Targeted co-delivery of rapamycin and oxaliplatin by liposomes suppresses tumor growth and metastasis of colorectal cancer.

The activation of tumor cell immunogenicity through oxaliplatin (OXP)-induced immunogenic cell death (ICD) has significant implications in cancer treatment. However, the anti-tumor effect of OXP monotherapy still has many shortcomings, and the systemic administration of OXP leads to low drug concentration at the tumor site, which is susceptible to systemic toxic side effects. In this study, a combined therapeutic strategy using folate-modified nanoliposomes co-delivered with rapamycin (Rapa) and OXP (abbreviated as FA@R/O Lps) is proposed for the treatment of colorectal cancer (CRC). Rapa and OXP can directly inhibit tumor cell proliferation and induce apoptosis. OXP induces ICD by triggering the release of danger signals, such as HMGB1, ATP, and calreticulin. FA@R/O Lps with a particle size of about 134.1±1.8 nm and a small dispersion were successfully prepared. This novel liposomal system can be used to target and increase drug accumulation in tumors. In-vivo experiments showed that FA@R/O Lps successfully inhibit CRC growth and liver metastasis, and simultaneously reduce off-target toxicity. In particular, FA@R/O Lps showed greater therapeutic effects than free Rapa/OXP and R/O Lps. Taken together, this study provides a novel combination of Rapa and OXP, and a nano-delivery system for enhanced anti-CRC efficacy. The results suggest that FA@R/O Lps could be a promising strategy for the treatment of CRC.

The role of cancer-associated fibroblasts in the invasion and metastasis of colorectal cancer.

Colorectal cancer (CRC) is the third most common cancer and has ranked the third leading cause in cancerassociated death globally. Metastasis is the leading cause of death in colorectal cancer patients. The role of tumor microenvironment (TME) in colorectal cancer metastasis has received increasing attention. As the most abundant cell type in the TME of solid tumors, cancer-associated fibroblasts (CAFs) have been demonstrated to have multiple functions in advancing tumor growth and metastasis. They can remodel the extracellular matrix (ECM) architecture, promote epithelial-mesenchymal transition (EMT), and interact with cancer cells or other stromal cells by secreting growth factors, cytokines, chemokines, and exosomes, facilitating tumor cell invasion into TME and contributing to distant metastasis. This article aims to analyze the sources and heterogeneity of CAFs in CRC, as well as their role in invasion and metastasis, in order to provide new insights into the metastasis mechanism of CRC and its clinical applications.

Constructing a Transient Ischemia Attack Model Utilizing Flexible Spatial Targeting Photothrombosis with Real-Time Blood Flow Imaging Feedback.

Transient ischemic attack (TIA) is an early warning sign of stroke and death, necessitating suitable animal models due to the associated clinical diagnostic challenges. In this study, we developed a TIA model using flexible spatially targeted photothrombosis combined with real-time blood flow imaging feedback. By modulating the excitation light using wavefront technology, we precisely created a square light spot (50 × 250 µm), targeted at the distal middle cerebral artery (dMCA). The use of laser speckle contrast imaging (LSCI) provided real-time feedback on the ischemia, while the excitation light was ceased upon reaching complete occlusion. Our results demonstrated that the photothrombus formed in the dMCA and spontaneously recanalized within 10 min (416.8 ± 96.4 s), with no sensorimotor deficits or infarction 24 h post-TIA. During the acute phase, ischemic spreading depression occurred in the ipsilateral dorsal cortex, leading to more severe ischemia and collateral circulation establishment synchronized with the onset of dMCA narrowing. Post-reperfusion, the thrombi were primarily in the sensorimotor and visual cortex, disappearing within 24 h. The blood flow changes in the dMCA were more indicative of cortical ischemic conditions than diameter changes. Our method successfully establishes a photochemical TIA model based on the dMCA, allowing for the dynamic observation and control of thrombus formation and recanalization and enabling real-time monitoring of the impacts on cerebral blood flow during the acute phase of TIA.

Versatile Activated Carbon Fibers Derived from the Cotton Fibers Used as CO2 Solid-State Adsorbents and Electrode Materials.

Activated carbon has an excellent porous structure and is considered a promising adsorbent and electrode material. In this study, activated carbon fibers (ACFs) with abundant microporous structures, derived from natural cotton fibers, were successfully synthesized at a certain temperature in an Ar atmosphere and then activated with KOH. The obtained ACFs were characterized by field emission scanning electron microscopy (FESEM), transmission electron microscopy (TEM), elemental analysis, nitrogen and carbon dioxide adsorption-desorption analysis, X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS) and N2 adsorption-desorption measurement. The obtained ACFs showed high porous qualities and had a surface area from 673 to 1597 m2/g and a pore volume from 0.33 to 0.79 cm3/g. The CO2 capture capacities of prepared ACFs were measured and the maximum capture capacity for CO2 up to 6.9 mmol/g or 4.6 mmol/g could be achieved at 0 °C or 25 °C and 1 standard atmospheric pressure (1 atm). Furthermore, the electrochemical capacitive properties of as-prepared ACFs in KOH aqueous electrolyte were also studied. It is important to note that the pore volume of the pores below 0.90 nm plays key roles to determine both the CO2 capture ability and the electrochemical capacitance. This study provides guidance for designing porous carbon materials with high CO2 capture capacity or excellent capacitance performance.

Ergodic speckle contrast optical coherence tomography velocimetry of rapid blood flow.

Visualizing a 3D blood flow velocity field through noninvasive imaging is crucial for analyzing hemodynamic mechanisms in areas prone to disorders. However, traditional correlation-based optical coherence tomography (OCT) velocimetry techniques have a maximum measurable flow velocity depending on the A-line rate. We presented the ergodic speckle contrast OCT (ESCOCT) to break the bottleneck in measuring the rapid blood flow velocity. It achieved a measurement of blood flow velocity ranging from 9.5 to 280 mm/s using a 100 kHz swept-source (SS) OCT based on 100 A-repeats scanning mode. Addressing the non-ergodic problem of temporal OCT signals by integrating more consecutive A-scans, ESCOCT can enable the estimation for lower velocity flows by increasing A-repeats. ESCOCT provided a wide dynamic range with no upper limit on measuring blood flow velocity with an adequate signal-to-noise ratio and improved the sensitivity and accuracy of the hemodynamic assessment.

Antibody Fc-receptor FcεR1γ stabilizes cell surface receptors in group 3 innate lymphoid cells and promotes anti-infection immunity.

Group 3 innate lymphoid cells (ILC3) are crucial for maintaining mucosal homeostasis and regulating inflammatory diseases, but the molecular mechanisms governing their phenotype and function are not fully understood. Here, we show that ILC3s highly express Fcer1g gene, which encodes the antibody Fc-receptor common gamma chain, FcεR1γ. Genetic perturbation of FcεR1γ leads to the absence of critical cell membrane receptors NKp46 and CD16 in ILC3s. Alanine scanning mutagenesis identifies two residues in FcεR1γ that stabilize its binding partners. FcεR1γ expression in ILC3s is essential for effective protective immunity against bacterial and fungal infections. Mechanistically, FcεR1γ influences the transcriptional state and proinflammatory cytokine production of ILC3s, relying on the CD16-FcεR1γ signaling pathway. In summary, our findings highlight the significance of FcεR1γ as an adapter protein that stabilizes cell membrane partners in ILC3s and promotes anti-infection immunity.

Discovery of Aurovertin B as a Potent Metastasis Inhibitor against Triple-Negative Breast Cancer: Elucidating the Complex Role of the ATF3-DUSP1 Axis.

Triple-negative breast cancer (TNBC) is characterized by high mortality rates primarily due to its propensity for metastasis. Addressing this challenge necessitates the development of effective antimetastatic therapies. This study aimed to identify natural compounds with potential antimetastatic properties mainly based on the high-throughput phenotypic screening system. This system, utilizing luciferase reporter gene assays combined with scratch wound assays, evaluates compounds based on their influence on the epithelial-mesenchymal transition (EMT) marker E-cadherin. Through this approach, aurovertin B (AVB) was revealed to have significant antimetastatic capability. Notably, AVB exhibited substantial metastasis suppression in many TNBC cell lines, including MDA-MB-231, HCC1937 and 4T1. Also, its remarkable antimetastatic activity was demonstrated in vivo via the orthotopic breast cancer mouse model. Further exploration revealed a pronounced association between AVB-induced upregulation of DUSP1 (dual-specificity phosphatase 1) and its inhibitory effect on TNBC metastasis. Additionally, microarray analysis conducted to elucidate the underlying mechanism of the AVB-DUSP1 interaction identified ATF3 (activating transcription factor 3) as a critical transcription factor instrumental in DUSP1 transcriptional activation. This discovery, coupled with observations of enhanced ATF3-DUSP1 expression and consequent reduction in TNBC metastatic foci in response to AVB, provides novel insights into the molecular mechanisms driving metastasis in TNBC. Significance Statement We construct a high-throughput phenotypic screening system utilizing EMT marker E-cadherin promoter luciferase reporter gene combined with scratch wound assays. Aurovertin B was revealed to possess significant antimetastatic activity through this approach, which was further demonstrated via in vivo and in vitro experiments. The discovery of the regulatory role of the ATF3-DUSP1 pathway enriches our understanding of TNBC metastasis mechanism and suggests the potential of ATF3 and DUSP1 as biomarkers for diagnosing TNBC metastasis.

Rapamycin circumvents anti PD-1 therapy resistance in colorectal cancer by reducing PD-L1 expression and optimizing the tumor microenvironment.

The unresectable or postoperative recurrence of advanced metastatic colorectal cancer (CRC) is the difficulty of its clinical management, and pharmacological therapy is the main source of benefit. Immune checkpoint inhibitors are therapeutic options but are effective in approximately 5 % of patients with deficient mismatch repair (MMR)/microsatellite instability CRC and are ineffective in patients with MMR-proficient (pMMR)/microsatellite stable (MSS) CRCs, which may be associated with the tumor microenvironment (TME). Here, we propose a new combination strategy and evaluate the efficacy of rapamycin (Rapa) combined with anti-PD-1 (αPD-1) in CT26 tumor-bearing mice, azoxymethane (AOM)/dextran sodium sulfate (DSS) inflammation-associated CRC mice, CT26-Luc tumor-bearing mice with postoperative recurrence, and CT26 liver metastasis mice. The results revealed that Rapa improved the therapeutic effect of αPD-1 and effectively inhibited colorectal carcinogenesis, postoperative recurrence, and liver metastasis. Mechanistically, Rapa improved the anticancer effect of αPD-1, associated with Rapa reprograming of the immunosuppressive TME. Rapa effectively depleted α-SMA+ cancer-associated fibroblasts and degraded collagen in the tumor tissue, increasing T lymphocyte infiltration into the tumor tissue. Rapa induced the downregulation of programed cell death 1 ligand 1 (PD-L1) protein and transcript levels in CT26 cells, which may be associated with the inhibition of the mTOR/P70S6K signaling axis. Furthermore, co-culture of tumor cells and CD8+ T lymphocytes demonstrated that Rapa-induced PD-L1 downregulation in tumor cells increased spleen-derived CD8+ T lymphocyte activation. Therefore, Rapa improves the anti-tumor effect of αPD-1 in CRCs, providing new ideas for its use to improve combinatorial strategies for anti-PD-1 immunotherapy.

p85α deficiency alleviates ischemia-reperfusion injury by promoting cardiomyocyte survival.

Myocardial ischemia-reperfusion (I/R) injury is a prevalent cause of myocardial injury, involving a series of interconnected pathophysiological processes. However, there is currently no clinical therapy for effectively mitigating myocardial I/R injury. Here, we show that p85α protein levels increase in response to I/R injury through a comprehensive analysis of cardiac proteomics, and confirm this in the I/R-injured murine heart and failing human myocardium. Genetic inhibition of p85α in mice activates the Akt-GSK3ß/Bcl-x(L) signaling pathway and ameliorates I/R-induced cardiac dysfunction, apoptosis, inflammation, and mitochondrial dysfunction. p85α silencing in cardiomyocytes alleviates hypoxia-reoxygenation (H/R) injury through activating the Akt-GSK3ß/Bcl-x(L) signaling pathway, while its overexpression exacerbates the damage. Mechanistically, the interaction between MG53 and p85α triggers the ubiquitination and degradation of p85α, consequently enhancing Akt phosphorylation and ultimately having cardioprotective effects. Collectively, our findings reveal that substantial reduction of p85α and subsequently activated Akt signaling have a protective effect against cardiac I/R injury, representing an important therapeutic strategy for mitigating myocardial damage.

Nanoliposomes Encapsulated Rapamycin/Resveratrol to Induce Apoptosis and Ferroptosis for Enhanced Colorectal Cancer Therapy.

OBJECTIVES: Monotherapy is often ineffective for treating colorectal cancer. In this study, we developed PEG-modified liposomes loaded with rapamycin (Rapa) and resveratrol (Res) (Rapa/Res liposomes, or RRL) to investigate their therapeutic potential in colorectal cancer. METHODS: RRL were constructed using the reversed-phase evaporation method. We assessed the cytotoxicity, apoptosis, and ferroptotic effects of RRL on colorectal cancer HCT116 cells. The anti-tumor efficacy of RRL was evaluated in HCT116 xenograft mice. RESULTS: RRL had a particle size of 86.67 ± 1.10 nm and a zeta potential of -33.13 ± 0.49 mV. The coloaded formulation demonstrated satisfactory performance both in vitro and in vivo, resulting in increased cytotoxicity to HCT116 cells and significant suppression of HCT116 xenografts tumor growth. Mechanically, RRL significantly increased the apoptosis rate of HCT116 cells, induced ROS accumulation in tumor cells, and effectively downregulated the expression of the ferroptosis-associated proteins GPX4 and SLC7A11, demonstrating its superior efficacy compared to that of Rapa liposomes (Rapa/Lps) or Res liposomes (Res/Lps) alone. CONCLUSION: Coloading Rapa and Res into liposomes to promote apoptosis and ferroptosis in tumor cells represents a promising strategy for the treatment of colorectal cancer.

Dihalogenated nitrophenols exposure induces developmental neurotoxicity in zebrafish embryo.

2,6-Dihalogenated nitrophenols (2,6-DHNPs) are emerging halogenated nitroaromatic pollutants that have been detected in various water environments. However, there is currently limited research available regarding their potential impacts on locomotion behavior and neurotoxicity. Therefore, this study utilized zebrafish embryos to investigate the potential neurotoxic effects of 2,6-DHNPs by examining their impact on the nervous system at a concentration defined as 10% of the median lethal concentration. Our findings demonstrated that exposure to 2,6-DHNPs resulted in a significant 30 % decrease in the total swimming distance of zebrafish larvae, accompanied by notable impairments in motor neuron development and central nervous system. These effects were evidenced by a substantial 25% decrease in axonal growth, as well as disruptions in synapse formation and neuronal differentiation. Additionally, neurotransmitter analysis revealed marked decreases of 40%, 35%, and 30% in dopamine, 5-hydroxytryptamine, and acetylcholine levels respectively, highlighting disturbances in their synthesis, transport, and degradation mechanisms. These results emphasize the considerable neurotoxicity of 2,6-DHNPs at concentrations previously considered safe; thus necessitating a re-evaluation of environmental risk assessments and regulatory standards for such emerging contaminants.

Autophagic-lysosomal damage induced by swainsonine is protected by trehalose through activation of TFEB-regulated pathway in renal tubular epithelial cells.

Swainsonine (SW) is the main toxic component of locoweed. Previous studies have shown that kidney damage is an early pathologic change in locoweed poisoning in animals. Trehalose induces autophagy and alleviates lysosomal damage, while its protective effect and mechanism against the toxic injury induced by SW is not clear. Based on the published literature, we hypothesize that transcription factor EB(TFEB) -regulated is targeted by SW and activating TFEB by trehalose would reverse the toxic effects. In this study, we investigate the mechanism of protective effects of trehalose using renal tubular epithelial cells. The results showed that SW induced an increase in the expression level of microtubule-associated protein light chain 3-II and p62 proteins and a decrease in the expression level of ATPase H+ transporting V1 Subunit A, Cathepsin B, Cathepsin D, lysosome-associated membrane protein 2 and TFEB proteins in renal tubular epithelial cells in a time and dose-dependent manner suggesting TFEB-regulated lysosomal pathway is adversely affected by SW. Conversely, treatment with trehalose, a known activator of TFEB promote TFEB nuclear translocation suggesting that TFEB plays an important role in protection against SW toxicity. We demonstrated in lysosome staining that SW reduced the number of lysosomes and increased the luminal pH, while trehalose could counteract these SW-induced effects. In summary, our results demonstrated for the first time that trehalose could alleviate the autophagy degradation disorder and lysosomal damage induced by SW. Our results provide an interesting method for reversion of SW-induced toxicity in farm animals and furthermore, activation of TFEB by trehalose suggesting novel mechanism of treating lysosomal storage diseases.

Fabrication of Single-Crystal Violet Phosphorus Flakes For Ultrasensitive Photodetection.

Violet phosphorus (VP) has attracted a lot of attention for its unique physicochemical properties and emerging potential in photoelectronic applications. Although VP has a van der Waals (vdW) structure similar to that of other 2D semiconductors, direct synthesis of VP on a substrate is still challenging. Moreover, optoelectronic devices composed of transfer-free VP flakes have not been demonstrated. Herein, a bismuth-assisted vapor phase transport technique is designed to grow uniform single-crystal VP flakes on the SiO2/Si substrate directly. The size of the crystalline VP flakes is an order of magnitude larger than that of previous liquid-exfoliated samples. The photodetector fabricated with the VP flakes shows a high responsivity of 12.5 A W-1 and response/recovery time of 3.82/3.03 ms upon exposure to 532 nm light. Furthermore, the photodetector shows a small dark current (<1 pA) that is beneficial to high-sensitivity photodetection. As a result, the detectivity is 1.38 × 1013 Jones that is comparable with that of the vdW p-n heterojunction detector. The results reveal the great potential of VP in optoelectronic devices as well as the CVT technique for the growth of single-crystal semiconductor thin films.

A T-Cell Inspired Sonoporation System Enhances Low-Dose X-Ray-Mediated Pyroptosis and Radioimmunotherapy Efficacy by Restoring Gasdermin-E Expression.

Genome editing has the potential to improve the unsatisfactory therapeutic effect of antitumor immunotherapy. However, the cell plasma membrane prevents the entry of almost all free genome-manipulation agents. Therefore, a system can be spatiotemporally controlled and can instantly open the cellular membrane to allow the entry of genome-editing agents into target cells is needed. Here, inspired by the ability of T cells to deliver cytotoxins to cancer cells by perforation, an ultrasound (US)-controlled perforation system (UPS) is established to enhance the delivery of free genome-manipulating agents. The UPS can perforate the tumor cell membrane while maintaining cell viability via a controllable lipid peroxidation reaction. In vitro, transmembrane-incapable plasmids can enter cells and perform genome editing with the assistance of UPS, achieving an efficiency of up to 90%. In vivo, the UPS is biodegradable, nonimmunogenic, and tumor-targeting, enabling the puncturing of tumor cells under US. With the application of UPS-assisted genome editing, gasdermin-E expression in 4T1 tumor-bearing mice is successfully restored, which leads to pyroptosis-mediated antitumor immunotherapy via low-dose X-ray irradiation. This study provides new insights for designing a sonoporation system for genome editing. Moreover, the results demonstrate that restoring gasdermin expression by genome editing significantly improves the efficacy of radioimmunotherapy.

High remnant cholesterol as a risk factor for developing chronic kidney disease in patients with prediabetes and type 2 diabetes: a cross-sectional study of a US population.

AIMS: To examine any potential links between remnant cholesterol (RC) and comorbid chronic kidney disease (CKD) in individuals with prediabetes and type 2 diabetes mellitus (T2DM). METHODS: We used data from 2709 American people aged > 20 years from the National Health and Nutrition Examination Survey (NHANES) during 2011-2018. Subjects were categorized according to whether they had comorbid CKD. Logistic regression models and smoothed curve fitting methods were employed to assess the association of RC with comorbid CKD in patients with prediabetes and T2DM. RESULTS: The 2709 participants included 1473 patients with T2DM and 1236 with prediabetes [impaired glucose tolerance (IGT) and impaired fasting glucose (IFG)], of whom 744 (27.46%) had comorbid CKD. In multivariate-adjusted analysis, both RC and triglycerides (TG) were significantly associated with an increased risk of comorbid CKD, and a 1 mmol/L elevation of RC increased the risk by 38.1% [OR (95% CI) 1.636 (1.242, 2.156)], which was higher than the risk associated with a 1 mmol/L increase in TG [1.255 (1.106, 1.424)]. Additionally, those in the highest quartile of RC had a 43.6% higher risk of concomitant renal damage than those in the lowest quartile. RC was linearly and positively associated with the incidence of comorbid CKD in this population. CONCLUSIONS: RC is an independent risk factor for comorbid CKD in patients with prediabetes and T2DM. This finding provides a novel insight into the management and early detection of renal disease in patients with impaired glucose metabolism.

Intraoperative evaluation of local cerebral hemodynamic change by laser speckle contrast imaging for predicting postoperative cerebral hyperperfusion during STA-MCA bypass in adult patients with moyamoya disease.

Cerebral hyperperfusion (CHP) occurred frequently after direct superficial temporal artery-middle cerebral artery (STA-MCA) bypass surgery for moyamoya disease (MMD). We analyzed cortical microvascular density (CMD) and the change of cerebral blood flow (LΔCBF) using intraoperative laser speckle contrast imaging (LSCI) on 130 hemispheres of 95 consecutive adult patients with MMD. The demographic characteristics, cortical hemodynamic sources, bypass methods, intraoperative blood flow data, and relative CBF changes on single-photon emission computed tomography (SPECT) examination (SΔrCBF) were compared between the groups with and without CHP. The median values for CMD, LΔCBF, and SΔrCBF were significantly higher in the CHP group than in the non-CHP group (CMD 0.240 vs 0.206, P = 0.004; LΔCBF 2.285 vs 1.870, P < 0.001; SΔCBF 1.535 vs 1.260, P < 0.001). Multivariate analysis revealed that hemodynamic sources of recipient parasylvian cortical arteries from MCA (M-PSCAs), end-to-side (E-S) bypass method, CMD ≥ 0.217, and LΔCBF ≥ 1.985 were the risk factors for CHP. Intraoperative LSCI was useful for evaluating hemodynamics and predicting CHP in patients with MMD.

LONG-TERM OUTCOME OF TRANSSCLERAL FOUR-POINT FIXATION OF AKREOS INTRAOCULAR LENS WITH CLOSED CONTINUOUS-LOOP SUTURE.

PURPOSE: To report the long-term clinical outcomes of transscleral four-point fixation of Akreos intraocular lens using a closed continuous-loop suture technique. METHODS: This was a retrospective, multicenter, interventional case series. Primary outcome measures were best-corrected visual acuity, intraocular pressure, corneal endothelial cell density, and complications with a minimum of 1-year follow-up. RESULTS: One hundred and ninety-two eyes of 177 patients from two surgical hospital sites were identified. The mean best-corrected visual acuity improved from 0.88 ± 0.74 logarithm of the minimum angle of resolution (Snellen 20/152) preoperatively to 0.42 ± 0.52 logarithm of the minimum angle of resolution (Snellen 20/53) postoperatively ( P < 0.001). The mean preoperative intraocular pressure was 17.51 ± 8.67 mmHg, and the mean postoperative intraocular pressure at final follow-up was 15.08 ± 4.18 mmHg ( P = 0.001). The mean corneal endothelial cell density significantly reduced from 2,259 ± 729 cells/mm 2 to 2077 ± 659 cells/mm 2 , representing a cell loss of 5.73% ( P < 0.001). The intraocular lens was fixed well during follow-up. There were no intraoperative complications noted. Postoperative complications included transient ocular hypertension in 15 eyes (7.81%), hypotony in two eyes (1.04%), retinal detachment in one eye (0.52%), and macular edema in one eye (0.52%). CONCLUSION: The transscleral four-point fixation Akreos intraocular lens using the closed continuous-loop suture technique was effective and safe with satisfactory visual acuity with a minimum of 1-year follow-up.

Climate warming could free cold-adapted trees from C-conservative allocation strategy of storage over growth.

Carbon allocation has been fundamental for long-lived trees to survive cold stress at their upper elevation range limit. Although carbon allocation between non-structural carbohydrate (NSC) storage and structural growth is well-documented, it still remains unclear how ongoing climate warming influences these processes, particularly whether these two processes will shift in parallel or respond divergently to warming. Using a combination of an in situ downward-transplant warming experiment and an ex situ chamber warming treatment, we investigated how subalpine fir trees at their upper elevation limit coordinated carbon allocation priority among different sinks (e.g., NSC storage and structural growth) at whole-tree level in response to elevated temperature. We found that transplanted individuals from the upper elevation limit to lower elevations generally induced an increase in specific leaf area, but there was no detected evidence of warming effect on leaf-level saturated photosynthetic rates. Additionally, our results challenged the expectation that climate warming will accelerate structural carbon accumulation while maintaining NSC constant. Instead, individuals favored allocating available carbon to NSC storage over structural growth after 1 year of warming, despite the amplification in total biomass encouraged by both in situ and ex situ experimental warming. Unexpectedly, continued warming drove a regime shift in carbon allocation priority, which was manifested in the increase of NSC storage in synchrony to structural growth enhancement. These findings imply that climate warming would release trees at their cold edge from C-conservative allocation strategy of storage over structural growth. Thus, understanding the strategical regulation of the carbon allocation priority and the distinctive function of carbon sink components is of great implication for predicting tree fate in the future climate warming.

Isoquercitrin attenuates the progression of non-alcoholic steatohepatitis in mice by modulating galectin-3-mediated insulin resistance and lipid metabolism.

BACKGROUND: Non-alcoholic steatohepatitis (NASH) is a global health problem with no effective treatment. Isoquercitrin (IQ) alters hepatic lipid metabolism and inhibits adipocyte differentiation. The underlying regulatory mechanisms of IQ in regulating insulin resistance (IR) and lipid metabolism remain unclear. PURPOSE: This study was aimed at investigating the effects of IQ on NASH and deciphering whether the underlying mechanisms are via modulation of galectin-3 mediated IR and lipid metabolism. METHODS: IR-HepG2 cell lines were used to demonstrate the ability of IQ to modulate galectin-3-mediated glucose disposal and lipid metabolism. A 20-week high-fat diet (HFD)-induced NASH model was established in C57BL/6J mice, and the protective effect of IQ on lipid disposal in the liver was verified. Further, the mRNA and protein levels of glucose and lipid metabolism were investigated, and lysophosphatidylcholine (LPC) and acylcarnitine (AC) profiling were performed to characterize the changes in endogenous substances associated with mitochondrial function and lipid metabolism in serum and cells. Furthermore, the pharmacokinetic features of IQ were explored in a rat model of NASH. RESULTS: IQ restored liver function and ameliorated inflammation and lipid accumulationin NASH model mice. Notably, significant regulation of the proteins included fatty acid-generating and transporting, cholesterol metabolism enzymes, nuclear transcription factors, mitochondrial metabolism, and IR-related enzymes was noted to be responsible for the therapeutic mechanisms of IQ against experimental NASH. Serum lipid metabolism-related metabolomic assay confirmed that LPC and AC biosynthesis mostly accounted for the therapeutic effect of IQ in mice with NASH and that IQ maintained the homeostasis of LPC and AC levels. CONCLUSION: This is the first study showing that IQ protects against of NASH by modulating galectin-3-mediated IR and lipid metabolism. The mechanisms responsible for liver protection and improved lipid metabolic disorder by IQ may be related to the suppression of IR and regulation of mitochondrial function and lipid metabolism. Galectin-3 down-regulation represents a potentially novel approach for the treatment and prevention of NASH.