Energy Metabolism Disorder Research Articles

Energy Crisis Links to Autophagy and Ferroptosis in Alzheimer's Disease: Current Evidence and Future Avenues.

Alzheimer's disease (AD) is one of the most common neurodegenerative diseases worldwide. The occult nature of the onset and the uncertainty of the etiology largely impede the development of therapeutic strategies for AD. Previous studies revealed that the disorder of energy metabolism in the brains of AD patients appears far earlier than the typical pathological features of AD, suggesting a tight association between energy crisis and the onset of AD. Energy crisis in the brain is known to be induced by the reductions in glucose uptake and utilization, which may be ascribed to the diminished expressions of cerebral glucose transporters (GLUTs), insulin resistance, mitochondrial dysfunctions, and lactate dysmetabolism. Notably, the energy sensors such as peroxisome proliferators-activated receptor (PPAR), transcription factor EB (TFEB), and AMP-activated protein kinase (AMPK) were shown to be the critical regulators of autophagy, which play important roles in regulating beta-amyloid (Aβ) metabolism, tau phosphorylation, neuroinflammation, iron dynamics, as well as ferroptosis. In this study, we summarized the current knowledge on the molecular mechanisms involved in the energy dysmetabolism of AD and discussed the interplays existing between energy crisis, autophagy, and ferroptosis. In addition, we highlighted the potential network in which autophagy may serve as a bridge between energy crisis and ferroptosis in the progression of AD. A deeper understanding of the relationship between energy dysmetabolism and AD may provide new insight into developing strategies for treating AD; meanwhile, the energy crisis in the progression of AD should gain more attention.

Ginsenoside Rg5 Improves Sleep by Regulating Energy Metabolism in Sleep-Deprived Rats.

Sleep deprivation (SD) has become a universal social problem. There is a causal relationship between SD and energy metabolism disorder. Phytochemicals have been demonstrated to have excellent sleep-promoting effects, and studies have shown that ginsenoside Rg5 (Rg5) exerts sedative and hypnotic effects. The present study aimed to investigate the role of Rg5 in regulating energy metabolism and explore the potential mechanism of improving sleep. Sleep-deprived rats were randomly divided into a control group (Ctrl), SD model group (SD), Rg5 group (GRg5), and melatonin group (MT). Sleep-deprived model rats were generated by housing rats in an SD box for 4 weeks. The Ctrl and SD groups were given equal volumes of saline. The Rg5 groups were given 25[Formula: see text]mg/kg Rg5 or 50[Formula: see text]mg/kg Rg5, and the MT group was given 0.27[Formula: see text]g/kg MT. A Western blot analysis and ELISA were used to detect the metabolic levels, mitochondrial functional proteins, AMPK pathway proteins, clock-related proteins, adenosine receptors, and neurotransmitter receptors. The results showed that Rg5 corrected abnormal glucose and lipid metabolism as well as improved ATP levels. In addition, Rg5 alleviated mitochondrial structural damage and improved the expression of proteins involved in mitochondrial biosynthesis, fission, and fusion. Moreover, Rg5 improved the expression of AMPK/PGC-1/Nrf-1 pathway proteins, regulated mitochondrial biological functions, and affected the rhythm characteristics of circadian clock-related proteins. Further, Rg5 improved the expression of A1R and A[Formula: see text]R as well as regulated the expression levels of GABAA1[Formula: see text] and mGluR5 to improve sleep in SD rats.

Selenium deficiency caused hepatitis in chickens via the miR-138-5p/SelM/ROS/Ca2+ overload pathway induced by hepatocyte necroptosis.

Selenoprotein M (SelM), a key thioredoxin like enzyme in the endoplasmic reticulum (ER), is closely related to hepatocyte degeneration. However, the role of miR-138-5p/SelM and necroptosis in chicken SelM-deficient hepatitis and the specific biological mechanism of liver inflammation caused by SelM deficiency have not been elucidated. We established an in vivo chicken liver Se deficiency model by feeding a low-Se diet. The miR-138-5p knockdown and overexpression models and SelM knockdown models were established in LMH cells for an in vitro study. Transmission electron microscopy, H&E staining, Fluo4-AM/ER staining, and flow cytometry were used to detect the morphological changes in chicken liver tissue and the expression changes of necroptosis and inflammation in chicken liver cells. We observed that Se deficiency resulted in liver inflammation, up-regulation of miR-138-5p expression and down-regulation of SelM expression in chickens. Oxidative stress, Ca2+ overload, energy metabolism disorder and necroptosis occurred in chicken liver tissue. Importantly, ROS and the Ca2+ inhibitor could effectively alleviate the energy metabolism disorder, necroptosis and inflammatory cytokine secretion caused by miR-138-5p overexpression and SelM knockdown in LMH cells. In conclusion, selenium deficiency causes hepatitis by upregulating miR-138-5p targeting SelM. Our research findings enrich our knowledge about the biological functions of SelM and provide a theoretical basis for the lack of SelM leading to liver inflammation in chickens.

The influence of environmental factors on the prevalence of «thrifty genotypes» as predictors of metabolic disorders

"Thrifty genotypes" are the risk factors for obesity and lipid and energy metabolism disorders. Hence, it is important to assess the contribution of environmental factors that influenced the thrifty genotypes' population distribution. Aim of the study - systematization and critical analysis of published data on population variability, relationship with climatic and environmental characteristics, association with traditional types of lifestyles, and nutrition for the «thrifty genotypes» of APOE, UCP1, UCP3, and FTO genes. Material and methods. The selection of publications from the last 20-25 years presented in the PubMed database (https://pubmed.ncbi.nlm.nih.gov) was carried out by the keywords of the generalizing rank (thrifty genotype, thrifty phenotype, drifty genotype), then narrowed down to the APOE, UCP, FTO. The final set includes publications that consider the association of genotypes with the ecological conditions of the population. Results. Our analysis of publications has confirmed the ethnic and geographical variability in the allele distribution of APOE, UCP1, UCP3, and FTO genes. However, the nature of this variability hasn't been studied sufficiently; the contribution of individual factors of the natural and anthropogenic environment remains unclear. The information on the geographical distribution of the APOE gene alleles is quite complete, while the data on the «thrifty genotypes» of UCP and FTO require further study. Conclusion. The frequency of the UCP1 and UCP3 alleles associated with effective non-contractile thermogenesis is increased in populations adapted to low temperatures. However, the population-geographical pattern of the UCP thrifty genotypes' variability as a determinant of increased fat deposition has been studied insufficiently. The carriage of FTO mutant variants increases the adaptability of groups with a traditional lifestyle and diet but is maladaptive in an urbanized environment. The influence of natural and ecological conditions on the formation of the FTO allele geographical distribution requires more attention. The results obtained allow us to propose the included groups' ranking according to the past environmental management and nutrition will facilitate the search for ecological factors that influenced the geographical distribution of genotypes (and, accordingly, populations with different levels of risk of metabolic disorders).

Thermogenic Brown Fat in Humans: Implications in Energy Homeostasis, Obesity and Metabolic Disorders.

In mammals including humans, there are two types of adipose tissue, white and brown adipose tissues (BATs). White adipose tissue is the primary site of energy storage, while BAT is a specialized tissue for non-shivering thermogenesis to dissipate energy as heat. Although BAT research has long been limited mostly in small rodents, the rediscovery of metabolically active BAT in adult humans has dramatically promoted the translational studies on BAT in health and diseases. It is now established that BAT, through its thermogenic and energy dissipating activities, plays a role in the regulation of body temperature, whole-body energy expenditure, and body fatness. Moreover, increasing evidence has demonstrated that BAT secretes various paracrine and endocrine factors, which influence other peripheral tissues and control systemic metabolic homeostasis, suggesting BAT as a metabolic regulator, other than for thermogenesis. In fact, clinical studies have revealed an association of BAT not only with metabolic disorders such as insulin resistance, diabetes, dyslipidemia, and fatty liver, but also with cardiovascular diseases including hypertension and atherosclerosis. Thus, BAT is an intriguing tissue combating obesity and related metabolic diseases. In this review, we summarize current knowledge on human BAT, focusing its patho-physiological roles in energy homeostasis, obesity and related metabolic disorders. The effects of aging and sex on BAT are also discussed.

Comparative analysis of the effect of diclofenac sodium and etoricoxib on energy metabolism in rat liver in the acute general cooling model

When the ambient temperature decreases, physiological mechanisms that prevent heat loss are activated. However, under cold stress hypothermia develops, which significantly disrupts the functioning of the body and can be transformed into life-threatening. Preventive use of nonsteroidal anti-inflammatory drugs, especially diclofenac sodium and etoricoxib, has been found to reduce the severity of cold trauma. Given that their frigoprotective effect can accompany the impact on the synthesis of eicosanoids when exposed to low temperatures, it is advisable to study mechanisms for preventing hypothermia independent of cyclooxygenase, particularly the influence on energy metabolism. The aim of the study was to figure out the effect of diclofenac sodium and etoricoxib on the indicators of energy metabolism in the liver of rats after acute general cooling. Experiments were carried out on 28 sexually mature male rats, which were given diclofenac sodium (7 mg/kg), etoricoxib (5 mg/kg), or solvent 30 minutes before cold trauma intragastrically (in the intact control and pathology control groups). Acute hypothermia was caused by exposure of animals for 2 hours at a temperature of -18°C. Rectal temperature was measured before and after acute general cooling. The content of lactate, pyruvate and adenosine triphosphate in the liver was measured and the lactate/pyruvate ratio was calculated. Diclofenac sodium, unlike etoricoxib, was found to significantly reduce the severity of hypothermia. Both nonsteroidal anti-inflammatory drugs prevent energy metabolism disorders caused by exposure to cold, namely, reducing the concentration of lactic acid and the ratio of lactate/pyruvate, increasing the content of pyruvate and adenosine triphosphate in the liver of animals. Etoricoxib normalizes the content of energy metabolism intermediates to their levels in intact animals. Diclofenac sodium has a similar effect, the expression of which is inferior to the selective cyclooxygenase-2 inhibitor. Therefore, when administered prophylactically before acute general cooling, diclofenac sodium effectively prevents hypothermia in rats, surpassing etoricoxib. Etoricoxib completely prevents a decrease in the content of pyruvate and adenosine triphosphate, as well as the accumulation of lactic acid in the liver. Diclofenac sodium is inferior to etoricoxib in its effect on energy metabolism, which indicates other mechanisms of frigoprotective action of a non-selective cyclooxygenase inhibitor. The frigoprotective and energotropic properties of nonsteroidal anti-inflammatory drugs dissociate.

Nanoenabled Tumor Energy Metabolism Disorder via Sonodynamic Therapy for Multidrug Resistance Reversal and Metastasis Inhibition.

Cancer multidrug resistance (MDR) is an important reason that results in chemotherapy failure. As a main mechanism of MDR, overexpressed P-glycoprotein (P-gp) utilizes adenosine triphosphate (ATP) to actively pump chemotherapy drugs out of cells. In addition, metabolic reprogramming of drug-resistant tumor cells (DRTCs) exacerbates the specific hypoxic microenvironment and promotes tumor metastasis and recurrence. Therefore, we propose a novel sonodynamic therapy (SDT) paradigm to induce energy metabolism disorder and drug resistance change of DRTCs. A US-controlled "Nanoenabled Energy Metabolism Jammer" (TL@HPN) is designed using perfluoropentane (PFP) adsorbing oxygen in the core, and a targeting peptide (CGNKRTR) is attached to the liposome as the delivery carrier shell to incorporate hematoporphyrin monomethyl ether (HMME) and paclitaxel (PTX). The TL@HPN with ultrasonic/photoacoustic imaging (PAI/USI) precisely controlled the release of drugs and oxygen after being triggered by ultrasound (US), which attenuated the hypoxic microenvironment. SDT boosted the reactive oxygen species (ROS) content in tumor tissues, preferentially inducing mitochondrial apoptosis and maximizing immunogenic cell death (ICD). Persistently elevated oxidative stress levels inhibited ATP production and downregulated P-gp expression by disrupting the redox balance and electron transfer of the respiratory chain. We varied the effect of TL@HPN combined with PD-1/PD-L1 to activate autoimmunity and inhibit tumor metastasis, providing a practical strategy for expanding the use of SDT-mediated tumor energy metabolism.

Gut microbiome in PCOS associates to serum metabolomics: a cross-sectional study

The association between gut microbiome and chronic metabolic disease including polycystic ovary syndrome (PCOS), is well documented, however, the relationship between the gut microbiota and serum metabolites remains unknown. In this study, untargeted metabolomics together with a 16S rRNA gene sequencing tool was used to detect small molecule serum metabolites and the gut microbiome. We identified 15 differential metabolites between PCOS patients and the healthy control. Lysophosphatidylcholine (LPC) (18:2, 20:3, 18:1, P-16:0, 17:0, 15:0, 18:3, 20:4), phosphatidylcholine(PC), ganglioside GA2 (d18:1/16:0) and 1-linoleoylglycerophosphocholine were increased in the PCOS group, and the concentrations of phosphoniodidous acid, bilirubin, nicotinate beta-d-ribonucleotide and citric acid were decreased in the PCOS group, suggesting a lipid metabolism and energy metabolism disorder in the PCOS patients. The diversity of gut microbiota in PCOS group was lower than that in healthy controls. Escherichia/Shigella, Alistipes and an unnamed strain 0319_6G20 belonging to Proteobacteria were important distinguishing genera (LDA > 3.5) in PCOS. Prevotella_9 was positively correlated with phosphoniodidous acid, nicotinate beta-d-ribonucleotide and citric acid concentrations, and negatively correlated with the concentration of LPC (20:3) and 1-linoleoylglycerophosphocholine; Roseburia was negatively correlated with LPC concentration (20:4), while the characteristic genus 0319_6G20 of PCOS was positively correlated with LPC concentration (20:3) (COR > 0.45). SF-36 in the PCOS group was significantly lower than that in the healthy control (HC) group, which was associated with the presence of Escherichia-Shigella and Alistipes. Our finding demonstrated the correlation between the gut microbiota and serum metabolites in PCOS, and therefore characteristic gut microbiota and metabolites may play an important role in the insulin resistance and the mood changes of PCOS patients.

Serum metabolic signatures of schizophrenia patients complicated with hepatitis B virus infection: A 1H NMR-based metabolomics study.

Schizophrenia (SZ) is a severe chronic mental disorder with increased risk of hepatitis B virus (HBV) infection, which is incurable currently and induces various negative emotions and psychological pressures in patients to exacerbate mental disorders. To facilitate the therapeutic design for SZ patients complicated with HBV infection (SZ + HBV), it is helpful to first elucidate the metabolic perturbations in SZ + HBV patients. In this study, metabolic profiles of the serum samples from four groups of participants comprising healthy controls (HC, n = 72), HBV infection (n = 52), SZ patients (n = 37), and SZ + HBV (n = 41) patients were investigated using a high-resolution 1H NMR-based metabolomics approach. Distinguishable metabolic profiles were found in the four groups. In comparison with HC, HBV infection induced increased levels of citrate and succinate to perturbate the tricarboxylic acid cycle and succinate-related pathways. Similar to SZ cases, SZ + HBV patients exhibited decreased glucose but increased citrate, pyruvate, and lactate, suggesting the occurrence of disturbance in glucose metabolism. Moreover, in comparison with HC, several serum amino acid levels in SZ + HBV patients were significantly altered. Our findings suggest that Warburg effect, energy metabolism disorders, neurotransmitter metabolism abnormalities, mitochondrial dysfunction and several disturbed pathways in relation to tyrosine and choline appear to play specific and central roles in the pathophysiology of SZ + HBV. Apart from replicating metabolic alterations induced by SZ and HBV separately (e.g., in energy metabolism and Warburg effect), the specific metabolic abnormalities in the SZ + HBV group (e.g., several tyrosine- and choline-related pathways) highlighted the existence of a synergistic action between SZ and HBV pathologies. Current study revealed the metabolic alterations specific to the interaction between SZ and HBV pathologies, and may open important perspectives for designing precise therapies for SZ + HBV patients beyond the simple combination of two individual treatments.

Study on the mechanism of Fufang E'jiao Jiang on precancerous lesions of gastric cancer based on network pharmacology and metabolomics

Ethnopharmacological relevanceFufang E'jiao Jiang (FEJ) is a prominent traditional Chinese medicine prescription, which consists of Asini Corii Colla (Donkey-hide gelatin prepared by stewing and concentrating from the hide of Equus asinus Linnaeus., ACC), Codonopsis Radix (the dried roots of Codonopsis pilosula (Franch.) Nannf., CR), Ginseng Radix et Rhizoma Rubra (the steamed and dried root of Panax ginseng C.A. Mey., GRR), Crataegi Fructus (the mature fruits of Crataegus pinnatifida Bunge., CF), and Rehmanniae Radix Praeparata (the steamed and sun dried tuber of Rehmannia glutinosa (Gaertn.) Libosch. ex Fisch. & C.A. Mey., RRP). It is a popularly used prescription for “nourishing Qi and nourishing blood”. Aim of the studyTo explore the potential mechanism of FEJ on precancerous lesion of gastric cancer in rats by combining network pharmacology and metabolomics. MethodsTraditional Chinese Medicine Systems Pharmacology and Bioinformatics Analysis Tool for Molecular mechanism of Traditional Chinese Medicine were used to identify the ingredients and potential targets of FEJ. GeneCards database was used to define PLGC-associated targets. We built a herb-component-disease-target network and analyzed the protein-protein interaction network. Underlying mechanisms were identified using Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis. In addition, 40% ethanol, N-methyl-N′-nitro-N-nitroguanidine and irregular eating were used to establish PLGC rats model. We also evaluated the efficacy of FEJ on MNNG-induced PLGC rats by body weight, histopathology, blood routine and cytokine levels, while the predicted pathway was determined by the Western blot. Ultra-performance liquid chromatography-tandem mass spectrometry-based serum non-targeted metabolomics was used to select potential biomarkers and relevant pathways for FEJ in the treatment of PLGC. ResultsNetwork pharmacology showed that FEJ exhibited anti-PLGC effects through regulating ALB, TNF, VEGFA, TP53, AKT1 and other targets, and the potential pathways mainly involved cancer-related, TNF, PI3K-AKT, HIF-1, and other signaling pathways. Animal experiments illustrated that FEJ could suppress inflammation, regulate gastrointestinal hormones, and inhibit the expression of PI3K/AKT/HIF-1α pathway-related proteins. Based on serum non-targeted metabolomics analysis, 12 differential metabolites responding to FEJ treatment were identified, and metabolic pathway analysis showed that the role of FEJ was concentrated in 6 metabolic pathways. ConclusionBased on network pharmacology, animal experiments and metabolomics, we found that FEJ might ameliorate gastric mucosal injury in PLGC rats by regulating gastrointestinal hormones and inhibiting inflammation, and its mechanism of action is related to the inhibition of excessive activation of PI3K/AKT/HIF-1α signaling pathway and regulation of disorders of body energy metabolism. This comprehensive strategy also provided a reasonable way for unveiling the pharmacodynamic mechanisms of multi-components, multi-targets, and multi-pathways in Traditional Chinese Medicine.

Antibacterial activity and metabolomic analysis of linalool against bovine mastitis pathogen Streptococcus agalactiae

Streptococcus agalactiae is among the major causative pathogens of bovine mastitis, as well as crucial pathogen leading to human morbidity and mortality. Being a promising natural antibacterial agent, linalool has been broadly applied in medicine and food processing. However, its antibacterial effect against S. agalactiae has barely been elucidated. This study is the first to investigate the antibacterial activity and action mechanism of linalool against S. agalactiae causing bovine mastitis. Linalool exhibited significant antibacterial activity against S. agalactiae, with an inhibition zone diameter of 23 mm and a minimum inhibitory concentration of 1.875 μL/mL. In addition, linalool damaged cell structural integrity of S. agalactiae, leading to the leakage of intracellular components (alkaline phosphatase, nucleic acids and protein). Linalool also exhibited a scavenging effect on biofilm. Moreover, untargeted metabolomics analysis revealed that linalool stress substantially disrupted intracellular metabolism of S. agalactiae. Linalool caused energy metabolism disorder, and obstructed nucleic acid synthesis in S. agalactiae. Furthermore, downregulation of amino acids (e.g., proline, alanine) and upregulation of saturated fatty acids provide strong evidence for linalool induced cell wall and membrane damage. Overall, linalool exhibited strong antibacterial activity against S. agalactiae by destroying the cell structure and disrupting intracellular metabolism. This study provides a new insight and theoretical foundation for linalool application in preventing S. agalactiae infection.

Problems of cow health in dairy farming: known and unknown aspects

The article reflects the problematic aspects underlying the development of pathobiochemical processes, disorders of energy metabolism and pathophysiological conditions of cows. Currently, it is generally recognized that no feed sources can meet the high energy needs of high-yielding cows. Moreover, attempts to increase the energy capacity of feed by introducing a large amount of grain concentrates into the diet of high-yielding cows inevitably leads to a violation of the evolutionarily developed digestion. And not only. Orientation to the concentrate type of cow feeding, in which easily fermentable starch predominates, generates the problem of severe acidosis. The fact is that starch of grain concentrates causes a high rate of glycolysis with the formation of a large number of volatile fatty acids, among which the strongest lactic acid prevails [6,12]. Intensive acidification of the rumen also occurs due to the feeding of cows with acidic canned food, also containing a large amount of lactic acid. The result of such feeding is chronization or acute development of acidosis of the scar [6,12,14]. But that's not all. During acidification of the body, vital trace elements are poorly absorbed, and some of them, such as Ca, Na, K, Mg, Fe, are intensively excreted (hypomicroelementosis) [10,21]. The concentration of hemoglobin decreases (anemia syndrome). Oxygen transfer to organs and tissues worsens (hypoxia) [10]. In conditions of acute hypoxia, the final product of glycolysis - pyruvate - does not undergo decarboxylation and is not involved in the Krebs cycle. What is even worse turns into new portions of lactate [10]. The problems of reproduction and the loss of the genetic potential of high milk and meat productivity are closely related to the mass development of pathobiochemical processes. Currently, the average yield of calves per 100 cows rarely exceeds 70%. The above complex of problems requires from science and practice a qualitatively different approach to the issues of ensuring the health, preservation and realization of the genetic potential of high dairy productivity of cows. The profitability of modern dairy farming depends on whether veterinary science and practice can find a solution to these very serious problems.

Xiao-Xu-Ming decoction extracts promotes mitochondrial biogenesis and improves neurobehavioral deficits in cerebral ischemia/reperfusion rats

Introduction: Stroke is one of the leading causes of death and disability in the worldwide. Traditional Chinese medicine plays an important role in preventing and treatment of stroke. Xiao-Xu-Ming decoction (XXM) is an effective traditional Chinese prescription for the treatment of stroke and its sequelae. Previous studies have reported the extracts of XXM has a good therapeutic effect on experimental animal stroke. However, the mechanism is unclear. Our present study focused on metabolic remodeling in cerebral ischemia-reperfusion to investigate the mechanism of XXM on cerebral ischemia/reperfusion (I/R). Methods: The cerebral I/R rat model was established by 90 min middle cerebral artery occlusion following reperfusion. XXM at doses of 37.5, 75 and 150 mg/kg was administered for the continuous 7 day after cerebral I/R. Behavioral testing, cerebral infarction detected by TTC staining, Nissl staining, NeuN immunohistochemical staining, and MAP2 immunofluorescence staining were conducted to evaluate the effect of XXM treatment on cerebral I/R of rats. TUNEL staining was used to detect DNA damage. The expression of related proteins was detected by qPCR and western blotting. Results: 7 day XXM treatment improved neurological and behavioral deficits, regulated the biogenesis and dynamic process of mitochondria, promoted the recovery of mitochondrial function, and improved the energy metabolism disorder after cerebral I/R. Furthermore, XXM also had an improving effect on mitochondrial-dependent apoptosis after cerebral I/R. Conclusion: we found that XXM regulated metabolic remodeling in cerebral ischemia-reperfusion and improve neurological deficits.

Insight into the Prospects for Tumor Therapy Based on Photodynamic Immunotherapy.

Malignancy is one of the common diseases with high mortality worldwide and the most important obstacle to improving the overall life expectancy of the population in the 21st century. Currently, single or combined treatments, including surgery, chemotherapy, and radiotherapy, are still the mainstream regimens for tumor treatment, but they all present significant side effects on normal tissues and organs, such as organ hypofunction, energy metabolism disorders, and various concurrent diseases. Based on this, theranostic measures for the highly selective killing of tumor cells have always been a hot area in cancer-related fields, among which photodynamic therapy (PDT) is expected to be an ideal candidate for practical clinical application due to its precise targeting and excellent safety performance, so-called PDT refers to a therapeutic method mainly composed of photosensitizers (PSs), laser light, and reactive oxygen species (ROS). Photoimmunotherapy (PIT), a combination of PDT and immunotherapy, can induce systemic antitumor immune responses and inhibit continuing growth and distant metastasis of residual tumor cells, demonstrating a promising application prospect. This article reviews the types of immune responses that occur in the host after PDT treatment, including innate and adaptive immunity. To further help PIT-related drugs improve their pharmacokinetic properties and bioavailability, we highlight the potential improvement of photodynamic immunotherapy from three aspects: immunostimulatory agents, tumor-associated antigens (TAAs) as well as different immune cells. Finally, we focus on recent advances in various strategies and shed light on their corresponding mechanisms of immune activation and possible clinical applications such as cancer vaccines. Having discovered the inherent potential of PDT and the mechanisms that PDT triggers host immune responses, a variety of immunotherapeutic strategies have been investigated in parallel with approaches to improve PDT efficiency. However, it remains to be further elucidated under what conditions the immune effect induced by PDT can achieve tumor immunosuppression and to what extent PDT-induced antitumor immunity will lead to complete tumor rejection. Currently, PIT presents several outstanding intractable challenges, such as the aggregation ability of PSs locally in tumors, deep tissue penetration ability of laser light, immune escape, and biological toxicity, and it is hoped that these issues raised will help to point out the direction of preclinical research on PIT and accelerate its transition to clinical practice.

Divergent neurocircuitry dissociates two components of the stress response: glucose mobilization and anxiety-like behavior.

Stress is a risk factor for emotion and energy metabolism disorders. However, the neurocircuitry mechanisms for emotion initiation and glucose mobilization underlying stress responses are unclear. Here we demonstrate that photoactivation of Gad2+ projection from the anterior bed nucleus of the stria terminalis (aBNST) to the arcuate nucleus (ARC) induces anxiety-like behavior as well as acute hyperglycemia. Photoinhibition of the circuit is anxiolytic and blocks hyperglycemia induced by restraint stress. Pharmacogenetic inhibition of the ARCGad2+→raphe obscurus nucleus (ROb) and photoactivation of the aBNSTGad2+→ARC circuits simultaneously leads to significant hypoglycemia and anxiety-like behavior. Pharmacogenetic inhibition of the ARCGad2+→nucleus of the solitary tract (NTS) whilst photoactivation of the aBNSTGad2+→ARC circuit only induces hyperglycemia. Our results reveal that the aBNSTGad2+→ARCGad2+→ROb circuit is recruited for the stress response of rapid glucose mobilization and the aBNSTGad2+→ARCGad2+→NTS circuit for behavioral symptoms of stress response. This study identifies a possible general strategy for neurocircuitry structural organization dealing with multiple organs involved in responses, with potential therapeutic targets for emotion and energy metabolism disorders underlying psychiatric disorders.

Targeting Emerging Pathogenic Mechanisms by Natural Molecules as Potential Therapeutics for Neurodegenerative Diseases.

Natural molecules with favorable safety profile and broad pharmacological activities have shown great promise in the treatment of various neurodegenerative diseases (NDDs). Current studies applying natural molecules against NDDs mainly focus on well-recognized conventional pathogenesis, such as toxic protein aggregation, oxidative stress, and neuroinflammation. However, accumulating evidence reveals that some underlying pathogenic mechanisms are involved earlier and more deeply in the occurrence and development of NDDs, such as ferroptosis, energy metabolism disorders, autophagy-lysosomal dysfunction, endoplasmic reticulum stress, and gut dysbiosis. Therefore, determining whether natural molecules can play therapeutic roles in these emerging pathogenic mechanisms will help clarify the actual targets of natural molecules and their future clinical translation. Furthermore, how to overcome the inability of most poorly water-soluble natural molecules to cross the blood-brain barrier is also critical for effective NDD treatment. This review summarizes emerging pathogenic mechanisms targeted by natural molecules for NDD treatment, proposes nanocarrier-based drug delivery and intranasal administration to enhance the intracerebral bioavailability of natural molecules, and summarizes the current state of clinical research on natural product-based therapeutics.

Comparative study of aluminum speciation on brain-type creatine kinase: Enzyme kinetic, molecular docking, cellular experiment, and mouse model study

Brain-type Creatine kinase (CK-BB), which has a high affinity for Aluminum (Al), and its abnormality is closely related to neurodegenerative diseases. In this study, the comparative effect of Al speciation on the bioactivity of CK-BB has been studied by the inhibition kinetics method, molecular docking, cellular experiment, and mouse model study. Results showed that the half-inhibitory concentration of AlCl3 was 0.67 mM, while Al(mal)3 was 3.81 mM. Fluorescence spectra showed that Al(mal)3 had a more substantial effect on the endogenous fluorescence of CK-BB than AlCl3. Molecular docking showed that AlCl3 was closer to the active site of CK-BB. C6 cells were used to explore the enzyme activity and intracellular distribution of CK-BB by AlCl3 or Al(mal)3. AlCl3 treatment may directly affect CK-BB activity and cause insufficient local ATP supply in cells which affected the formation of F-actin and cell morphology. The change in the hydrophobicity of CK-BB induced by Al(mal)3 affected the movement of CK-BB, which subsequently activated thecytochrome C (Cyt C)/Caspase 9/Caspase 3 pathway. Similar results have been found in vivo experiments. This study demonstrated that interaction between Al and CK-BB might be related to the process of Al-induced energy metabolism disorders, in which the Al speciation revealed differentiated toxicity mechanisms.

Cardiac energy metabolism disorder mediated by energy substrate imbalance and mitochondrial damage upon tebuconazole exposure

Tebuconazole exposure has been described as an increasing hazard to human health. An increasing number of recent studies have shown a positive association between tebuconazole exposure and cardiovascular disease risk, which is characterized by the reduction of adenosine triphosphate (ATP) synthesis. However, researches on the damage of tebuconazole exposure to energy metabolism and the related molecular mechanisms are limited. In the present study, male C57BL/6 mice were treated with tebuconazole at different low concentrations for 4 weeks. The results indicated that tebuconazole could accumulate in the heart and further induce the decrease of ATP content in the mouse heart. Importantly, tebuconazole induced an obvious shift in substrate utilization of fatty acid and glucose by disrupting their corresponding transporters (GLUT1, GLUT4, CD36, FABP3 and FATP1) expression, and significantly repressed the expression of mitochondrial biogenesis (Gabpa and Tfam) and oxidative phosphorylation (CS, Ndufa4, Sdhb, Cox5a and Atp5b) related genes in a dose-dependent manner. Further investigation revealed that these alterations were related to the IRS1/AKT and PPARγ/RXRα pathways. These findings contribute to a better understanding of triazole fungicide-induced cardiovascular disease by revealing the key indicators associated with this phenomenon.

In vivo identification of the pharmacodynamic ingredients of Polygonum cuspidatum for remedying the mitochondria to alleviate metabolic dysfunction–associated fatty liver disease

Metabolic dysfunction–associated fatty liver disease (MAFLD) is a chronic liver disease that currently lacks approved pharmacological treatment options. The mechanisms and active ingredients of Polygonum cuspidatum (PC) that regulate the mitochondria to relieve MAFLD have not been assessed. Thus, this study was designed to explore the bioactive components of PC extract in regulating mitochondria to alleviate high-fat diet–induced MAFLD using mitochondrial pharmacology and pharmacochemistry. Our results demonstrate that PC protected the mitochondrial ultrastructure and inhibited oxidative stress and energy metabolism disorder in the liver mitochondria. Furthermore, PC-derived components in the liver mitochondria attenuated oxidative stress and restored the energy metabolism of fat emulsion–induced steatosis in L02 cell. Sixteen compounds were identified in the liver–mitochondrial extracts of PC-treated rats. The antisteatotic effects of three identified monomers and anti-MAFLD ability of the monomer group were confirmed. Collectively, our data suggest that the extract of PC can alleviate lipid metabolism disorder in MAFLD by protecting the mitochondrial ultrastructure, reducing oxidative stress injury, and promoting energy metabolism. The sixteen identified compounds were potentially the main effective ingredients of PC in treating MAFLD. Thus, PC shows potential in treating MAFLD and related mitochondrial dysfunction. The proposed strategy to identify the ingredients of herbal medicines based on mitochondrial pharmacology and pharmacochemistry presents a new approach in exploring the pharmacodynamic components of herbal medicines that regulate mitochondria in preventing and treating diseases.

Exposure to melamine cyanuric acid in adult mice caused motor activity and skeletal muscle energy metabolism disorder

Thyroid hormone has a variety of physiological functions and plays an important role in the development of central nervous system, skeletal muscle and lung, as well as body temperature regulation. Skeletal muscle is a key determinant of basal metabolic rate and systemic energy metabolism. It contains Myopsin (SLN) which plays an important role in muscle heat production and energy metabolism. Melamine cyanuric acid (MCA) is an important component of the new flame retardant, but also a chemical interfering substance that can affect the endocrine in the body. It is mainly distributed in nylon and other flame retardant substances. Therefore, in this study, male mice were exposed to MCA at 10, 20 and 30 mg/kg for four weeks. We explored the effects of MCA exposure on skeletal muscle morphology, thermogenic gene expression and motor activity to explore whether MCA exposure could induce skeletal muscle hyperthermia and energy metabolism disorders and its underlying mechanisms. The results showed that the motor activity of male mice exposed to MCA was decreased, the morphology of skeletal muscle tissue was impaired, and the levels of morphological and thermogenic genes in skeletal muscle were destroyed. These findings are intended to provide a preliminary reference for studying the effects of MCA exposure on thermogenesis and energy metabolism in adult mice.