migraine-related alterations in resting-state brain functional connectivity in the default mode network and in local regional spontaneous neuronal activity is not adequate. METHODS: This study used functional magnetic resonance imaging to acquire resting-state scans in 22 migraineurs without aura and in 22 healthy matched controls. Independent component analysis, a data-driven method, was used to calculate the resting-state functional connectivity of the default mode network in the patient and healthy control groups. Regional homogeneity (ReHo) was used to analyse the local features of spontaneous resting-state brain activity in the migraineurs without aura. RESULTS: Compared with the healthy controls, migraineurs without aura showed increased functional connectivity in the left precuneus/posterior cingulate cortex within the default mode network and significant increase in ReHo values in the bilateral precuneus/posterior cingulate cortex, left pons and trigeminal nerve entry zone. In addition, functional connectivity was decreased between the areas with abnormal ReHo (using the peaks in the precuneus/posterior cingulate cortex) and other brain areas. CONCLUSIONS: The abnormalities in the precuneus/posterior cingulate cortex suggest that migraineurs without aura may exhibit information transfer and multimodal integration dysfunction and that pain sensitivity and pian processing may also be affected.

Predictive role of CHADS2 and CHA2DS2-VASc scores on stroke and thromboembolism in patients without atrial fibrillation: a meta-analysis.

OBJECTIVE: CHA2DS2-VASc is the extension of the CHADS2 score developed by Birmingham 2009. This risk stratification schema is often used in clinical setting when considering additional risk factors for developing stroke in AF patients. However, its role in the non-AF population is unknown. This study was designed to evaluate the accuracy of the CHADS2 and the CHA2DS2-VASc scoring systems. METHODS: Studies designed for CHADS2 and CHA2DS2-VASc score in stratifying the risks for stroke development in non-AF patients were included. RESULTS: Among the 114 studies identified, six trials were chosen finally and included for meta-analysis. The pooled diagnostic odds ratio (DOR) for CHADS2 and CHA2DS2-VASc was 2.86 (95% CI =1.83-4.28) and 2.80 (95% CI =1.83-4.28), respectively. CHA2DS2-VASc score was of better sensitivity than CHADS2 score (0.920 vs. 0.768). However, both scores were showed to have inherent heterogeneity and poor specificity. CONCLUSIONS: Though having good diagnostic accuracy, the clinical application of the CHADS2 and CHA2DS2-VASc scores in predicting risk of stroke development in non-AF patients still needs further validation. Key message The overall diagnostic accuracy of CHADS2 and CHA2DS2-VASc in stroke-risk stratification was good in patients with non-atrial fibrillation.

Pulse pressure as an independent predictor of stroke: a systematic review and a meta-analysis.

BACKGROUND: Recent evidence suggests that pulse pressure (PP) is a strong cardiovascular diseases' risk factor. We systematically evaluated all relevant studies to determine whether PP can be used as an independent predictor of stroke and mortality. METHODS AND RESULTS: A meta-analysis was performed by searching the published literature using MEDLINE, Cochrane and Google Scholar databases up to December 15, 2015. We measured the effect size expressed by hazard ratio (HR) and 95 % confidence interval (95 % CI). Eleven publications were included in the analysis. Pooled results demonstrated that 10 mmHg increase in PP was associated with increased risk of stroke occurrence (pooled HR 1.046, 95 % CI 1.025-1.068, P < 0.001). Additionally, systolic blood pressure (SBP) (pooled HR 1.053, 95 % CI 1.033-1.073, P < 0.001) and diastolic blood pressure (DPB) (pooled HR 1.056, 95 % CI 1.038-1.074, P < 0.001) were found to be significant predictors for stroke. We did not find a significant association between PP and all-cause mortality (pooled HR 1.022, 95 % CI 0.983-1.063, P = 0.270). We found SBP (pooled HR 1.008, 95 % CI 1.002-1.014, P = 0.012), but not DBP (pooled HR 1.023, 95 % CI 0.964-1.085, P = 0.451) to be significantly associated with all-cause mortality. CONCLUSIONS: Current data confirms that PP is an independent risk factor for stroke but is not a predictor of mortality.

Blood Pressure Reduction in the Acute Phase of an Ischemic Stroke Does Not Improve Short- or Long-Term Dependency or Mortality: A Meta-Analysis of Current Literature.

The purpose of this study was to perform a meta-analysis of current literature to determine whether lowering blood pressure (BP) during the acute phase of an ischemic stroke improves short- and long-term outcomes. PubMed, Cochrane, and Embase were searched until September 5, 2014 using combinations of the search terms: blood pressure reduction, reduced blood pressure, lowering blood pressure, ischemic stroke, acute stroke, and intra-cerebral hemorrhage. Inclusion criteria were randomized controlled trial and patients with acute stroke (ischemic or hemorrhagic) treated with an antihypertensive agent or placebo. Outcome measures were change in systolic and diastolic BP (SBP, DBP) after treatment, and short- and long-term dependency and mortality rates. A total of 459 studies were identified, and ultimately 22 studies were included in the meta-analysis. The total number of participants in the treatment groups was 5672 (range, 6-2308), and in the control groups was 5416 (range, 6-2033). In most studies, more than 50% of the participants were males and the mean age was more than 60 years. The mean follow-up time ranged from 5 days to 12 months. As expected, treatment groups had a greater decrease in BP than control groups, and this effect was seen with different classes of antihypertensive drugs. Short-term and long-term dependency rates were similar between treatment and control groups (short-term dependency: pooled odds ratio [OR] = 1.041, 95% confidence interval [CI]: 0.936-1.159, P = 0.457; long-term dependency: pooled OR = 1.013, 95% CI: 0.915-1.120, P = 0.806). Short-term or long-term mortality was similar between the treatment and control groups (short-term mortality: pooled OR = 1.020, 95% CI: 0.749-1.388, P = .902; long-term mortality: pooled OR = 1.039, 95% CI: 0.883-1.222, P = 0.644). Antihypertensive agents effectively reduce BP during the acute phase of an ischemic stroke, but provide no benefit with respect to short- and long-term dependency and mortality.