The Anti-hypoxia Potentials of Trans-sodium Crocetinate in Hypoxiarelated Diseases: A Review.

Crocetin is a kind of apocarotenoid carboxylic acid extracted from saffron (Crocus sativus L.), which is effective in upregulating tissue oxygenation. However, crocetin is difficult to solubilize. It was shown that the trans isomer of crocetin is effective in improving oxygen diffusivity, while its cis isomer appears not to be. Hence, the isolated trans isomer of crocetin or trans-sodium crocetinate (TSC) can be used instead of crocetin. It is shown that TSC can upregulate hypoxic tissue oxygenation and be effective in treating some hypoxia-related diseases. Moreover, experimental and clinical studies have reported no adverse effects following TSC treatment, even at high doses. The current study will discuss the potential role of TSC in hemorrhagic shock, ischemia, brain tumor radiotherapy, and others.

Kinome Profiling Reveals Abnormal Activity of Kinases in Skeletal Muscle From Adults With Obesity and Insulin Resistance.

CONTEXT: Obesity-related insulin resistance (OIR) is one of the main contributors to type 2 diabetes and other metabolic diseases. Protein kinases are implicated in insulin signaling and glucose metabolism. Molecular mechanisms underlying OIR involving global kinase activities remain incompletely understood. OBJECTIVE: To investigate abnormal kinase activity associated with OIR in human skeletal muscle. DESIGN: Utilization of stable isotopic labeling-based quantitative proteomics combined with affinity-based active enzyme probes to profile in vivo kinase activity in skeletal muscle from lean control (Lean) and OIR participants. PARTICIPANTS: A total of 16 nondiabetic adults, 8 Lean and 8 with OIR, underwent hyperinsulinemic-euglycemic clamp with muscle biopsy. RESULTS: We identified the first active kinome, comprising 54 active protein kinases, in human skeletal muscle. The activities of 23 kinases were different in OIR muscle compared with Lean muscle (11 hyper- and 12 hypo-active), while their protein abundance was the same between the 2 groups. The activities of multiple kinases involved in adenosine monophosphate-activated protein kinase (AMPK) and p38 signaling were lower in OIR compared with Lean. On the contrary, multiple kinases in the c-Jun N-terminal kinase (JNK) signaling pathway exhibited higher activity in OIR vs Lean. The kinase-substrate-prediction based on experimental data further confirmed a potential downregulation of insulin signaling (eg, inhibited phosphorylation of insulin receptor substrate-1 and AKT1/2). CONCLUSIONS: These findings provide a global view of the kinome activity in OIR and Lean muscle, pinpoint novel specific impairment in kinase activities in signaling pathways important for skeletal muscle insulin resistance, and may provide potential drug targets (ie, abnormal kinase activities) to prevent and/or reverse skeletal muscle insulin resistance in humans.

Secondary Parkinsonism Due to a Large Anterior Cranial Fossa Meningioma.

Secondary Parkinson's disease or subacute Parkinson's may occur after stroke, drug overdose carbon monoxide or manganese toxicity, and rarely owing to a brain tumor. Loss of dopaminergic neurons in the substansia negra pars compacta (SNc), or presence of the proteinaceous inclusions called Lewy bodies are thought to be the cause of Parkinson's disease. Notwithstanding, in the past few decades, many case reports have been published describing Parkinson's symptoms following either stroke, ischemia, toxicity, brain haemorrhage or rarely neoplasm. LEARNING POINTS: Brain tumours can cause secondary parkinsonism.This type of secondary parkinsonism improves when the tumour is removed.

Atypical Presentation of Glioblastoma Multiforme.

BACKGROUND: Glioblastoma multiforme (GBM) is a highly malignant glial tumour classified by the World Health Organization (WHO) as a stage IV astrocytoma. It varies in shape and size and can be cystic, vascular and necrotic. It often appears as a ring-enhancing lesion on magnetic resonance imaging (MRI). The most common symptoms of GBM, such as headache, vomiting and seizures, are due to increased intracranial pressure. The objective of this case report is to describe an atypical presentation of GBM. CASE REPORT: A 53-year-old woman of Italian origin presented with a 2-week history of lack of coordination in her hands and some difficulty in speech. Electromyography for assessment of her arms and cranial bulbar function was normal. However, 2 days later, the patient presented to the emergency department with progressive weakness in her left arm and leg as well as difficulty in speech. Mild left facial asymmetry was noted. A brain MRI revealed a right frontal mass. Stereotactic surgical resection was performed 2 days later, and biopsy confirmed the diagnosis of GBM. Although headache and other features of raised intracranial pressure are the most common initial symptoms of GBM, any atypical neurological or psychiatric presentation in an adult patient should raise suspicion for this tumour. CONCLUSION: Careful analysis of an adult with atypical signs and symptoms along with thorough review of radiological tests will facilitate early diagnosis of dangerous tumours such as GBM. LEARNING POINT: An adult patient with symptoms that do not conform to a neurological condition should be investigated for a brain tumour.Careful history taking and examination are essential for reaching the correct diagnosis as soon as possible.Meticulous review of radiological images in order to detect subtle changes in brain anatomy is essential.

Plasma Lactate Levels Increase during Hyperinsulinemic Euglycemic Clamp and Oral Glucose Tolerance Test.

Insulin resistance, which plays a central role in the pathogenesis of type 2 diabetes (T2D), is an early indicator that heralds the occurrence of T2D. It is imperative to understand the metabolic changes that occur at the cellular level in the early stages of insulin resistance. The objective of this study was to determine the pattern of circulating lactate levels during oral glucose tolerance test (OGTT) and hyperinsulinemic euglycemic clamp (HIEC) study in normal nondiabetic subjects. Lactate and glycerol were determined every 30 minutes during OGTT and HIEC on 22 participants. Lactate progressively increased throughout the HIEC study period (P < 0.001). Participants with BMI < 30 had significantly higher mean M-values compared to those with BMI ≥ 30 at baseline (P < 0.05). This trend also continued throughout the OGTT. In addition, those with impaired glucose tolerance test (IGT) had significantly higher mean lactate levels compared to those with normal glucose tolerance (P < 0.001). In conclusion, we found that lactate increased during HIEC study, which is a state of hyperinsulinemia similar to the metabolic milieu seen during the early stages in the development of T2D.

Increased interaction with insulin receptor substrate 1, a novel abnormality in insulin resistance and type 2 diabetes.

Insulin receptor substrate 1 (IRS1) is a key mediator of insulin signal transduction. Perturbations involving IRS1 complexes may lead to the development of insulin resistance and type 2 diabetes (T2D). Surprisingly little is known about the proteins that interact with IRS1 in humans under health and disease conditions. We used a proteomic approach to assess IRS1 interaction partners in skeletal muscle from lean healthy control subjects (LCs), obese insulin-resistant nondiabetic control subjects (OCs), and participants with T2D before and after insulin infusion. We identified 113 novel endogenous IRS1 interaction partners, which represents the largest IRS1 interactome in humans and provides new targets for studies of IRS1 complexes in various diseases. Furthermore, we generated the first global picture of IRS1 interaction partners in LCs, and how they differ in OCs and T2D patients. Interestingly, dozens of proteins in OCs and/or T2D patients exhibited increased associations with IRS1 compared with LCs under the basal and/or insulin-stimulated conditions, revealing multiple new dysfunctional IRS1 pathways in OCs and T2D patients. This novel abnormality, increased interaction of multiple proteins with IRS1 in obesity and T2D in humans, provides new insights into the molecular mechanism of insulin resistance and identifies new targets for T2D drug development.