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PloS One 2024Diet-induced obesity reduces oocyte quality mainly by impacting oocyte mitochondrial functions. Moreover, maternal obesity is associated with mitochondrial dysfunction...
Diet-induced obesity reduces oocyte quality mainly by impacting oocyte mitochondrial functions. Moreover, maternal obesity is associated with mitochondrial dysfunction in oocytes of their adult offspring. However, these effects were reported only in fully grown oocytes, mainly in the form of abnormal mitochondrial ultrastructure. It is unknown if obesogenic (OB) diets or maternal obesity already impact the primordial and preantral follicles. Considering the long duration and dynamics of folliculogenesis, determining the stage at which oocytes are affected and the extent of the damage is crucial for optimal reproductive management of obese patients and their daughters. Potential interaction between maternal and offspring diet effects are also not described, yet pivotal in our contemporary society. Therefore, here we examined the impact of OB diets on oocyte mitochondrial ultrastructure in primordial and activated preantral follicles in offspring from diet-induced obese or lean mothers. We used an outbred Swiss mouse model to increase the pathophysiological relevance to humans. Female mice were fed control or OB diets for 7 weeks, then mated with control males. Their female offspring were fed control or OB diets after weaning for 7 weeks (2-by-2 factorial design). Adult offspring ovarian sections were examined using transmission electron microscopy. We characterised and classified unique features of oocyte mitochondrial ultrastructure in the preantral follicles. An increase in mitochondrial matrix density was the most predominant change during follicle activation in secondary follicles, a feature that is linked with a higher mitochondrial activity. Maternal obesity increased mitochondrial density already in the primordial follicles suggesting an earlier increase in bioenergetic capacity. Maternal obesity did not induce abberant ultrastructure (abnormalities and defects) in primordial or preantral follicles. In contrast, offspring OB diet increased mitochondrial abnormalities in the primordial follicles. Further investigation of the consequences of these changes on oocyte metabolic regulation and stress levels during folliculogenesis is needed.
Topics: Animals; Oocytes; Female; Ovarian Follicle; Mice; Mitochondria; Pregnancy; Obesity; Male; Obesity, Maternal; Prenatal Exposure Delayed Effects; Diet, High-Fat
PubMed: 38935642
DOI: 10.1371/journal.pone.0305912 -
Clinical and Translational Medicine Jul 2024Hepatitis B virus (HBV) infection playsa significant role in the etiology and progression of liver-relatedpathologies, encompassing chronic hepatitis, fibrosis,... (Review)
Review
Hepatitis B virus (HBV) infection playsa significant role in the etiology and progression of liver-relatedpathologies, encompassing chronic hepatitis, fibrosis, cirrhosis, and eventual hepatocellularcarcinoma (HCC). Notably, HBV infection stands as the primary etiologicalfactor driving the development of HCC. Given the significant contribution ofHBV infection to liver diseases, a comprehensive understanding of immunedynamics in the liver microenvironment, spanning chronic HBV infection,fibrosis, cirrhosis, and HCC, is essential. In this review, we focused on thefunctional alterations of CD8 T cells within the pathogenic livermicroenvironment from HBV infection to HCC. We thoroughly reviewed the roles ofhypoxia, acidic pH, metabolic reprogramming, amino acid deficiency, inhibitory checkpointmolecules, immunosuppressive cytokines, and the gut-liver communication in shapingthe dysfunction of CD8 T cells in the liver microenvironment. Thesefactors significantly impact the clinical prognosis. Furthermore, we comprehensivelyreviewed CD8 T cell-based therapy strategies for liver diseases,encompassing HBV infection, fibrosis, cirrhosis, and HCC. Strategies includeimmune checkpoint blockades, metabolic T-cell targeting therapy, therapeuticT-cell vaccination, and adoptive transfer of genetically engineered CD8 T cells, along with the combined usage of programmed cell death protein-1/programmeddeath ligand-1 (PD-1/PD-L1) inhibitors with mitochondria-targeted antioxidants.Given that targeting CD8 T cells at various stages of hepatitis Bvirus-induced hepatocellular carcinoma (HBV + HCC) shows promise, we reviewedthe ongoing need for research to elucidate the complex interplay between CD8 T cells and the liver microenvironment in the progression of HBV infection toHCC. We also discussed personalized treatment regimens, combining therapeuticstrategies and harnessing gut microbiota modulation, which holds potential forenhanced clinical benefits. In conclusion, this review delves into the immunedynamics of CD8 T cells, microenvironment changes, and therapeuticstrategies within the liver during chronic HBV infection, HCC progression, andrelated liver diseases.
Topics: Humans; CD8-Positive T-Lymphocytes; Hepatitis B virus; Hepatitis B, Chronic; Carcinoma, Hepatocellular; Liver Neoplasms; Liver Diseases
PubMed: 38935536
DOI: 10.1002/ctm2.1731 -
EJNMMI Radiopharmacy and Chemistry Jun 20244-[F]fluorobenzyl-triphenylphosphonium ([F]FBnTP) is a lipophilic cation PET tracer. The cellular uptake of [F]FBnTP is correlated with oxidative phosphorylation by...
BACKGROUND
4-[F]fluorobenzyl-triphenylphosphonium ([F]FBnTP) is a lipophilic cation PET tracer. The cellular uptake of [F]FBnTP is correlated with oxidative phosphorylation by mitochondria, which has been associated with multiple critical diseases. To date, [F]FBnTP has been successfully applied for imaging myocardial perfusion, assessment of severity of coronary artery stenosis, delineation of the ischemic area after transient coronary occlusion, and detection/quantification of apoptosis in various animal models. Recent preclinical and clinical studies have also expanded the possibilities of using [F]FBnTP in oncological diagnosis and therapeutic monitoring. However, [F]FBnTP is typically prepared through a tediously lengthy four-step, three-pot reaction and required multiple synthesizer modules; Thus, such an approach remains a challenge for this promising radiopharmaceutical to be implemented for routine clinical studies. Herein, we report an optimized one-step, one-pot automated approach to produce [F]FBnTP through a single standard commercially-available radiosynthesizer that enables centralized production for clinical use.
RESULTS
The fully automated production of [F]FBnTP took less than 55 min with radiochemical yields ranging from 28.33 ± 13.92% (non-decay corrected), apparent molar activity of 69.23 ± 45.62 GBq/µmol, and radiochemical purities of 99.79 ± 0.41%. The formulated [F]FBnTP solution was determined to be sterile and colorless with a pH of 4.0-6.0. Our data has indicated no observable radiolysis after 8 h from the time of final product formulation and maximum assay of 7.88 GBq.
CONCLUSIONS
A simplified and cGMP-compliant radiosynthesis of [F]FBnTP has been established on the commercially available synthesizer in high activity concentration and radiochemical purity. While the preclinical and clinical studies using [F]FBnTP PET are currently underway, the automated approaches reported herein facilitate clinical adoption of this radiotracer and warrant centralized production of [F]FBnTP for imaging multiple patients.
PubMed: 38935218
DOI: 10.1186/s41181-024-00274-y -
Journal of the American Heart... Jul 2024Wild-type transthyretin amyloid (ATTRwt) cardiomyopathy is increasingly recognized in the development of heart failure. The link between cardiac performance,...
BACKGROUND
Wild-type transthyretin amyloid (ATTRwt) cardiomyopathy is increasingly recognized in the development of heart failure. The link between cardiac performance, hemodynamics, and mitochondrial function in disease stages of ATTRwt has not previously been studied but may provide new insights into the pathophysiology and clinical performance of the patients.
METHODS AND RESULTS
The study investigated 47 patients diagnosed with ATTRwt at Aarhus University Hospital, Denmark. Patients were stratified according to the disease stages of the National Amyloidosis Centre (NAC) as NAC I with low levels of NT-proBNP (N-terminal pro-B-type natriuretic peptide) (NAC I-L, n=14), NAC I with high levels NT-proBNP (NAC I-H, n=20), and NAC II-III (n=13). Exercise testing with simultaneous right heart catheterization was performed in all patients. Endomyocardial biopsies were collected from the patients and the mitochondrial oxidative phosphorylation capacity was assessed. All NAC disease groups, even in the NAC I-L group, a significant abnormal increase in biventricular filling pressures were noted during exercise while the filling pressures was normal or near normal at rest. The inotropic response to exercise was reduced with diminished increase in cardiac output which was significantly more pronounced in the NAC I-H (Diff. -2.4, 95% CI (-4.2: -0.7), =0.00) and the NAC II-III group (Diff: -3.1 L/min, 95% CI (-5.2: -1.1), =0.00) compared with the NAC I-L group. The pulmonary artery wedge pressure to cardiac output ratio at peak exercise was significantly different between NAC I-L and NAC II-III (Diff: 1.6 mm Hg*min/L, 95% CI (0.01:3.3, =0.04)). Patients with ATTRwt had a reduced oxidative phosphorylation capacity which correlated to left ventricular mass but not to cardiac output capacity.
CONCLUSIONS
An abnormal restrictive left ventricle and right ventricle response to exercise was demonstrated, even present in patients with early-stage ATTRwt. In more advanced disease stages a progressive impairment of the pressure-flow relationship was noted. The myocyte energetics is deranged but not associated to the contractile reserve or restrictive filling characteristics in ATTRwt.
Topics: Humans; Male; Female; Aged; Cardiomyopathies; Middle Aged; Amyloid Neuropathies, Familial; Hemodynamics; Mitochondria, Heart; Oxidative Phosphorylation; Natriuretic Peptide, Brain; Peptide Fragments; Exercise Test; Denmark; Cardiac Catheterization; Ventricular Function, Left; Biopsy; Myocardial Contraction; Biomarkers; Ventricular Function, Right; Ventricular Pressure; Prealbumin
PubMed: 38934860
DOI: 10.1161/JAHA.124.034213 -
Neural Regeneration Research Jun 2024In the pathogenesis of major depressive disorder, chronic stress-related neuroinflammation hinders favorable prognosis and antidepressant response. Mitochondrial DNA may...
In the pathogenesis of major depressive disorder, chronic stress-related neuroinflammation hinders favorable prognosis and antidepressant response. Mitochondrial DNA may be an inflammatory trigger, after its release from stress-induced dysfunctional central nervous system mitochondria into peripheral circulation. This evidence supports the potential use of peripheral mitochondrial DNA as a neuroinflammatory biomarker for the diagnosis and treatment of major depressive disorder. Herein, we critically review the neuroinflammation theory in major depressive disorder, providing compelling evidence that mitochondrial DNA release acts as a critical biological substrate, and that it constitutes the neuroinflammatory disease pathway. After its release, mitochondrial DNA can be carried in the exosomes and transported to extracellular spaces in the central nervous system and peripheral circulation. Detectable exosomes render encaged mitochondrial DNA relatively stable. This mitochondrial DNA in peripheral circulation can thus be directly detected in clinical practice. These characteristics illustrate the potential for mitochondrial DNA to serve as an innovative clinical biomarker and molecular treatment target for major depressive disorder. This review also highlights the future potential value of clinical applications combining mitochondrial DNA with a panel of other biomarkers, to improve diagnostic precision in major depressive disorder.
PubMed: 38934398
DOI: 10.4103/NRR.NRR-D-23-01878 -
Frontiers in Nutrition 2024
PubMed: 38933887
DOI: 10.3389/fnut.2024.1436894 -
Pharmaceuticals (Basel, Switzerland) Jun 2024spp. can cause a sight threatening disease. At present, the current treatments used to treat spp. Infections, such as biguanide-based antimicrobials, remain...
spp. can cause a sight threatening disease. At present, the current treatments used to treat spp. Infections, such as biguanide-based antimicrobials, remain inefficacious, with the appearance of resistant forms and high cytotoxicity to host cells. In this study, an initial screening was conducted against Neff and murine macrophages J774A.1 using alamarBlue™. Among the 160 compounds included in the cited box, 90% exhibited an inhibition of the parasite above 80%, while only 18.75% of the compounds inhibited the parasite with a lethality towards murine macrophage lower than 20%. Based on the amoebicidal activity, the cytotoxicity assay, and availability, Terconazole was chosen for the elucidation of the action mode in two clinical strains, and L10. A fluorescence image-based system and proteomic techniques were used to investigate the effect of the present azole on the cytoskeleton network and various programmed cell death features, including chromatin condensation and mitochondria dysfunction. Taking all the results together, we can suggest that Terconazole can induce programmed cell death (PCD) via the inhibition of sterol biosynthesis inhibition.
PubMed: 38931475
DOI: 10.3390/ph17060808 -
Pharmaceuticals (Basel, Switzerland) Jun 2024Obesity has become a pandemic, as currently more than half a billion people worldwide are obese. The etiology of obesity is multifactorial, and combines a contribution... (Review)
Review
Obesity has become a pandemic, as currently more than half a billion people worldwide are obese. The etiology of obesity is multifactorial, and combines a contribution of hereditary and behavioral factors, such as nutritional inadequacy, along with the influences of environment and reduced physical activity. Two types of adipose tissue widely known are white and brown. While white adipose tissue functions predominantly as a key energy storage, brown adipose tissue has a greater mass of mitochondria and expresses the uncoupling protein 1 () gene, which allows thermogenesis and rapid catabolism. Even though white and brown adipocytes are of different origin, activation of the brown adipocyte differentiation program in white adipose tissue cells forces them to transdifferentiate into "beige" adipocytes, characterized by thermogenesis and intensive lipolysis. Nowadays, researchers in the field of small molecule medicinal chemistry and gene therapy are making efforts to develop new drugs that effectively overcome insulin resistance and counteract obesity. Here, we discuss various aspects of white-to-beige conversion, adipose tissue catabolic re-activation, and non-shivering thermogenesis.
PubMed: 38931457
DOI: 10.3390/ph17060790 -
Pharmaceuticals (Basel, Switzerland) Jun 2024G-quadruplexes (G4s) are guanine-rich non-canonical secondary structures of nucleic acids that were identified in vitro almost half a century ago. Starting from the...
G-quadruplexes (G4s) are guanine-rich non-canonical secondary structures of nucleic acids that were identified in vitro almost half a century ago. Starting from the early 1980s, these structures were also observed in eukaryotic cells, first at the telomeric level and later in regulatory regions of cancer-related genes, in regulatory RNAs and within specific cell compartments such as lysosomes, mitochondria, and ribosomes. Because of the involvement of these structures in a large number of biological processes and in the pathogenesis of several diseases, including cancer, the interest in G4 targeting has exponentially increased in the last few years, and a great number of novel G4 ligands have been developed. Notably, G4 ligands represent a large family of heterogeneous molecules that can exert their functions by recognizing, binding, and stabilizing G4 structures in multiple ways. Regarding anti-cancer activity, the efficacy of G4 ligands was originally attributed to the capability of these molecules to inhibit the activity of telomerase, an enzyme that elongates telomeres and promotes endless replication in cancer cells. Thereafter, novel mechanisms through which G4 ligands exert their antitumoral activities have been defined, including the induction of DNA damage, control of gene expression, and regulation of metabolic pathways, among others. Here, we provided a perspective on the structure and function of G4 ligands with particular emphasis on their potential role as antitumoral agents. In particular, we critically examined the problems associated with the clinical translation of these molecules, trying to highlight the main aspects that should be taken into account during the phases of drug design and development. Indeed, taking advantage of the successes and failures, and the more recent technological progresses in the field, it would be possible to hypothesize the development of these molecules in the future that would represent a valid option for those cancers still missing effective therapies.
PubMed: 38931438
DOI: 10.3390/ph17060771 -
Nutrients Jun 2024Skeletal muscle is composed of bundles of muscle fibers with distinctive characteristics. Oxidative muscle fiber types contain higher mitochondrial content, relying...
Skeletal muscle is composed of bundles of muscle fibers with distinctive characteristics. Oxidative muscle fiber types contain higher mitochondrial content, relying primarily on oxidative phosphorylation for ATP generation. Notably, as a result of obesity, or following prolonged exposure to a high-fat diet, skeletal muscle undergoes a shift in fiber type toward a glycolytic type. Mitochondria are highly dynamic organelles, constantly undergoing mitochondrial biogenesis and dynamic processes. Our study aims to explore the impact of obesity on skeletal muscle mitochondrial biogenesis and dynamics and also ascertain whether the skeletal muscle fiber type shift occurs from the aberrant mitochondrial machinery. Furthermore, we investigated the impact of exercise in preserving the oxidative muscle fiber types despite obesity. Mice were subjected to a normal standard chow and water or high-fat diet with sugar water (HFS) with or without exercise training. After 12 weeks of treatment, the HFS diet resulted in a noteworthy reduction in the markers of mitochondrial content, which was recovered by exercise training. Furthermore, higher mitochondrial biogenesis markers were observed in the exercised group with a subsequent increase in the mitochondrial fission marker. In conclusion, these findings imply a beneficial impact of moderate-intensity exercise on the preservation of oxidative capacity in the muscle of obese mouse models.
Topics: Animals; Obesity; Diet, High-Fat; Physical Conditioning, Animal; Organelle Biogenesis; Muscle, Skeletal; Mice; Male; Disease Models, Animal; Mitochondria, Muscle; Mice, Inbred C57BL; Biomarkers; Mitochondrial Dynamics; Muscle Fibers, Skeletal
PubMed: 38931191
DOI: 10.3390/nu16121836