SASAN: Spectrum-Axial Spatial Approach Networks for Medical Image Segmentation.

Ophthalmic diseases such as central serous chorioretinopathy (CSC) significantly impair the vision of millions of people globally. Precise segmentation of choroid and macular edema is critical for diagnosing and treating these conditions. However, existing 3D medical image segmentation methods often fall short due to the heterogeneous nature and blurry features of these conditions, compounded by medical image clarity issues and noise interference arising from equipment and environmental limitations. To address these challenges, we propose the Spectrum Analysis Synergy Axial-Spatial Network (SASAN), an approach that innovatively integrates spectrum features using the Fast Fourier Transform (FFT). SASAN incorporates two key modules: the Frequency Integrated Neural Enhancer (FINE), which mitigates noise interference, and the Axial-Spatial Elementum Multiplier (ASEM), which enhances feature extraction. Additionally, we introduce the Self-Adaptive Multi-Aspect Loss (LSM), which balances image regions, distribution, and boundaries, adaptively updating weights during training. We compiled and meticulously annotated the Choroid and Macular Edema OCT Mega Dataset (CMED-18k), currently the world's largest dataset of its kind. Comparative analysis against 13 baselines shows our method surpasses these benchmarks, achieving the highest Dice scores and lowest HD95 in the CMED and OIMHS datasets. Our code is publicly available at https://github.com/IMOP-lab/SASAN-Pytorch.

Recent Progress in Improving Rate Performance of Cellulose-Derived Carbon Materials for Sodium-Ion Batteries.

Cellulose-derived carbon is regarded as one of the most promising candidates for high-performance anode materials in sodium-ion batteries; however, its poor rate performance at higher current density remains a challenge to achieve high power density sodium-ion batteries. The present review comprehensively elucidates the structural characteristics of cellulose-based materials and cellulose-derived carbon materials, explores the limitations in enhancing rate performance arising from ion diffusion and electronic transfer at the level of cellulose-derived carbon materials, and proposes corresponding strategies to improve rate performance targeted at various precursors of cellulose-based materials. This review also presents an update on recent progress in cellulose-based materials and cellulose-derived carbon materials, with particular focuses on their molecular, crystalline, and aggregation structures. Furthermore, the relationship between storage sodium and rate performance the carbon materials is elucidated through theoretical calculations and characterization analyses. Finally, future perspectives regarding challenges and opportunities in the research field of cellulose-derived carbon anodes are briefly highlighted.

Woven fabric-based separators with low tortuosity for sodium-ion batteries.

In order to achieve high-performance and stable sodium-ion batteries, numerous attempts have been made to construct continuous ion transport pathways, in which a separator is one of the key components that affects the battery performance. In this study, a novel low-tortuosity woven fabric separator is fabricated by combining a weaving technique with a cellulose-solution method, followed by an infusion of a TEMPO-oxidized bacterial cellulose slurry into woven fabric substrates. The macropores in the fabric combine with the micropores in the oxidized bacterial cellulose to form a separator with a suitable pore structure and low tortuosity, forming a continuous sodium ion transport channel within the sodium-ion battery and effectively enhancing ion transport dynamics. The results show that, compared with a commercial polypropylene separator, the TEMPO-oxidized bacterial cellulose-woven fabric separator has a special weaving structure and lower tortuosity (0.77), as well as significant advantages in tensile strength (3.07 MPa), ionic conductivity (1.15 mS c), ionic transfer number (0.75), thermal stability, and electrochemical stability. This novel and simple preparation method provides new possibilities for achieving high-performance separators of sodium-ion batteries through rational structural design by textile technology.

Low-input lipidomics reveals lipid metabolism remodelling during early mammalian embryo development.

Lipids are indispensable for energy storage, membrane structure and cell signalling. However, dynamic changes in various categories of endogenous lipids in mammalian early embryonic development have not been systematically characterized. Here we comprehensively investigated the dynamic lipid landscape during mouse and human early embryo development. Lipid signatures of different developmental stages are distinct, particularly for the phospholipid classes. We highlight that the high degree of phospholipid unsaturation is a conserved feature as embryos develop to the blastocyst stage. Moreover, we show that lipid desaturases such as SCD1 are required for in vitro blastocyst development and blastocyst implantation. One of the mechanisms is through the regulation of unsaturated fatty-acid-mediated fluidity of the plasma membrane and apical proteins and the establishment of apical-basal polarity during development of the eight-cell embryo to the blastocyst. Overall, our study provides an invaluable resource about the remodelling of the endogenous lipidome in mammalian preimplantation embryo development and mechanistic insights into the regulation of embryogenesis and implantation by lipid unsaturation.

Segmentation of Low-Light Optical Coherence Tomography Angiography Images under the Constraints of Vascular Network Topology.

Optical coherence tomography angiography (OCTA) offers critical insights into the retinal vascular system, yet its full potential is hindered by challenges in precise image segmentation. Current methodologies struggle with imaging artifacts and clarity issues, particularly under low-light conditions and when using various high-speed CMOS sensors. These challenges are particularly pronounced when diagnosing and classifying diseases such as branch vein occlusion (BVO). To address these issues, we have developed a novel network based on topological structure generation, which transitions from superficial to deep retinal layers to enhance OCTA segmentation accuracy. Our approach not only demonstrates improved performance through qualitative visual comparisons and quantitative metric analyses but also effectively mitigates artifacts caused by low-light OCTA, resulting in reduced noise and enhanced clarity of the images. Furthermore, our system introduces a structured methodology for classifying BVO diseases, bridging a critical gap in this field. The primary aim of these advancements is to elevate the quality of OCTA images and bolster the reliability of their segmentation. Initial evaluations suggest that our method holds promise for establishing robust, fine-grained standards in OCTA vascular segmentation and analysis.

MAGPIE: accurate pathogenic prediction for multiple variant types using machine learning approach.

Identifying pathogenic variants from the vast majority of nucleotide variation remains a challenge. We present a method named Multimodal Annotation Generated Pathogenic Impact Evaluator (MAGPIE) that predicts the pathogenicity of multi-type variants. MAGPIE uses the ClinVar dataset for training and demonstrates superior performance in both the independent test set and multiple orthogonal validation datasets, accurately predicting variant pathogenicity. Notably, MAGPIE performs best in predicting the pathogenicity of rare variants and highly imbalanced datasets. Overall, results underline the robustness of MAGPIE as a valuable tool for predicting pathogenicity in various types of human genome variations. MAGPIE is available at https://github.com/shenlab-genomics/magpie .

Spatiotemporal Modulated Scaffold for Endogenous Bone Regeneration via Harnessing Sequentially Released Guiding Signals.

The design of a scaffold that can regulate the sequential differentiation of bone marrow mesenchymal stromal cells (BMSCs) according to the endochondral ossification (ECO) mechanism is highly desirable for effective bone regeneration. In this study, we successfully fabricated a dual-networked composite hydrogel composed of gelatin and hyaluronic acid (termed GCDH-M), which can sequentially release chondroitin sulfate (CS) and magnesium/silicon (Mg/Si) ions to provide spatiotemporal guidance for chondrogenesis, angiogenesis, and osteogenesis. The fast release of CS is from the GCDH hydrogel, and the sustained releases of Mg/Si ions are from poly(lactide-co-glycolide) microspheres embedded in the hydrogel. There is a difference in the release rates between CS and ions, resulting in the ability for the fast release of CS and sustained release of ions. The dual networks between the modified gelatin and hyaluronic acid via covalent bonding and host-guest interactions render the hydrogel with some dynamic feature to meet the differentiation development of BMSCs laden inside the hydrogel, i.e., transforming into a chondrogenic phenotype, further to a hypertrophic phenotype and eventually to an osteogenic phenotype. As evidenced by the results of in vitro and in vivo evaluations, this GCDH-M composite hydrogel was proved to be able to create an optimal microenvironment for embedded BMSCs responding to the sequential guiding signals, which aligns with the rhythm of the ECO process and ultimately boosts bone regeneration. The promising outcome achieved with this innovative hydrogel system sheds light on novel scaffold design targeting bone tissue engineering.

De novo identification of expressed cancer somatic mutations from single-cell RNA sequencing data.

Identifying expressed somatic mutations from single-cell RNA sequencing data de novo is challenging but highly valuable. We propose RESA - Recurrently Expressed SNV Analysis, a computational framework to identify expressed somatic mutations from scRNA-seq data. RESA achieves an average precision of 0.77 on three in silico spike-in datasets. In extensive benchmarking against existing methods using 19 datasets, RESA consistently outperforms them. Furthermore, we applied RESA to analyze intratumor mutational heterogeneity in a melanoma drug resistance dataset. By enabling high precision detection of expressed somatic mutations, RESA substantially enhances the reliability of mutational analysis in scRNA-seq. RESA is available at https://github.com/ShenLab-Genomics/RESA .

Beyond radiologist-level liver lesion detection on multi-phase contrast-enhanced CT images by deep learning.

Accurate detection of liver lesions from multi-phase contrast-enhanced CT (CECT) scans is a fundamental step for precise liver diagnosis and treatment. However, the analysis of multi-phase contexts is heavily challenged by the misalignment caused by respiration coupled with the movement of organs. Here, we proposed an AI system for multi-phase liver lesion segmentation (named MULLET) for precise and fully automatic segmentation of real-patient CECT images. MULLET enables effectively embedding the important ROIs of CECT images and exploring multi-phase contexts by introducing a transformer-based attention mechanism. Evaluated on 1,229 CECT scans from 1,197 patients, MULLET demonstrated significant performance gains in terms of Dice, Recall, and F2 score, which are 5.80%, 6.57%, and 5.87% higher than state of the arts, respectively. MULLET has been successfully deployed in real-world settings. The deployed AI web server provides a powerful system to boost clinical workflows of liver lesion diagnosis and could be straightforwardly extended to general CECT analyses.

Assessment of visual function in blind mice and monkeys with subretinally implanted nanowire arrays as artificial photoreceptors.

Retinal prostheses could restore image-forming vision in conditions of photoreceptor degeneration. However, contrast sensitivity and visual acuity are often insufficient. Here we report the performance, in mice and monkeys with induced photoreceptor degeneration, of subretinally implanted gold-nanoparticle-coated titania nanowire arrays providing a spatial resolution of 77.5 µm and a temporal resolution of 3.92 Hz in ex vivo retinas (as determined by patch-clamp recording of retinal ganglion cells). In blind mice, the arrays allowed for the detection of drifting gratings and flashing objects at light-intensity thresholds of 15.70-18.09 µW mm-2, and offered visual acuities of 0.3-0.4 cycles per degree, as determined by recordings of visually evoked potentials and optomotor-response tests. In monkeys, the arrays were stable for 54 weeks, allowed for the detection of a 10-µW mm-2 beam of light (0.5° in beam angle) in visually guided saccade experiments, and induced plastic changes in the primary visual cortex, as indicated by long-term in vivo calcium imaging. Nanomaterials as artificial photoreceptors may ameliorate visual deficits in patients with photoreceptor degeneration.

Hydralazine inhibits neuroinflammation and oxidative stress in APP/PS1 mice via TLR4/NF-κB and Nrf2 pathways.

Alzheimer's disease (AD) is a common chronic progressive neurodegenerative disorder, and curative treatment has not been developed. The objective of this study was to investigate the potential effects of hydralazine (Hyd, a hypertension treatment drug) on the development process of AD and its mechanisms. We treated 6-month-old male APP/PS1 mice with Hyd for 5 weeks, measured changes in behavior and pathological status, and analyzed differences in gene expression by RNA sequencing. The results demonstrated that Hyd improved cognitive deficits and decreased amyloid beta protein deposition in the cortex and hippocampus, while RNA sequencing analysis suggested that the regulation of neuroinflammation and energy metabolism might play pivotal roles for Hyd's beneficial effects. Therefore, we further investigated inflammatory response, redox state, and mitochondrial function, as well as the expression of toll-like receptor 4 (TLR4)/nuclear factor Kappa B (NF-κB)-dependent neuroinflammation gene and nuclear factor erythroid 2-related factor 2 (Nrf2)-mediated antioxidant gene in AD mice. The results showed that Hyd reduced the damage of neuroinflammation and oxidative stress, improved mitochondrial dysfunction, downregulated pro-inflammation gene expression, and upregulated antioxidant gene expression. The results in lipopolysaccharide (LPS)-induced BV2 cell model demonstrated that Hyd suppressed pro-inflammatory response via TLR4/NF-κB signaling pathway. In addition, by silencing the Nrf2 gene expression, it was found that Hyd can reduce LPS-induced reactive oxygen species production by activating the Nrf2 signaling pathway. Therefore, administration of Hyd in the early stage of AD might be beneficial in delaying the pathological development of AD via inhibiting neuroinflammation and oxidative stress.

Temporally integrated transcriptome analysis reveals ASFV pathology and host response dynamics.

African swine fever virus (ASFV) causes a lethal swine hemorrhagic disease and is currently responsible for widespread damage to the pig industry. The pathogenesis of ASFV infection and its interaction with host responses remain poorly understood. In this study, we profiled the temporal viral and host transcriptomes in porcine alveolar macrophages (PAMs) with virulent and attenuated ASFV strains. We identified profound differences in the virus expression programs between SY18 and HuB20, which shed light on the pathogenic functions of several ASFV genes. Through integrated computational analysis and experimental validation, we demonstrated that compared to the virulent SY18 strain, the attenuated HuB20 quickly activates expression of receptors, sensors, regulators, as well as downstream effectors, including cGAS, STAT1/2, IRF9, MX1/2, suggesting rapid induction of a strong antiviral immune response in HuB20. Surprisingly, in addition to the pivotal DNA sensing mechanism mediated by cGAS-STING pathway, infection of the DNA virus ASFV activates genes associated with RNA virus response, with stronger induction by HuB20 infection. Taken together, this study reveals novel insights into the host-virus interaction dynamics, and provides reference for future mechanistic studies of ASFV pathogenicity.

The complete chloroplast genome of a karst-dwelling plant Primulina tenuituba (Gesneriaceae).

Primulina tenuituba is a species in the Gesneriaceae family that is widely distributed in China. It is a karst-dwelling species with an enormous tolerance for extreme drought and high temperatures. The species is also used in traditional Chinese medicine. In this study, the complete chloroplast genome of P. tenuituba was assembled and characterized for the first time. The complete chloroplast genome exhibited a typical quadripartite cycle of 153,236 bp in length, including a pair of inverted repeats (IRs) of 25,494 bp, which were separated by a large single-copy (LSC) region of 84,364 bp and a small single copy (SSC) region of 17,884 bp. The GC content was 37.6%. The complete chloroplast genome of P. tenuituba contains 114 genes, including 80 protein-coding genes, 30 tRNAs genes, and four rRNAs. The phylogenetic analysis showed that P. tenuituba is closely related to P. eburnea. The newly reported chloroplast genome of P. tenuituba would provide valuable data for further studies on its evolution and adaptation mechanism.

Bacterial cellulose-derived micro/mesoporous carbon anode materials controlled by poly(methyl methacrylate) for fast sodium ion transport.

An advanced nanostructure with rational micro/mesoporous distribution plays an important role in achieving high electrochemical performance in sodium ion batteries (SIBs), especially the energy storage efficiency in the low-potential region during the charging/discharging processes. Here we propose a method of polymer-blended bacterial cellulose (BC) matrix to tune the micro/mesopores of polymer-BC derived carbon under a mild carbonization temperature. The targeted pore structure and electrochemical performance are optimized by controlling the amount of methyl methacrylate monomers via free-radical polymerization, and carbonized temperature via pyrolysis treatment. The constructed carbon materials display a stable 3D fibrous network with a large specific area and abundant micro/mesopores formed during the pyrolysis of the polymer poly(methyl methacrylate) (PMMA). Taking advantage of the constructed pore structure, the optimized carbon anodes derived from BC/PMMA composites show an enhanced Na+ diffusion rate with a high capacity of 380.66 mA h g-1 at 0.03 A g-1. It is interesting that it possesses superior low-potential capacity, and retains 42% of the total capacity even at a high scan rate of 1 mV s-1. The proposed method of polymer-blended on cellulose matrix provides an energy-efficient way to achieve high low-potential capacity under facile processing conditions for fast sodium ion transport in SIBs.

Nrf2 Deficiency Attenuates Testosterone Efficiency in Ameliorating Mitochondrial Function of the Substantia Nigra in Aged Male Mice.

Reduced testosterone level is a common feature of aging in men. Aging, as a risk factor for several neurodegenerative disorders, shows declined mitochondrial function and downregulated mitochondrial biogenesis and mitochondrial dynamics. Mitochondrial biogenesis and mitochondrial dynamics are crucial in maintaining proper mitochondrial function. Supplementation with testosterone is conducive to improving mitochondrial function of males during aging. Nuclear factor erythroid 2-related factor 2 (Nrf2), a regulator of redox homeostasis, is involved in the ameliorative effects of testosterone supplementation upon aging. To explore Nrf2 role in the effects of testosterone supplementation on mitochondrial function during aging, we studied the efficiency of testosterone supplementation in improving mitochondrial function of Nrf2 knockout- (KO-) aged male mice by analyzing the changes of mitochondrial biogenesis and mitochondrial dynamics. It was found that wild-type- (WT-) aged male mice showed low mitochondrial function and expression levels of PGC-1α, NRF-1\NRF-2, and TFAM regulating mitochondrial biogenesis, as well as Drp1, Mfn1, and OPA1 controlling mitochondrial dynamics in the substantia nigra (SN). Nrf2 KO aggravated the defects above in SN of aged male mice. Testosterone supplementation to WT-aged male mice significantly ameliorated mitochondrial function and upregulated mitochondrial biogenesis and mitochondrial dynamics, which were not shown in Nrf2 KO-aged male mice due to Nrf2 deficiency. Testosterone deficiency by gonadectomy (GDX) decreased mitochondrial function, downregulated mitochondrial biogenesis, and altered mitochondrial dynamics balance in young male mice. Supplementation with testosterone to Nrf2 KO-GDX mice only ameliorated the alterations above but did not reverse them to sham level. Nrf2 deficiency attenuated testosterone efficiency in ameliorating mitochondrial function in the SN of aged male mice through mitochondrial biogenesis and mitochondrial dynamics to some extent. Activation of Nrf2 might contribute to testosterone-upregulating mitochondrial biogenesis and mitochondrial dynamics in the SN during aging to produce efficient mitochondria for ATP production.

StructADMM: Achieving Ultrahigh Efficiency in Structured Pruning for DNNs.

Weight pruning methods of deep neural networks (DNNs) have been demonstrated to achieve a good model pruning rate without loss of accuracy, thereby alleviating the significant computation/storage requirements of large-scale DNNs. Structured weight pruning methods have been proposed to overcome the limitation of irregular network structure and demonstrated actual GPU acceleration. However, in prior work, the pruning rate (degree of sparsity) and GPU acceleration are limited (to less than 50%) when accuracy needs to be maintained. In this work, we overcome these limitations by proposing a unified, systematic framework of structured weight pruning for DNNs. It is a framework that can be used to induce different types of structured sparsity, such as filterwise, channelwise, and shapewise sparsity, as well as nonstructured sparsity. The proposed framework incorporates stochastic gradient descent (SGD; or ADAM) with alternating direction method of multipliers (ADMM) and can be understood as a dynamic regularization method in which the regularization target is analytically updated in each iteration. Leveraging special characteristics of ADMM, we further propose a progressive, multistep weight pruning framework and a network purification and unused path removal procedure, in order to achieve higher pruning rate without accuracy loss. Without loss of accuracy on the AlexNet model, we achieve 2.58× and 3.65× average measured speedup on two GPUs, clearly outperforming the prior work. The average speedups reach 3.15× and 8.52× when allowing a moderate accuracy loss of 2%. In this case, the model compression for convolutional layers is 15.0× , corresponding to 11.93× measured CPU speedup. As another example, for the ResNet-18 model on the CIFAR-10 data set, we achieve an unprecedented 54.2× structured pruning rate on CONV layers. This is 32× higher pruning rate compared with recent work and can further translate into 7.6× inference time speedup on the Adreno 640 mobile GPU compared with the original, unpruned DNN model. We share our codes and models at the link http://bit.ly/2M0V7DO.

Pentoxifylline Enhances Antioxidative Capability and Promotes Mitochondrial Biogenesis in D-Galactose-Induced Aging Mice by Increasing Nrf2 and PGC-1α through the cAMP-CREB Pathway.

Aging is a complex phenomenon associated with oxidative stress and mitochondrial dysfunction. The objective of this study was to investigate the potential ameliorative effects of the phosphodiesterase inhibitor pentoxifylline (PTX) on the aging process and its underlying mechanisms. We treated D-galactose- (D-gal-) induced aging mice with PTX and measured the changes in behavior, degree of oxidative damage, and mitochondrial ultrastructure and content as well as the expression of nuclear factor erythroid 2-related factor 2- (Nrf2-) mediated antioxidant genes and peroxisome proliferator-activated receptor-gamma coactivator 1-alpha- (PGC-1α-) dependent mitochondrial biogenesis genes. The results demonstrated that PTX improved cognitive deficits, reduced oxidative damage, ameliorated abnormal mitochondrial ultrastructure, increased mitochondrial content and Nrf2 activation, and upregulated antioxidant and mitochondrial biogenesis gene expression in the hippocampus of wild-type aging mice. However, the above antiaging effects of PTX were obviously decreased in the brains of Nrf2-deficient D-gal-induced aging mice. Moreover, in hydrogen peroxide-treated SH-SY5Y cells, we found that cyclic adenosine monophosphate (cAMP) response element-binding protein (CREB) and Nrf2/PGC-1α act in a linear way by CREB siRNA transfection. Thus, PTX administration improved the aging-related decline in brain function by enhancing antioxidative capability and promoting mitochondrial biogenesis, which might depend on increasing Nrf2 and PGC-1α by activating the cAMP-CREB pathway.

Testosterone ameliorates age-related brain mitochondrial dysfunction.

Brain mitochondrial dysfunction and reduced testosterone levels are common features of aging in men. Although evidence suggests that the two phenomena are interrelated, it is unclear whether testosterone supplementation ameliorates mitochondrial dysfunction in the aging male brain. Here, we show that testosterone supplementation significantly alleviates exploratory behavioral deficits and oxidative damage in the substantia nigra and hippocampus of aging male rats. These effects were consistent with improved mitochondrial function, reflected by testosterone-induced increases in mitochondrial membrane potential (MMP), antioxidant enzyme (GSH-PX, catalase, and Mn-SOD) expression/activity, and mitochondrial respiratory complex activities in both brain regions. Furthermore, elevated PGC-1α, NRF-1, and TFAM expression (suggestive of enhanced mitochondrial biogenesis), increased citrate synthase activity, mtDNA copy number, and ND1, COX1, and ATP6 expression (indicative of increased mitochondrial content), as well as increased PINK1/Parkin and decreased P62 expression (suggesting mitophagy activation), were detected in the substantial nigra and hippocampus of aged male rats after testosterone supplementation. These findings suggest that testosterone supplementation may be a viable approach to ameliorating brain mitochondrial dysfunction and thus prevent or treat cognitive-behavioral deficits and neurodegenerative conditions associated with aging.

Parecoxib alleviates the motor behavioral decline of aged rats by ameliorating mitochondrial dysfunction in the substantia nigra via COX-2/PGE2 pathway inhibition.

Mitochondrial dysfunction manifests as an early event in the substantia nigra (SN) in aging and Parkinson disease. Cyclooxygenase 2 (COX-2), the rate-limiting enzyme in the prostaglandin E2 (PGE2) synthesis pathway, is implicated in aging and age-related neurodegenerative diseases; moreover, inhibition of COX-2 expression has been shown to be neuroprotective for nigrostriatal dopaminergic neurons. However, it is not known whether the neuroprotective effect of COX-2 inhibition is related to improved mitochondrial function during the aging process. To this end, we explored the effects of the selective COX-2 inhibitor parecoxib on mitochondrial function in the SN of aged rats. We found that parecoxib administration to aged rats for 10 weeks decreased COX-2/PGE2 expression, increased tyrosine hydroxylase and dopamine transporter expression in nigrostriatal dopaminergic neurons, and alleviated motor behavioral decline. Decreased malondialdehyde levels and an increased GSH/GSSG ratio as well as enhanced enzymatic activities of catalase and manganese superoxide dismutase in parecoxib-treated aged rats indicate that parecoxib administration elevated antioxidative ability in the SN during the aging process. Parecoxib treatment to aged rats promoted mitochondrial biogenesis by upregulating PGC-1α/NRF-1/TFAM, enhancing mitochondrial fusion by decreasing Drp1 levels and increasing Mfn1 and OPA1 levels, and activated mitophagy by increasing PINK1/Parkin levels while reducing p62/SQSTM1 levels, thereby coordinating mitochondrial homeostasis via inhibiting the COX-2/PGE2 pathway. Thus, our results strongly support the conclusion that parecoxib treatment is conducive to improving mitochondrial dysfunction in the SN upon aging in rats.

Pentoxifylline enhances antioxidative capability and promotes mitochondrial biogenesis for improving age-related behavioral deficits.

Pentoxifylline (PTX) is a non-specific phosphodiesterase inhibitor with pleiotropic effects that is routinely used to treat peripheral vascular disease. In this study, we tested whether PTX could also counteract the detrimental effects of aging in the brain. To accomplish that, we treated aged rats with PTX and measured resulting behavioral alterations as well as changes in dopaminergic neurochemical levels, oxidative balance markers, mitochondrial function, nuclear factor erythroid 2-related factor 2 (Nrf2), peroxisome proliferator activated receptor-gamma coactivator 1-alpha (PGC-1α) and downstream gene expression, and cyclic adenosine monophosphate (cAMP) content in the brain. The results demonstrated that PTX improved motor and cognitive deficits and restored levels of dopamine and its metabolites in the brains of aged rats. PTX also reduced malondialdehyde levels and increased the GSH/GSSG ratio, mitochondrial ATP, nuclear Nrf2, and cAMP levels, and upregulated PGC-1α, nuclear respiratory factor 1, and mitochondrial transcription factor A expression in the substantia nigra and hippocampus of aged rats. Thus, increased nuclear Nrf2 levels and upregulation of PGC-1α, which enhance antioxidative capability and promote mitochondrial biogenesis, may be responsible for PTX-induced amelioration of behavioral deficits in aged rats.