Blocking the TRAIL-DR5 Pathway Reduces Cardiac Ischemia-Reperfusion Injury by Decreasing Neutrophil Infiltration and Neutrophil Extracellular Traps Formation.

PURPOSE: Acute myocardial infarction (AMI) is a leading cause of mortality. Neutrophils penetrate injured heart tissue during AMI or ischemia-reperfusion (I/R) injury and produce inflammatory factors, chemokines, and extracellular traps that exacerbate heart injury. Inhibition of the TRAIL-DR5 pathway has been demonstrated to alleviate cardiac ischemia-reperfusion injury in a leukocyte-dependent manner. However, it remains unknown whether TRAIL-DR5 signaling is involved in regulating neutrophil extracellular traps (NETs) release. METHODS: This study used various models to examine the effects of activating the TRAIL-DR5 pathway with soluble mouse TRAIL protein and inhibiting the TRAIL-DR5 signaling pathway using DR5 knockout mice or mDR5-Fc fusion protein on NETs formation and cardiac injury. The models used included a co-culture model involving bone marrow-derived neutrophils and primary cardiomyocytes and a model of myocardial I/R in mice. RESULTS: NETs formation is suppressed by TRAIL-DR5 signaling pathway inhibition, which can lessen cardiac I/R injury. This intervention reduces the release of adhesion molecules and chemokines, resulting in decreased neutrophil infiltration and inhibiting NETs production by downregulating PAD4 in neutrophils. CONCLUSION: This work clarifies how the TRAIL-DR5 signaling pathway regulates the neutrophil response during myocardial I/R damage, thereby providing a scientific basis for therapeutic intervention targeting the TRAIL-DR5 signaling pathway in myocardial infarction.

Mechanistic Insights into Oxidation of Benzaldehyde by Co-Peroxo Complexes.

Transition metal-peroxide complexes play a crucial role as intermediates in oxidation reactions. To unravel the mechanism of benzaldehyde oxidation by the Co-peroxo complex, we conducted density functional theory (DFT) calculations. The identified competing mechanisms include nucleophilic attack and hydrogen atom transfer (HAT). The nucleophilic attack pathway involves Co-O cleavage and nucleophilic attack, leading to the formation of the benzoate product. And the HAT pathway comprises O-O cleavage and HAT, ultimately resulting in the benzoate product. DFT calculations revealed that the formation of the end-on Co-superoxo complex 2 through Co-O cleavage, starting from the side-on Co-peroxo complex 1, is much more favorable than the formation of the two-terminal oxyl-radical intermediate 3 through O-O cleavage. Compared with the nucleophilic attack of benzaldehyde by 2, the abstraction of a hydrogen atom from benzaldehyde by 3 requires higher energy. The nature of the nucleophilicity of 2 and 3 accounts for the reactivity of the reaction.

The green tide causative-species Ulva prolifera responding to exposure to oil and dispersant.

In order to study the role of oil spills in the occurrence of green tide in the Yellow Sea, the physiological characteristics and photosynthetic activities of green tide causative-species Ulva prolifera was monitored under different conditions including two oil water-accommodated fractions (WAFs) of diesel oil and crude oil, dispersed water-accommodated fractions (DWAFs) and dispersant GM-2. The results showed that, the physiological parameters of U. prolifera including the growth, pigment, carbohydrate and protein contents decreased with the increased diesel oil WAF (WAFDO) concentration, while crude oil WAF (WAFCO) showed low concentration induction and high concentration inhibition effect. In addition, with the increase of WAFs concentration, two antioxidant activities were activated. However, compared with WAFDO alone and WAFCO alone, the mixture of oil and dispersant enhanced the toxicity on the above physiological characteristics of U. prolifera. On the other hand, the photosynthetic efficiency of U. prolifera showed a similar trend. Two WAFs showed significant concentration effects on the chlorophyll-a fluorescence transients and JIP-test. The addition of dispersant further blocked the electron flow beyond QA and from plastoquinone (PQ) to PSI acceptor side, damaged the active OEC centers at the PSII donor side, suppressed the pool size and the reduction rate of PSI acceptor side, and reduced the energy transfer efficiency between PSII functional units. These results implied that the crude oil spills may induce the formation of U. prolifera green tide, and the oil dispersant GM-2 used after the oil spills is unlikely to further stimulate the scale of bloom, while the diesel oil spills is always not conducive to the outbreak of green tide of U. prolifera.

Inhibition of METTL3 ameliorates doxorubicin-induced cardiotoxicity through suppression of TFRC-mediated ferroptosis.

BACKGROUND: Doxorubicin (DOX) is a chemotherapeutic drug, while its clinical use is greatly limited by the life-threatening cardiotoxicity. N6-methyladenosine (m6A) RNA modification participates in varieties of cellular processes. Nonetheless, it remains elusive whether m6A modification and its methyltransferase METTL3 are involved in the progression of DOX-induced cardiotoxicity (DIC). METHODS: Mice were administrated with DOX (accumulative dosage of 20 mg/kg) repeatedly to establish a chronic DIC model. Cardiomyocyte-specific conditional METTL3 knockout mice were employed to evaluate the effects of altered m6A RNA modification on DIC. The effects of METTL3 on cardiomyocyte ferroptosis were also examined in response to DOX stimulation. RESULTS: DOX led to increased levels in m6A modification and METTL3 expression in cardiomyocytes in a c-Jun-dependent manner. METTL3-knockout mice exhibited improved cardiac function, remodeling and injury following DOX insult. Besides, inhibition of METTL3 alleviated DOX-induced iron accumulation and ferroptosis in cardiomyocytes, whereas METTL3 overexpression exerted the opposite effects. Mechanistically, METTL3 promoted m6A modification of TFRC mRNA, a critical gene governing iron uptake, and enhanced its stability through recognition of the m6A reader protein, IGF2BP2. Moreover, pharmacological administration of a highly selective METTL3 inhibitor STM2457 effectively ameliorated DIC in mice. CONCLUSION: METTL3 plays a cardinal role in the etiology of DIC by regulating cardiac iron metabolism and ferroptosis through TFRC m6A modification. Inhibition of METTL3 might be a potential therapeutic avenue for DIC.

Survival outcome and optimal candidates of primary tumor resection for patients with metastatic medullary thyroid cancer.

CONTEXT: Medullary thyroid cancer (MTC) often exhibits aggressive growth with distant organ metastasis, leading to poor survival. OBJECTIVE: The question of whether primary tumor resection (PTR) is beneficial for patients with metastatic MTC remains a subject of debate. In this study, we evaluated the prognostic significance of organ-specific metastases and the number of metastatic organs in these patients, and we also conducted an analysis to determine the therapeutic value of PTR in managing this rare malignancy. MATERIALS AND METHODS: Patients initially diagnosed with metastatic MTC were identified within the Surveillance, Epidemiology, and End Results (SEER) database. Univariable and multivariable Cox proportional hazards regression models were performed to identify survival predictors. Survival outcomes were calculated using the Kaplan-Meier method and compared using the log-rank tests. RESULTS: A total of 186 patients with metastatic MTC at initial diagnosis from 2010 to 2020 were included. Bone, lung and liver were the most common metastatic organs. Patients with brain metastasis had significantly worse overall survival (OS) (p = 0.007) and cancer-specific survival (CSS) (p = 0.0013). Among all patients, 105 (56.45%) underwent PTR, and this group showed reduced overall mortality (OM) and cancer-specific mortality (CSM) (all p < 0.05). When analyzing different metastatic patterns, PTR significantly lowered the risk of OM and CSM for patients with bone, lung, liver, or distant lymph node (DLN) involvement (all p < 0.05). Additionally, among patients with one or two metastases, those undergoing surgical resection were significantly associated with favorable OS (p = 0.008) and CSS (p = 0.0247). CONCLUSIONS: PTR may confer therapeutic benefits for carefully selected individuals with metastatic MTCs. To integrate these insights into clinical decision-making settings, it is imperative to undertake multicenter prospective studies in the future.

iSCORE-PD: an isogenic stem cell collection to research Parkinson's Disease.

Parkinson's disease (PD) is a neurodegenerative disorder caused by complex genetic and environmental factors. Genome-edited human pluripotent stem cells (hPSCs) offer the uniique potential to advance our understanding of PD etiology by providing disease-relevant cell-types carrying patient mutations along with isogenic control cells. To facilitate this experimental approach, we generated a collection of 55 cell lines genetically engineered to harbor mutations in genes associated with monogenic PD (SNCA A53T, SNCA A30P, PRKN Ex3del, PINK1 Q129X, DJ1/PARK7 Ex1-5del, LRRK2 G2019S, ATP13A2 FS, FBXO7 R498X/FS, DNAJC6 c.801 A>G+FS, SYNJ1 R258Q/FS, VPS13C A444P, VPS13C W395C, GBA1 IVS2+1). All mutations were generated in a fully characterized and sequenced female human embryonic stem cell (hESC) line (WIBR3; NIH approval number NIHhESC-10-0079) using CRISPR/Cas9 or prime editing-based approaches. We implemented rigorous quality controls, including high density genotyping to detect structural variants and confirm the genomic integrity of each cell line. This systematic approach ensures the high quality of our stem cell collection, highlights differences between conventional CRISPR/Cas9 and prime editing and provides a roadmap for how to generate gene-edited hPSCs collections at scale in an academic setting. We expect that our isogenic stem cell collection will become an accessible platform for the study of PD, which can be used by investigators to understand the molecular pathophysiology of PD in a human cellular setting.

Comprehensive DNA Methylation Profiling of Medullary Thyroid Carcinoma: Molecular Classification, Potential Therapeutic Target, and Classifier System.

PURPOSE: Medullary thyroid carcinoma (MTC) presents a distinct biological context from other thyroid cancers due to its specific cellular origin. This heterogeneous and rare tumor has a high prevalence of advanced diseases, making it crucial to address the limited therapeutic options and enhance complex clinical management. Given the high clinical accessibility of methylation information, we construct the largest MTC methylation cohort to date. EXPERIMENTAL DESIGN: Seventy-eight fresh-frozen MTC samples constituted our methylation cohort. The comprehensive study process incorporated machine learning, statistical analysis, and in vitro experiments. RESULTS: Our study pioneered the identification of a three-class clustering system for risk stratification, exhibiting pronounced epigenomic heterogeneity. The elevated overall methylation status in MTC-B, combined with the "mutual exclusivity" of hypomethylated sites displayed by MTC-A and MTC-C, distinctively characterized the MTC-specific methylation pattern. Integrating with the transcriptome, we further depicted the features of these three clusters to scrutinize biological properties. Several MTC-specific aberrant DNA methylation events were emphasized in our study. NNAT expression was found to be notably reduced in poor-prognostic MTC-C, with its promoter region overlapping with an upregulated differentially methylated region. In vitro experiments further affirmed NNAT's therapeutic potential. Moreover, we built an elastic-net logistic regression model with a relatively high AUC encompassing 68 probes, intended for future validation and systematic clinical application. CONCLUSIONS: Conducting research on diseases with low incidence poses significant challenges, and we provide a robust resource and comprehensive research framework to assist in ongoing MTC case inclusion and facilitate in-depth dissection of its molecular biological features.

TBC1D15 deficiency protects against doxorubicin cardiotoxicity via inhibiting DNA-PKcs cytosolic retention and DNA damage.

Clinical application of doxorubicin (DOX) is heavily hindered by DOX cardiotoxicity. Several theories were postulated for DOX cardiotoxicity including DNA damage and DNA damage response (DDR), although the mechanism(s) involved remains to be elucidated. This study evaluated the potential role of TBC domain family member 15 (TBC1D15) in DOX cardiotoxicity. Tamoxifen-induced cardiac-specific Tbc1d15 knockout (Tbc1d15CKO) or Tbc1d15 knockin (Tbc1d15CKI) male mice were challenged with a single dose of DOX prior to cardiac assessment 1 week or 4 weeks following DOX challenge. Adenoviruses encoding TBC1D15 or containing shRNA targeting Tbc1d15 were used for Tbc1d15 overexpression or knockdown in isolated primary mouse cardiomyocytes. Our results revealed that DOX evoked upregulation of TBC1D15 with compromised myocardial function and overt mortality, the effects of which were ameliorated and accentuated by Tbc1d15 deletion and Tbc1d15 overexpression, respectively. DOX overtly evoked apoptotic cell death, the effect of which was alleviated and exacerbated by Tbc1d15 knockout and overexpression, respectively. Meanwhile, DOX provoked mitochondrial membrane potential collapse, oxidative stress and DNA damage, the effects of which were mitigated and exacerbated by Tbc1d15 knockdown and overexpression, respectively. Further scrutiny revealed that TBC1D15 fostered cytosolic accumulation of the cardinal DDR element DNA-dependent protein kinase catalytic subunit (DNA-PKcs). Liquid chromatography-tandem mass spectrometry and co-immunoprecipitation denoted an interaction between TBC1D15 and DNA-PKcs at the segment 594-624 of TBC1D15. Moreover, overexpression of TBC1D15 mutant (∆594-624, deletion of segment 594-624) failed to elicit accentuation of DOX-induced cytosolic retention of DNA-PKcs, DNA damage and cardiomyocyte apoptosis by TBC1D15 wild type. However, Tbc1d15 deletion ameliorated DOX-induced cardiomyocyte contractile anomalies, apoptosis, mitochondrial anomalies, DNA damage and cytosolic DNA-PKcs accumulation, which were canceled off by DNA-PKcs inhibition or ATM activation. Taken together, our findings denoted a pivotal role for TBC1D15 in DOX-induced DNA damage, mitochondrial injury, and apoptosis possibly through binding with DNA-PKcs and thus gate-keeping its cytosolic retention, a route to accentuation of cardiac contractile dysfunction in DOX-induced cardiotoxicity.

Extracellular vesicles in cardiovascular diseases: From pathophysiology to diagnosis and therapy.

Extracellular vesicles (EVs), encompassing exosomes, microvesicles (MVs), and apoptotic bodies (ABs), are cell-derived heterogeneous nanoparticles with a pivotal role in intercellular communication. EVs are enclosed by a lipid-bilayer membrane to escape enzymatic degradation. EVs contain various functional molecules (e.g., nucleic acids, proteins, lipids and metabolites) which can be transferred from donor cells to recipient cells. EVs provide many advantages including accessibility, modifiability and easy storage, stability, biocompatibility, heterogeneity and they readily penetrate through biological barriers, making EVs ideal and promising candidates for diagnosis/prognosis biomarkers and therapeutic tools. Recently, EVs were implicated in both physiological and pathophysiological settings of cardiovascular system through regulation of cell-cell communication. Numerous studies have reported a role for EVs in the pathophysiological progression of cardiovascular diseases (CVDs) and have evaluated the utility of EVs for the diagnosis/prognosis and therapeutics of CVDs. In this review, we summarize the biology of EVs, evaluate the perceived biological function of EVs in different CVDs along with a consideration of recent progress for the application of EVs in diagnosis/prognosis and therapies of CVDs.

Colonial morphology weakens the response of different inorganic carbon uptake systems to CO2 levels in Microcystis population.

Rising atmospheric CO2 concentration negatively impacts aquatic ecosystems and may induce evolutionary changes in the CO2-concentrating mechanism (CCM) of cyanobacteria. As the most notorious freshwater cyanobacteria, Microcystis strains have high phenotypic plasticity to form colonies and blooms in lakes and reservoirs worldwide. However, phenotypic plasticity of Microcystis responses to elevated CO2 is still a major open question. Here, we studied how Microcystis strains with two genotype of inorganic carbon uptake systems, bicA and sbtA, and different colonial morphology response to 200 ppm, 400 ppm, and 800 ppm CO2 levels. The results revealed that sbtA genotypes showed significantly higher specific growth rates, Chl a concentration, and photosynthetic efficiency at 200 ppm CO2, whereas higher specific growth rates, Chl a concentration, and photosynthetic efficiency were found in bicA genotype at 800 ppm CO2. The highest values of specific growth rates, Chl a concentration, Fv/Fm, and maximal net photosynthesis (Pm) were observed in unicellular morphology, followed by small colony and large colonial morphology at all CO2 levels. The values of K0.5 (DIC), K0.5 (CO2), and K0.5 (HCO3-) in the large colonials increased with rising CO2 levels, but these values significantly decreased in the unicellular and small colonials. ANOSIM analysis indicated that colonial morphology reduced significantly inter-group differences between bicA and sbtA genotypes at all CO2 treatments. These results suggest that colonial morphology of Microcystis can weakens the response of different inorganic carbon uptake systems to CO2 levels. Moreover, phenotypic and genotypic plasticity is likely to broaden strongly the fitness of Microcystis from rising atmospheric CO2.

DNA-dependent protein kinase catalytic subunit (DNA-PKcs) drives angiotensin II-induced vascular remodeling through regulating mitochondrial fragmentation.

BACKGROUND: DNA-dependent protein kinase catalytic subunit (DNA-PKcs) is a novel instigator for mitochondrial dysfunction, and plays an important role in the pathogenesis of cardiovascular diseases. However, the role and mechanism of DNA-PKcs in angiotensin II (Ang II)-induced vascular remodeling remains obscure. METHODS: Rat aortic smooth muscle cells (SMC) and VSMC-specific DNA-PKcs knockout (DNA-PKcsΔVSMC) mice were employed to examine the role of DNA-PKcs in vascular remodeling and the underlying mechanisms. Blood pressure of mice was monitored using the tail-cuff and telemetry methods. The role of DNA-PKcs in vascular function was evaluated using vascular relaxation assessment. RESULTS: In the tunica media of remodeled mouse thoracic aortas, and renal arteries from hypertensive patients, elevated DNA-PKcs expression was observed along with its cytoplasmic translocation from nucleus, suggesting a role for DNA-PKcs in vascular remodeling. We then infused wild-type (DNA-PKcsfl/fl) and DNA-PKcsΔVSMC mice with Ang II for 14 days to establish vascular remodeling, and demonstrated that DNA-PKcsΔVSMC mice displayed attenuated vascular remodeling through inhibition of dedifferentiation of VSMCs. Moreover, deletion of DNA-PKcs in VSMCs alleviated Ang II-induced vasodilation dysfunction and hypertension. Mechanistic investigations denoted that Ang II-evoked rises in cytoplasmic DNA-PKcs interacted with dynamin-related protein 1 (Drp1) at its TQ motif to phosphorylate Drp1S616, subsequently promoting mitochondrial fragmentation and dysfunction, as well as reactive oxygen species (ROS) production. Treatment of irbesartan, an Ang II type 1 receptor (AT1R) blocker, downregulated DNA-PKcs expression in VSMCs and aortic tissues following Ang II administration. CONCLUSION: Our data revealed that cytoplasmic DNA-PKcs in VSMCs accelerated Ang II-induced vascular remodeling by interacting with Drp1 at its TQ motif and phosphorylating Drp1S616 to provoke mitochondrial fragmentation. Maneuvers targeting DNA-PKcs might be a valuable therapeutic option for the treatment of vascular remodeling and hypertension.

A new emerging target in cancer immunotherapy: Galectin-9 (LGALS9).

Over the past few decades, advances in immunological knowledge have led to the identification of novel immune checkpoints, reinvigorating cancer immunotherapy. Immunotherapy, represented by immune checkpoint inhibitors, has become the leader in the precision treatment of cancer, bringing a new dawn to the treatment of most cancer patients. Galectin-9 (LGALS9), a member of the galectin family, is a widely expressed protein involved in immune regulation and tumor pathogenesis, and affects the prognosis of various types of cancer. Galectin-9 regulates immune homeostasis and tumor cell survival through its interaction with its receptor Tim-3. In the review, based on a brief description of the signaling mechanisms and immunomodulatory activities of galectin-9 and Tim-3, we summarize the targeted expression patterns of galectin-9 in a variety of malignancies and the promising mechanisms of anti-galectin-9 therapy in stimulating anti-tumor immune responses.

Engineered Extracellular Vesicles for Delivery of an IL-1 Receptor Antagonist Promote Targeted Repair of Retinal Degeneration.

Retinal degeneration (RD) is an irreversible blinding disease that seriously affects patients' daily activities and mental health. Targeting hyperactivated microglia and regulating polarization are promising strategies for treating the disease. Mesenchymal stem cell (MSC) transplantation is proven to be an effective treatment due to its immunomodulatory and regenerative properties. However, the low efficiency of cell migration and integration of MSCs remains a major obstacle to clinical use. The goal of this study is to develop a nanodelivery system that targets hyperactivated microglia and inhibits their release of proinflammatory factors, to achieve durable neuroprotection. This approach is to engineer extracellular vesicles (EVs) isolated from MSC, modify them with a cyclic RGD (cRGD) peptide on their surface, and load them with an antagonist of the IL-1 receptor, anakinra. Comparing with non-engineered EVs, it is observed that engineered cRGD-EVs exhibit an increased targeting efficiency against hyperactivated microglia and strongly protected photoreceptors in experimental RD cells and animal models. This study provides a strategy to improve drug delivery to degenerated retinas and offers a promising approach to improve the treatment of RD through targeted modulation of the immune microenvironment via engineered cRGD-EVs.

PDE4D/cAMP/IL-23 axis determines the immunotherapy efficacy of lung adenocarcinoma via activating the IL-9 autocrine loop of cytotoxic T lymphocytes.

Although immunotherapy has changed the prognosis of many advanced malignancies including lung adenocarcinoma (LUAD), many patients are insensitive to the drugs, with the mechanisms yet to be elucidated. Herein, we identified PDE4D as an immunotherapy efficacy-related gene through bioinformatics screening. By using a co-culture system of LUAD cells and tumor-cell-specific CD8+ T cells, a functional PDE4D/cAMP/IL-23 axis was further revealed in LUAD cells. Fluorescent multiplex immunohistochemistry analysis of patient-derived samples and the in vivo mouse LUAD xenograft tumors revealed not only the colocalization of IL-23 and CD8+ T cells but also the immune potentiating effect of IL-23 on cytotoxic T lymphocytes (CTLs) in LUAD tissues. Through transcriptome sequencing and functional validations, IL-23 was proven to up-regulate IL-9 expression in CTLs via activating the NF-κB signaling, leading to elevated productions of immune effector molecules and enhanced efficacy of antitumor immunotherapy. Interestingly, an autocrine loop of IL-9 was also uncovered during this process. In conclusion, PDE4D/cAMP/IL-23 axis determines the immunotherapy efficacy of human LUAD. This effect is mediated by the activation of an NF-κB-dependent IL-9 autocrine loop in CTLs.

Antidepressant effects of repeated s-ketamine administration as NMDAR Antagonist: Involvement of CaMKIIα and mTOR signaling in the hippocampus of CUMS mice.

With the approval of s-ketamine nasal spray as a novel antidepressant, its robust antidepressant effects have been intensively examined in clinical trials. However, the therapeutic efficacy and mechanisms of repeated intermittent drug administration remain unclear. In the present study, we applied a classic chronic unpredictable mild stress (CUMS) model to induce depressive-like behaviors of mice and evaluated the role of repeated s-ketamine administration (10 mg/kg, 7 consecutive days) in ameliorating depressive-like behaviors and modulating related molecular pathways. A battery of behavioral tests were performed to assess CUMS-induced depression. The protein expressions of GluN1, GluN2A, GluN2B, GluR1, CaMKIIα, phosphorylated CaMKIIα (p-CaMKIIα), BDNF, TrkB, phosphorylated TrkB (p-TrkB), mTOR, and phosphorylated mTOR (p-mTOR) as well as modification of synaptic ultrastructure was identified in hippocampal tissues. It turned out that s-ketamine manifested evident antidepressant effects with improved synaptic plasticity. Meanwhile, the results suggested that s-ketamine could differentially modulate glutamate receptors with upregulated GluN1 and GluR1 levels and downregulated GluN2B levels. CUMS-induced elevation of CaMKIIα phosphorylation and decline of BDNF, TrkB phosphorylation and mTOR could also be reversed through s-ketamine treatment. Together, our study provided evidence that selectively modulated glutamate receptors as well as CaMKIIα and mTOR signaling were involved in repeated s-ketamine administration.

Does temperature favour the spread of Raphidiopsis raciborskii, an invasive bloom-forming cyanobacterium, by altering cellular trade-offs?

As a tropical filamentous cyanobacterium, Raphidiopsis raciborskii has attracted much attention due to its expansion and toxin production. However, the mechanisms of its expansion to temperate regions have not been studied in detail. To address the potential strategies, the physiological and metabolomic profiles of R. raciborskii FACHB 1096 isolated from a temperate lake in China were determined and measured at different temperatures (10 °C, 15 °C, 20 °C, 25 °C, and 32 °C). The results demonstrated that temperature significantly changed cell viability, chlorophyll a content, specific growth rate, Chl a fluorescence, and filamentous shape of R. raciborskii. Low temperature decreased cell viability, specific growth rate, and photosynthetic efficiency, while the proportion of akinete and carbon fixation per unit cell were significantly increased compared with high temperature (32 °C). A constructed unimodal model indicated that filament length, cell volume, and cell length/width of R. raciborskii were significantly reduced in both high and low temperature environments. Under low-temperature conditions, R. raciborskii suffered different degrees of oxidative damage and produced corresponding antioxidant substances to resist oxidative stress, suggesting that low temperature changes the metabolic level of the cells, causing the cells to gradually switch from development to defense. Metabolomic data further confirmed that temperature change induced shifts in metabolic pathways in R. raciborskii, including starch and sucrose metabolic pathways, glutathione metabolic pathways, and the pentose phosphate pathways (PPP), as well as metabolic pathways related to the tricarboxylic acid (TCA) cycle. Our results indicated that the trade-offs of R. raciborskii cells among the growth, cell size, and metabolites can be significantly regulated by temperature, with broad implications for its global expansion in temperate waterbodies.

[Influence and Driving of Environmental Heterogeneity on the Epilithic Diatom Community in Xiangxi River, a Tributary of the Three Gorges Reservoir Area].

Environmental heterogeneity can not only increase species diversity to some extent but also affect the stability of terrestrial communities. However, how environmental heterogeneity affects species diversity of epilithic diatom communities in aquatic ecosystems is rarely reported. In this study, therefore, epilithic diatoms and their roles in driving species diversity were explored by quantifying and comparing the environmental heterogeneity in Xiangxi River, a tributary of the Three Gorges Reservoir Area (TGR), on a time scale. The results showed that environmental heterogeneity, taxonomic ß-diversity, and functional ß-diversity in non-impoundment periods were significantly higher than those in impoundment periods. Moreover, the turnover components in the two hydrological periods showed the highest contribution to ß-diversity. However, the taxonomic α-diversity in impoundment periods was significantly higher than that in non-impoundment periods. In addition, functional richness in functional α-diversity was significantly higher in non-impoundment periods than that in impoundment periods, whereas there was no significant difference in other functional α-diversity, i.e., functional dispersion and functional evenness, found between the two periods. Multiple regression on (dis)similarity matrices (MRM) analysis indicated that ammonium nitrogen (NH4+-N) and silicate (SiO32--Si) were the key environmental heterogeneous factors affecting the epilithic diatom community in Xiangxi River during the non-impoundment periods, whereas the key heterogeneous factors were ammonium nitrogen (NH4+-N), silicate (SiO32--Si), and total phosphorus (TP) during the impoundment periods. These results suggested that the environmental heterogeneity during different hydrological periods in TGR can significantly affect the community structure of epilithic diatoms, resulting in the differentiation of species within the community and even affecting the stability of aquatic ecosystems.

[Impounding Impacts of the Three Gorges Reservoir on Phytoplankton Function Groups and Its Relationship with Resource Use Efficiency].

In order to investigate the relationship between phytoplankton community functional group compositions and resource use efficiency in important tributaries of the Three Gorges Reservoir, phytoplankton and environment parameters were sampled from five tributaries, the Xiangxi River, Daning River, Meixi River, Pengxi River, and Huangjin River, in August and November, 2020. There were 119 species (variants) belonging to 62 genera and 7 phyla identified in summer, whereas 118 species (variants) belonging to 7 divisions of 58 genera were found in winter. According to Padisak's theory, all phytoplankton were divided into 25 functional groups, of which there were six important functional groups in both summer and winter:L0, H1, D, Y, MP, and P in summer and L0, H1, A, M, MP, and Y in winter. The α-diversity of the phytoplankton functional group in summer was higher than that in winter. Moreover, a higher α-diversity was also found in downstream samples relative to that in upstream samples, indicating that the community structure was more complex, and the community stability was relatively better in downstream regions of the rivers. Redundancy analysis (RDA) showed that the environment factors, i.e., ν, pH, permanganate index, WT, and RUETN, significantly affected phytoplankton functional groups (P<0.05). Variance partitioning analysis (VPA) indicated that environmental factors had a higher explanatory degree for the change in functional group composition in summer (45.23%); on the contrary, resource use efficiency had a higher explanatory degree in winter (42.33%). The linear fitted model showed that functional groups L0, H1, D, and Y showed a significant positive correlation relationship with RUETN and RUETP in summer, whereas only four functional groups (M, MP, Y, and A) had a linear relationship with RUETP, and all function groups had a good linear relationship with RUETN in winter. These results indicated that the functional groups belonging to cyanobacteria, dinoflagellates, and cryptophyta were more efficient at using limited resources in summer, whereas the diatoms had a good linear relationship with resource use efficiency and formed a dominant group in the low temperature environment of winter. These results suggest that the impounding of the Three Gorges Reservoir area can significantly change the resource use efficiency of phytoplankton, resulting in changes in the phytoplankton functional group composition and community structure.

The FACT-targeted drug CBL0137 enhances the effects of rituximab to inhibit B-cell non-Hodgkin's lymphoma tumor growth by promoting apoptosis and autophagy.

BACKGROUND: Aggressive B-cell non-Hodgkin's lymphoma (B-NHL) patients often develop drug resistance and tumor recurrence after conventional immunochemotherapy, for which new treatments are needed. METHODS: We investigated the antitumor effects of CBL0137. In vitro, cell proliferation was assessed by CCK-8 and colony formation assay. Flow cytometry was performed to analyze cell cycle progression, apoptosis, mitochondrial depolarization, and reactive oxygen species (ROS) production. Autophagy was detected by transmission electron microscopy and mGFP-RFP-LC3 assay, while western blotting was employed to detect proteins involved in apoptosis and autophagy. RNA-sequencing was conducted to analyze the transcription perturbation after CBL0137 treatment in B-NHL cell lines. Finally, the efficacy and safety of CBL0137, rituximab, and their combination were tested in vivo. RESULTS: CBL0137, a small molecule anticancer agent that has significant antitumor effects in B-NHL. CBL0137 sequesters the FACT (facilitates chromatin transcription) complex from chromatin to produce cytotoxic effects in B-NHL cells. In addition, we discovered novel anticancer mechanisms of CBL0137. CBL0137 inhibited human B-NHL cell proliferation by inducing cell cycle arrest in S phase via the c-MYC/p53/p21 pathway. Furthermore, CBL0137 triggers ROS generation and induces apoptosis and autophagy in B-NHL cells through the ROS-mediated PI3K/Akt/mTOR and MAPK signaling pathways. Notably, a combination of CBL0137 and rituximab significantly suppressed B-NHL tumor growth in subcutaneous models, consistent with results at the cellular level in vitro. CONCLUSIONS: CBL0137 has potential as a novel approach for aggressive B-NHL, and its combination with rituximab can provide new therapeutic options for patients with aggressive B-NHL. Video Abstract.

Mitochondrial quality control mechanisms as therapeutic targets in doxorubicin-induced cardiotoxicity.

Doxorubicin (DOX) is a chemotherapeutic drug that is utilized for solid tumors and hematologic malignancies, but its clinical application is hampered by life-threatening cardiotoxicity including cardiac dilation and heart failure. Mitochondrial quality control processes, including mitochondrial proteostasis, mitophagy, and mitochondrial dynamics and biogenesis, serve to maintain mitochondrial homeostasis in the cardiovascular system. Importantly, recent advances have unveiled a major role for defective mitochondrial quality control in the etiology of DOX cardiomyopathy. Moreover, specific interventions targeting these quality control mechanisms to preserve mitochondrial function have emerged as potential therapeutic strategies to attenuate DOX cardiotoxicity. However, clinical translation is challenging because of obscure mechanisms of action and potential adverse effects. The purpose of this review is to provide new insights regarding the role of mitochondrial quality control in the pathogenesis of DOX cardiotoxicity, and to explore promising therapeutic approaches targeting these mechanisms to aid clinical management.