Nitro-fatty acids (NO2-FAs) are a class of bioactive lipids that mediate metabolic, anti-oxidative stress, anti-inflammatory, and other signaling actions. Endogenously, NO2-FAs are derived from the non-enzymatic reactions of unsaturated fatty acids with reactive nitrogen species. The electrophilic properties of the nitro group results in NO2-FAs being able to undergo rapid and reversible reactions with biological nucleophiles, such as cysteine and histidine, thus supporting post-translational modifications of proteins. The reactions of NO2-FAs with biological nucleophiles regulate a range of key signaling pathways involved in gene expression responses, enzyme activity, and cellular processes. In disease animal models, NO2-FAs are produced under conditions of inflammation and oxidative stress and play a protective role in a variety of metabolic diseases, which have been associated with anti-atherosclerosis, blood-pressure lowering, and are involved in the regulation of glycolipid metabolism and insulin resistance. Based on these, more clinical studies might find a correlation between NO2-FAs levels and pathophysiology in patients with metabolic diseases. Importantly, NO2-FAs therapeutics are effective in clinical trials. In addition, dietary supplementation with nitrates and unsaturated fatty acids can endogenously increase NO2-FAs levels in mice and humans. These findings support dietary approaches that increase the endogenous levels of NO2-FAs might potentially reduce the risk of metabolic diseases. To identify the specific mechanism of action and therapeutic potential of NO2-FAs, we have summarized the main mechanisms of action of NO2-FAs in metabolic disease progression to provide insights for the development of new therapeutics for metabolic diseases.
Glioblastoma (GBM) is a malignant brain glioma characterized by a high number of tumor-associated macrophages (TAMs) within its tissues. These TAMs have a close relationship with tumor grade and prognosis. Targeting TAMs has been identified as a promising therapeutic strategy. However, TAM cells play both tumor-killing and tumor-promoting roles, making them a double-edged sword in the immune environment. The different subtypes of macrophages and their effects on the tumor microenvironment remain poorly understood. This study comprehensively elucidates the immunobiology of glioma-associated macrophages (GAMs), including their origin, classification, molecular mechanisms underlying glioma promotion and inhibition, polarization strategies, targeted therapy for GAMs and the current challenges and perspectives in immune modulation. Further research on macrophage function and mechanism may provide a new immunological basis for treating GBM patients and enhancing the efficacy of glioma immunotherapy.
Mitochondria serve as the primary site for metabolizing the three major nutrients, underscoring their pivotal role in cellular energy metabolism and the regulation of signaling pathways. Mitochondrial homeostatic imbalance is a key pathological cause of the development of many diseases. Hence, preserving mitochondrial homeostasis is vital for the normal growth and development of cells and organisms. Living organisms have evolved intricate regulatory mechanisms to ensure cellular mitochondrial homeostasis. This review focuses on recent advancements in comprehending the mechanisms responsible for maintaining mitochondrial homeostasis and addresses the current challenges in this field. We also provide an overview of the key functions of mitochondria in both physiological and pathological conditions. Emphasizing the potential therapeutic implications, we discuss strategies for preserving mitochondrial homeostasis, recognizing its significance in mitigating various health conditions.
Parkinson's disease (PD) is a neurodegenerative disorder that is caused by degeneration of nerve cells in the part of the brain called the substantia nigra, which controls movement. Although there is some considerable evidence with conventional drugs for PD, treating patients becomes increasingly difficult due to their short- and long-term adverse effects and other restrictions. This dire circumstance emphasizes the need for an innovative, strong alternative treatment for PD. Plants and natural products are considered one of the most important sources of bioactive molecules against a wide range of health disorders. With mechanistic insights, this systematic review explains the efficacy of clinically proven natural products in managing PD. This review is based on comprehensive literature searches from PubMed, Science Direct, Scopus, and Google Scholar databases using the keywords- “plants or natural products in Parkinson's”, “plants or herbs used in Parkinson's treatment”, or keywords that are similar to those. Natural products that have been clinically proven for their anti-Parkinson effect have only been selected for this study, and the products are- Mucuna pruriens, Caffeine, Camellia sinensis or green tea leaves, and a traditional Chinese herbal called Jiawei-Liujunzi Tang. In comparison to currently available medications, we firmly feel that the mentioned clinically proven natural products would be more effective at treating PD while having fewer adverse effects. However, further study is required to confirm their exact mechanism of action.
Retrospectively analyse the 99mTc-MDP SPECT whole-body bone scan in POEMS syndrome to explore its clinical value.
Twenty-four untreated patients with pathologically confirmed POEMS syndrome were included in the study. 24 of them underwent 99mTc-MDP SPECT whole-body bone scan, 24 underwent CT examination and 18 patients underwent X-ray examination in different parts. Features of bone lesions in 99mTc-MDP SPECT, and X-ray, CT were analysed. Three experienced radiologists read the images and gave diagnosed results for bone lesions.
Of the 24 POEMS syndrome patients, three types of bone lesions were found: osteosclerotic lesions, osteolytic lesions and mixed lesions, of which the most common type was osteosclerotic. 54.16% (13/24) patients were found bone lesions by SPECT; 44.44% (8/18) patients underwent X-ray and 62.50% (15/24) patients underwent CT were detected bone lesions. We compared the difference of the X-ray, CT and SPECT scans of the bone lesions by chi-square and found that there was no difference (P = 0.51) in detection of bone lesions among the three methods.
99mTc-MDP SPECT wholebody bone scan also useful in evaluating patients with suspected POEMS syndrome. We can use it as a supplement examination of the CT in the confirmation of one minor diagnostic criterion for POEMS syndrome: bone lesions.
Alzheimer's disease (AD) is the leading cause of dementia, characterized by neuropathological features such as amyloid-β (Aβ) plaques, neurofibrillary tau tangles, and neurodegeneration. Immunotherapy offers a promising potentially disease-modifying treatment for AD. We review recent advances in AD immunotherapy, specifically focusing on Aβ, tau, and neuroinflammation-targeted approaches, and gain insights from randomized controlled trials to propose disease-modifying directions.
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 MT supplement demonstrated effective protection against PM-induced oxidative stress and apoptosis in HBE cells. Importantly, exogenous MT 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 MT on airway epithelia by suppressing oxidative stress and maintaining metal ion homeostasis is beneficial in attenuating damage to pulmonary cells undergoing PM exposure.
Suicidality is a common and serious symptom of depression and patients with depression and suicidality often respond to electroconvulsive therapy (ECT), but the mechanism of its effect is poorly understood. We used resting-state functional magnetic resonance imaging (rs-fMRI) to explore changes in brain connectivity before and after ECT in depressed patients with suicidality.
Twenty-three depressed patients with suicidality underwent rs-fMRI at baseline and after 8–12 ECT sessions. Thirty-two age-, sex-, and education-matched healthy controls (HCs) underwent rs-fMRI once. We used functional connectivity (FC) analysis to identify brain regions with altered connectivity in patients compared to HCs and assess changes in FC before and after ECT. We also assessed the clinical symptoms using the Hamilton Depression Scale, 17-item (HAMD-17), and Beck Scale for Suicide Ideation (BSSI).
Compared to HCs, at baseline, patients had reduced FC between the left orbitofrontal cortex (OFC_ Ant_L) and left angular gyrus (Angular_L) (t = 3.849, P < 0.05) with OFC_Ant_L as ROI. With left superior frontal gyrus (Frontal_sup_L) as ROI, patients also had reduced FC between Frontal_sup_L and left superior medial frontal gyrus, medial orbital (Frontal_Med_Orb_L) and left precuneus (Precuneus_L) (t = 3.650, P < 0.05), and increased FC between Frontal_sup_L and right middle frontal gyrus (Frontal_Mid_R) (t = -4.220, P < 0.05). After ECT, with Frontal_sup_L as ROI, patients showed increased FC between Frontal_sup_L and Angular_L after ECT (t = -3.982, P < 0.05) and decreased FC between Frontal_sup_L and right superior and inferior parietal gyrus (Parietal_Sup&Inf_R). In ECT responders, the change in FC between Frontal_sup_L and Angular_L was negatively correlated with the change of the score of BSSI (r = -0.645, P = 0.042), and the change in FC between Frontal_sup_L and Parietal_Sup&Inf_R was positively correlated with the change of the score of BSSI (r = 0.714, P = 0.023). There was no correlation between changes in FC with changes in HAMD-17 score (all P > 0.05).
Our findings suggest that FC between Frontal_sup_L and Angular_L, and FC between Frontal_sup_L and Parietal_Sup&Inf_R may be involved in the mechanisms by which ECT exerts its effects on suicidality in patients with depression. Our findings provide insights into the neural underpinnings of ECT and may inform the development of more targeted novel therapeutic strategies for suicidality.
Chinese Clinical Trial Registry, ChiCTR2100048182, Registered 04 July 2021, www.chictr.org.cn
To review the criteria for the selection of estrogens and especially progestogens for optimizing Menopausal Hormone Therapy (MHT). The main criteria are primarily derived from the Women's Health Initiative (WHI)-trial, disclosing the main risks like endometrial cancer, coronary heart disease (CHD), stroke, venous tromboembolism (VTE) and breast cancer. In addition observational studies must be considered for individualizing MHT, because WHI has tested only one preparation and has a lot of problems like early opening of the hormone/placebo-code (i.e., loss of placebo control), in 60% MHT-initiation too late, and in 40% risk factors for cardiovascular diseases and breast cancer. Pharmacological properties should be considered, such as only oral, but not transdermal estradiol increases VTE-risk. The choice of progestogens could be dependent on the different "partial effects" on steroid receptors, e.g., use of anti-androgenic progestogens in metabolic syndrome, Polycystic Ovary Syndrome (PCOS) etc., taking advantage of the anti-mineralocorticoid effect of drospirenone to stabilize blood pressure and reduce the risk of stroke, selection of tibolone for patients with sexual dysfunctions because its androgenic properties etc. Most important for the selection of the progestogen is endometrial efficacy, primary indication for progestogens in MHT. Therefore regular endometrial monitoring is reommended, using sequential or continuous combined regimens; "hormonal curettage" and/or the progestogen challenge text to avoid endometrial hyperproliferation. Levonorgestrel-IUD as progestogen component can reduce progestogen-dependent risks, offering also contraception, but often with longer bleeding problems, in contrast to sequential regimens of MHT, which can be used to treat irregular bleedings. Other main indications are treatment of climacteric complaints and prevention of osteoporosis and possible other preventive options. Regarding contraindications, according to the general rules of "class-labeling", they are the same for every MHT despite there are differences in benefits and risks. Choice of the timing of MHT-initiation is crucial to whether cardiovascular prevention (early start) or (like in WHI) increased risk of CHD and stroke occurs. The increased risk of breast cancer can be reduced using progesterone or its isomer dydrogesterone. Since, however, this risk cannot been excluded with any MHT, recommendations for screening on the possible development of breast cancer are given, on the basis of own recent research. Criteria for the selection of MHT are mainly to reduce possible risks as seen in WHI since for every MHT efficacy is good and essentially the same. Often the best choice is estradiol combined with progesterone or dydrogesterone, but also other progestogens should be considered including LNG-IUD, to optimize and individualize MHT.