Acta Biochimica et Biophysica Sinica

The activation of thermogenesis in brown adipose tissue (BAT) represents a pivotal target for ameliorating disorders of glucose and lipid metabolism. This study sought to elucidate the regulatory effects of quercetin on thermogenesis and glucose-lipid metabolism within brown adipocytes, alongside its underlying molecular mechanisms. The findings demonstrated that quercetin markedly upregulated the expression of uncoupling protein 1 (UCP1), a critical thermogenic protein in brown adipocytes, thereby enhancing cellular thermogenic capacity and effectively mitigating glucose and lipid metabolism disorders. Subsequent mechanistic investigations confirmed that quercetin activated the COX2-PGE2-EP4-UCP1 signaling axis by augmenting the stability of cyclooxygenase 2 (COX2) protein, thus mediating its thermogenic-promoting and metabolism-improving effects. This study identifies quercetin as a potential therapeutic agent for the improvement of glucose and lipid metabolism disorders, uncovers a novel molecular mechanism through which quercetin regulates brown adipocyte thermogenesis, and provides a theoretical and experimental foundation for the application of quercetin in the prevention and treatment of obesity and related metabolic diseases.

The mosquito stage of the Plasmodium falciparum life cycle is an attractive target for intervention since it is crucial for the sexual reproduction and transmission of parasites to human host. Mosquito determinants crucial for parasite infection and growth pose as lucrative targets for transmission blockers. Owing to the fact that p38 MAPK has role in immune response and vector competence, we have evaluated the potential of PROTAC molecule (NR-7h) to degrade Anopheles stephensi p38 MAPK (Asp38 MAPK), a conserved serine/threonine kinase involved in stress reactions, midgut homeostasis, and parasite survival. PROTAC-mediated degradation of Asp38 MAPK led to the disrupted development of the parasite, suggesting its crucial function in vector competence. Furthermore, NR-7h-treated mosquitoes showed higher expression of immune genes such Rel-2, TEP1, APL1, and NOS, suggesting that p38 MAPK regulates host immunity in a way that promotes parasite persistence. PROTAC-mediated degradation of target proteins, provides a more persistent and resistance-proof therapeutic effect than traditional kinase inhibitors. Our findings establish PROTACs as a novel vector-targeted strategy for the development of endectocides to limit malaria transmission.

Ferroptosis is linked to various diseases, but the role of transferrin (TF) in endometriosis (EM) remains unclear. Expression levels of ferroptosis-related proteins, including transferrin (TF), transferrin receptor (TFRC), and glutathione peroxidase 4 (GPX4), were analyzed by western blotting. Compared to normal endometrial stromal cells, eutopic and ectopic endometrial stromal cells from EM patients exhibited significantly enhanced proliferative and migratory abilities, accompanied by a marked reduction in glutathione (GSH) levels in both eutopic and ectopic tissues. TF and TFRC expression was upregulated in ectopic endometrium relative to normal controls, while GPX4 expression was downregulated. To evaluate the functional role of TF, siRNA-mediated knockdown was performed in endometrial stromal cells, with knockdown efficiency confirmed by western blotting. Functional assays demonstrated that TF knockdown not only suppressed cell proliferation (CCK-8 and clonogenic assays) and migration (wound healing assay) but also significantly increased apoptosis rate (flow cytometry with Annexin V-FITC/PI staining).These findings implicate TF in the pathogenesis and progression of endometriosis, likely through modulating endometrial stromal cell proliferation, migration, and apoptosis.

This study investigates the therapeutic potential of secretomes derived from Adipose-derived Mesenchymal Stem Cells (ADMSC-CM) and Limbal-derived Mesenchymal Stem Cells (LMSC-CM) against oxidative stress-induced damage in Retinal Pigment Epithelium (RPE-1) cells. RPE dysfunction, often triggered by oxidative stress, is a hallmark of various retinal degenerations. Here, we induced RPE-1 injury using H2O2 and evaluated the restorative effects of both MSC-conditioned media (CM). Our results demonstrated that both ADMSC-CM and LMSC-CM significantly enhanced cell viability and successfully reversed H2O2-induced G2/M phase cell cycle arrest. While oxidative stress triggered a pro-inflammatory response characterized by elevated IL-1{beta}, IL-6, and IL-10 expression, MSC-CM treatment, particularly ADMSC-CM, effectively modulated these levels and suppressed the p38 MAPK signaling pathway. Furthermore, MSC-CM reduced the Bax/Bcl-2 ratio, indicating an anti-apoptotic effect, and appeared to stabilize autophagic flux. To investigate the impact of oxidative-stress induced alterations in retinal pigment epithelial cells on angiogenesis, the effects of RPE-derived secreted factors on endothelial cell function were evaluated. Crucially, in terms of safety and secondary complications, neither secretome exhibited pro-angiogenic tendencies; instead, they significantly inhibited HUVEC migration and invasion compared to the H2O2 damaged group. These findings suggest that both ADMSC and LMSC secretomes provide a potent multi-targeted therapeutic effect, making them promising candidates for cell-free therapies in retinal diseases.

Presenilin 1 (PS1), a key pathogenic factor in familial Alzheimers disease, is implicated in regulation of mitochondrial functions, yet its precise sub-mitochondrial localization and underlying mechanisms remain poorly understood. In this study, we generated PS1 knockout (PS1 KO) cell lines to investigate the role of PS1 in mitochondrial structure and function. Our results demonstrated that PS1 is directly localized to the mitochondrial inner membrane. PS1 deficiency led to reduced ATP production, impaired mitochondrial respiration capacity, decreased mitochondrial membrane potential, disrupted Ca2+ homeostasis, and elevated reactive oxygen species (ROS) accumulation. Moreover, loss of PS1 caused abnormal mitochondrial cristae structure. Further analysis revealed that PS1 interacts with mitochondrial inner membrane proteins. Its absence promotes ATAD3A oligomerization and disrupts its arrangement at mitochondrial cristae junctions, leading to expansion of the mitochondria-associated membrane (MAM) and instability of mitochondrial DNA (mtDNA). Our findings demonstrate that PS1 acts as a central regulator of mitochondrial cristae morphogenesis by modulating protein interaction networks at cristae junctions, thereby illuminating fundamental molecular mechanisms contributing to mitochondrial dysfunctions in Alzheimers disease.

ATAD2 possesses a C-terminal bromodomain (BRD) that plays a critical role in recognizing and binding to acetylated lysine residues. However, because the native intracellular structure of ATAD2 remains poorly defined, the mechanisms by which the ATAD2 BRD recruits acetylated histones and the regulatory pathways involved are not yet understood. In this study, we report that the ATAD2 BRD mediates the formation of liquid-liquid phase separation (LLPS) of ATAD2 in cells. This phase separation promotes the process of histone H4 acetylation, leading to the up-regulation of C-MYC, CCND3, and ATF2 gene expression and the facilitation of chromatin remodeling. Our findings elucidate a vital function of ATAD2, wherein BRD-mediated LLPS drives histone acetylation to promote cellular chromatin remodeling.

Myocardial ischemia-reperfusion injury significantly exacerbates cardiac damage and worsens clinical outcomes, with oxidative stress in cardiomyocytes representing a central pathological mechanism. In this study, we reveal that APEX1, a key redox regulator, is markedly downregulated in cardiomyocytes under oxidative stress conditions. Functional analyses demonstrate that APEX1 knockdown intensifies oxidative stress-induced cardiomyocyte injury, whereas APEX1 overexpression confers robust protection against hypoxia reoxygenation mediated damage. Mechanistically, APEX1 exerts its cardioprotective effects by stabilizing the p53 protein and modulating its ubiquitination status. These findings establish APEX1 as a critical defender against oxidative injury in cardiomyocytes through direct regulation of p53 protein stability, highlighting its potential as a therapeutic target for ischemia-reperfusion related heart disease.

Astrocytes play a key role in neuronal homeostasis and in various neural disorders. The generation of astrocytes from neural progenitor cells (NPCs) and its functions are under a complex control of several signaling networks and transcription factors. In this study, we demonstrate that the transcription factor, GLIS similar 3 (GLIS3), which has been implicated in several neurodegenerative diseases, is highly expressed in astrocytes, and is required for the efficient differentiation of human NPCs into astrocytes. Loss of GLIS3 function greatly impairs astrocytes differentiation, resulting in reduced expression of astrocyte markers, whereas expression of exogenous GLIS3 restores the induction of astrocyte specific genes indicating a critical role for GLIS3 in astrocyte differentiation. Integrated transcriptomic and cistromic analyses revealed that GLIS3 directly regulates the transcription of several astrocyte-associated genes, including GFAP, SLC1A2, NFIA, and ATF3, in coordination with lineage-determining factors, such as STAT3, NFIA, and SOX9. We hypothesize that GLIS3 dysfunction disrupts this transcriptional network thereby contributing to astrocyte-associated neurological disorders. Identification of GLIS3 as a key regulator of astrocyte differentiation and gene expression will advance our understanding of its role in neurodegenerative diseases and may provide a new therapeutic target.

Human papillomavirus 18 (HPV18) preferentially infects cervical stem cell-like cells and is strongly associated with adenocarcinoma. However, the mechanisms underlying differentiation into cervical adenocarcinoma remain unclear due to the lack of appropriate experimental models. We aimed to establish a model of HPV18-associated cervical adenocarcinoma and elucidate its molecular and cellular differentiation mechanisms. HPV18 E6/E7 were introduced into induced pluripotent stem cell-derived reserve cell-like cells (iRCs) to generate tumor models. Spatial transcriptomics and single-cell multi-omics analyses were performed to integrate histological and molecular data. A distinct component (Gland_A) exhibited morphological and immunohistochemical features of cervical adenocarcinoma and was efficiently induced in iRC-18 tumors. Gland_A showed increased chromatin accessibility and elevated expression of FOXA1, FOXA2, and ALDH1A1. Analysis of clinical samples confirmed enrichment of ALDH1A1 in HPV-associated adenocarcinomas. This model recapitulates key features of HPV18-associated cervical adenocarcinoma and provides insights into its differentiation mechanisms.

Alzheimers disease (AD) is a common neurodegenerative disorder primarily caused by Amyloid-beta (A{beta}) toxicity. Therefore, there is an urgent need to develop novel, effective, and safe drugs to treat AD. Traditional Chinese Medicine (TCM) has a long history of use in protecting against memory impairments. Recently, TCM has attracted growing attention from researchers as a source of potent neuroprotective compounds. In this study, we focus on four TCM herbs with multiple therapeutic properties: Valeriana jatamansi (V; 20 mg/mL), Acori tatarinowii (A; 10 mg/mL), Fructus Schisandrae (F; 5 mg/mL), and Scutellaria baicalensis (S; 2.5 mg/mL). The aim is to develop a neuroprotective anti-AD formulation, named "Zhi-Shi-Wu-Huang" derived from V, A, F, and S, and evaluate its efficacy in transgenic Caenorhabditis elegans models of AD. These four TCM herbs are among the most potent activators of the HSP-70 promoter, promoting the expression of heat shock protein 70 (HSP-70), which helps prevent protein misfolding and aggregation. Additionally, V, A, F, S, and the Zhi-Shi-Wu-Huang formula were found to reduce reactive oxygen species (ROS) production and enhance the expression of superoxide dismutase-3 (sod-3) and chymotrypsin-like proteasomes. Our findings demonstrate that both the individual extracts (V, A, F, S) and the Zhi-Shi-Wu-Huang formulation significantly reduce A{beta}-induced toxicity in transgenic worms by activating the insulin/DAF-16 signaling pathway.

Tumor heterogeneity highlights the necessity of precision cancer medicine, making the evaluation and screening of anticancer drugs a core challenge in cancer therapy. However, current cell-based efficacy assessment methods struggle to quantify the holistic impact of drugs on cellular behavior through specific target engagement. Here, we proposed a novel approach (DL-TCP-FRET) that integrates phenotypic and target-related evaluations: the logistic fitting analysis is performed on time- and concentration-dependent cellular phenotypic characteristics to construct a phenotypic score (P), while a target score (T) is established based on the FRET efficiency between target proteins. These two scores were then further combined to generate a unified drug efficacy score (PT). Validation in A549 cells demonstrated that our method can reliably distinguish EGFR-TKIs from non-targeted drugs. DL-TCP-FRET simplifies the experimental workflow of drug efficacy evaluation and improves the accuracy of targeted drug identification, providing a novel strategy for advancing precision cancer therapy.

Mesenchymal stem cells (MSCs) have garnered significant attention over the past three decades due to their robust regenerative potential, primarily mediated by their paracrine activity by releasing soluble bioactive factors and extracellular vesicles (EVs). The MSC secretome plays a pivotal role in wound healing by influencing cellular migration, inflammation, angiogenesis, extracellular matrix (ECM) remodeling, and re-epithelialization. SPARC (Secreted Protein Acidic and Rich in Cysteine), a multifunctional ECM glycoprotein involved in tissue repair and remodeling, regulates key processes such as cell migration, proliferation, angiogenesis, and survival. Despite its known role in ECM dynamics, the impact of SPARC expression on the regenerative properties of MSCs remains underexplored. In this study, we hypothesized that SPARC overexpression in MSCs enhances their secretomes regenerative capacity. Using lentiviral systems, we generated SPARC-overexpressing (+SPARC) and SPARC-knockdown (KD-SPARC) MSCs to investigate SPARCs role in wound healing. Conditioned media (CM) derived from these MSCs were analyzed in vitro for their effects on human skin keratinocytes and fibroblasts. Our results revealed that SPARC expression significantly influences cell-specific migration and cell cycle. Furthermore, in an in vivo wound healing model, CM from +SPARC MSCs accelerated regeneration, while SPARC absence in MSCs CM delayed the healing process. These findings underscore the critical role of SPARC in modulating MSC secretome composition and enhancing its regenerative efficacy. This study highlights SPARC as a promising therapeutic target for the development of advanced regenerative therapies aimed at improving cutaneous wound healing outcomes.

Brutons tyrosine kinase (BTK) has been reported to be important in the inflammatory response in many diseases. However, its role and explicit mechanisms in intracerebral hemorrhage (ICH) remain unclear. Here, we used a mouse ICH model and transcriptomic datasets to explore the effect of BTK on neuroinflammation after ICH. Inhibiting BTK with ibrutinib alleviated ICH-induced neurological deficits and neuroinflammation in mice. After analyzing RNA-sequencing data of ICH and control mice by weighted gene co-expression network analysis (WGCNA) and protein-protein interaction (PPI) analysis, we found that Btk was a hub gene in the green dynamic module. Also, 12 hub genes that closely interacted with BTK were identified in the key gene module, all having a critical role in the inflammatory process. Then, single cell RNA-sequencing data analysis showed that microglia were the immune cells that expressed the most BTK in the mouse brain. After dividing microglia in ICH mice into BTK_high and BTK_low groups, GO/KEGG enrichment analyses of differentially expressed genes (DEGs) between these two microglia groups revealed that most of the top 30 enriched pathways were immune-related. Then, gene set enrichment analysis (GSEA) of the BTK_high and BTK_low microglia showed that the expression levels of four anti-inflammatory and phagocytosis-related pathways were significantly lower in the BTK_high microglia than in the BTK_low microglia. Furthermore, gene set variation analysis (GSVA) demonstrated that multiple immune pathways were expressed differentially between the two microglia groups. Also, six microglia polarization scores were calculated, and the results showed that the BTK_high microglia tend to polarize towards M1 and M2b states, while the BTK_high microglia towards M2 (M2a, M2c) states. Finally, intercellular communication analysis was conducted, and BTK was revealed to promote communication between microglia and other immune cells both at the general level and in specific inflammatory pathways. In conclusion, our study showed that BTK is critical in promoting post-ICH neuroinflammation, at least partly by interacting with Btk-related hub genes and modulating microglias immune pathways, polarization, and intercellular communication.

Cisplatin is a cornerstone chemotherapeutic agent for a broad spectrum of solid malignancies, yet its clinical utility is substantially curtailed by dose-limiting organ toxicity, principally nephrotoxicity and hepatotoxicity, mediated through reactive oxygen species (ROS)-driven oxidative stress, glutathione depletion, and lipid peroxidation. Naringenin (NAR), a bioactive citrus flavanone, possesses potent free-radical scavenging, anti-inflammatory, and cytoprotective properties that make it a compelling candidate for chemoprotection. The present study investigated whether oral naringenin supplementation (50 mg/kg body weight/day for 30 days) could mitigate cisplatin-induced oxidative injury to the liver and kidney in male Swiss albino mice. Cisplatin was administered intraperitoneally at 2.3 mg/kg body weight in three cycles of five consecutive days followed by a five-day interval. Biochemical indices of oxidative stress, such as malondialdehyde (MDA), reduced glutathione (GSH), and glutathione S-transferase (GST) activity, were assayed in liver and kidney homogenates on day 45. Cisplatin administration significantly elevated hepatic and renal MDA levels, indicating pronounced lipid peroxidation, and markedly depleted the concentrations of GSH and the activity of GST in both organs. Compared with cisplatin alone, naringenin coadministration significantly attenuated the increase in the level of MDA, restored the level of GSH, and rescued the activity of GST in both tissues, with more pronounced effects in the kidney. Notably, compared with the control, naringenin alone did not alter any biochemical parameters, confirming its physiological safety at the administered dose. These findings demonstrate that naringenin has meaningful hepatoprotective and nephroprotective effects against cisplatin-induced oxidative toxicity, possibly through antioxidant augmentation, glutathione repletion, and membrane stabilization mechanisms. This study provides a rational preclinical basis for evaluating naringenin as a coadministered chemoprotectant in cisplatin-based chemotherapy regimens.

G-quadruplexes (G4s) are critical nucleic acid secondary structures that play pivotal roles in regulating gene expression. In this study, we conducted a proteome-wide in silico analysis across multiple viruses causing hemorrhagic fevers to identify candidate proteins containing a conserved G4-binding motif. Four peptides belonging to Marburg, Ebola, Hantaan and Yellow fever viruses were shown to bind to G4 in vitro. We selected the NS3 protease domain of Yellow Fever virus for further validation. Biochemical assays demonstrated that the NS3 protease domain binds G4 structures with high specificity and affinity, particularly favoring the parallel conformation. Molecular docking and simulations further revealed that the NS3 protease domain interacts with the terminal G-tetrads and loop regions of G4 via key residues, including PHE40, adopting an insertion and stacking composite binding mode. These findings expand our understanding of virus - G4 interactions and offer novel potential targets for G4-based antiviral strategies. Bullet points- We screened viruses causing hemorrhagic fevers for potential G4-binding peptides. - Four peptides belonging to Marburg, Ebola, Hantaan and Yellow fever viruses were shown to bind to G4 in vitro. - Biochemical assays demonstrated that the NS3 protease domain of YFV binds G4 structures with high specificity and affinity.

Long noncoding RNAs (LncRNAs) have emerged as a class of important regulatory ncRNAs and are known to fine-tune numerous cellular processes including proliferation, differentiation and development; however, their role in quiescence still remains largely unexplored. A miRNA host gene lncRNA, MIR503HG, has been reported to play important role in cancer development. Here, we demonstrate the role of MIR503HG lncRNA in regulating cellular quiescence. MIR503HG displays elevated levels in human diploid fibroblasts induced to undergo quiescence. Depletion of MIR503HG in HDFs affects the entry of cells into quiescence but has no effect on cell cycle progression, suggesting its role in quiescence attainment and/or maintenance. Additionally, MIR503HG depletion led to a drastic decrease in the levels of miR508 target, PTEN with a concomitant increase in pAkt levels, indicating its role in negative regulation of miR508. Further, we demonstrate that the lncRNA MIR503HG regulates PTEN levels by acting as a ceRNA for miR508 to maintain cellular quiescence. Our studies illustrate that MIR503HG can function synergistically with miR503 to maintain cells under quiescence and both the miRNA-HG and the miRNA encoded by its gene locus synergistically control the same biological process in different ways by regulating different downstream genes.

SGLT2 inhibitor (SGLT2i)-induced diabetic hyperketonemia is a life-threatening acute complication of diabetes. While Celastrol has been reported to exert beneficial effects on obesity; its potential role in ketogenesis remains unclear. In this study, Celastrol administration significantly attenuates the fasting-induced elevation of blood {beta}-hydroxybutyrate. Moreover, a 7-day course of Celastrol (1 mg/kg/day) leads to reductions in body weight and fat mass. Mechanistically, Celastrol specifically downregulates HMGCS2 expression and suppressess hepatic ketogenesis through inhibiting PPAR expression in the short term ([≤] 2 days). However, after prolonged treatment for 7 days, Celastrol modulates both PPARand serum free fatty acids (FFAs) levels. Furthermore, anti-ketogenic effect of Celastrol is abolished in Ppar{square} /{square} mice. Importantly, Celastrol effectively ameliorates SGLT2i-induced hyperketonemia. In summary, Celastrol curbs hepatic ketone overproduction in a PPAR-dependent manner, indicating its protective potential against SGLT2i-induced hyperketonemia.

The circadian clock maintains temporal control of metabolic processes and exerts a key role in adipocyte development. Discovery of clock-modulatory compounds may provide new avenues for metabolic disease therapy. Here we report the identification of flavonoid compounds, Quercetin and Fisetin, as clock-activating molecules with direct inhibitory action on adipogenesis and adipocyte lipid metabolism. Quercetin and Fisetin displayed robust ROR agonism that promoted clock oscillation with induction of clock genes. Treating preadipocytes with these compounds blocked their adipogenic differentiation. In mature adipocytes, Quercetin and Fisetin suppressed lipid accumulation by inhibiting lipogenic enzymes. Furthermore, activation of ROR by a synthetic agonist or ectopic expression were sufficient to inhibit adipogenesis. In mice treated with Quercetin or Fisetin, ROR was markedly induced in adipose depots with strong suppression of the adipogenic and lipogenic programs. While quercetin significantly attenuated lipid storage in adipose tissue in vivo accompanied with lowering of free fatty acids and improved insulin sensitivity, fisetin displayed a less robust effect with differential regulation of lipolytic pathway. Collectively, these findings uncovered the clock-activating properties of quercetin and fisetin that prevent adipocyte maturation and hypertrophy to limit adipose tissue expansion. These actions contribute, at least in part, to their beneficial effects on metabolic disorders.

Circular RNAs (circRNAs) originate from backsplicing of numerous genes in animals, but the functions of most circRNAs remain elusive. We previously demonstrated that circZNF827 forms a complex with hnRNPL/K and its host gene-encoded protein ZNF827 that acts in the nucleus to transcriptionally repress the nerve growth factor receptor (NGFR/p75NTR) gene during neuronal differentiation (Hollensen, 2020) [1]. To explore the mechanism of action, and to assess a potential role of the circZNF827-hnRNP complex on additional loci, we scrutinized the genome-wide consequences of circZNF827 and/or hnRNPL knockdown at the transcriptomic and epigenetic level. RNA-sequencing and CUT&RUN confirmed that NGFR and additional loci are transcriptionally repressed by the circZNF827-protein complex, and that these are primarily enriched for H3K27me3 signatures. Only a fraction of the massive transcriptomic changes could be ascribed to a direct circZNF827 transcription-regulated phenotype, suggesting that initial key regulatory events elicited by the circZNF827-hnRNP complex likely lead to a secondary response, which further augments neuronal differentiation.

During viral infection, viral replication perturbs endoplasmic reticulum (ER) homeostasis and triggers the unfolded protein response (UPR). XBP1s, a transcription factor generated by one branch of the UPR, is known to potentiate both innate and adaptive immunity, but its role in antiviral responses remains incompletely understood beyond its ability to augment type I interferon (IFN) mRNA induction. Here, we show that XBP1s positively regulates the RIG-I-like receptors (RLRs), ribonuclease L (RNase L), and protein kinase R (PKR) pathways, indicating that it enhances all three major antiviral response pathways. We further show that RNase L activation rapidly decreases XBP1 mRNA levels in an RNase activity-dependent manner, leading to a prompt reduction in XBP1s expression. Consistent with this, RNase L deletion significantly increased both thapsigargin-mediated XBP1s induction and XBP1s expression following Japan encephalitis virus infection. Poly(I:C)-induced IFNB mRNA expression was significantly enhanced in RNase L-knockout cells. This enhancement was completely abolished by RNase L reconstitution. XBP1 knockdown also significantly attenuated IFNB mRNA expression in RNase L-knockout cells. These findings suggest a negative-feedback loop in which RNase L suppresses XBP1s, thereby fine-tuning antiviral responsiveness during viral infection. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=77 SRC="FIGDIR/small/713401v1_ufig1.gif" ALT="Figure 1000"> View larger version (19K): org.highwire.dtl.DTLVardef@112d312org.highwire.dtl.DTLVardef@df79a9org.highwire.dtl.DTLVardef@1ac571borg.highwire.dtl.DTLVardef@18ac610_HPS_FORMAT_FIGEXP M_FIG C_FIG