Sequential deactivation across the thalamus-hippocampus-mPFC pathway during loss of consciousness.

How consciousness is lost in states such as sleep or anesthesia remains a mystery. To gain insight into this phenomenon, we conducted concurrent recordings of electrophysiology signals in the anterior cingulate cortex and whole-brain functional magnetic resonance imaging (fMRI) in rats exposed to graded propofol, undergoing the transition from consciousness to unconsciousness. Our results reveal that upon the loss of consciousness (LOC), as indicated by the loss of righting reflex, there is a sharp increase in low-frequency power of the electrophysiological signal. Additionally, simultaneously measured fMRI signals exhibit a cascade of deactivation across a pathway including the hippocampus, thalamus, and medial prefrontal cortex (mPFC) surrounding the moment of LOC, followed by a broader increase in brain activity across the cortex during sustained unconsciousness. Furthermore, sliding window analysis demonstrates a temporary increase in synchrony of fMRI signals across the hippocampus-thalamus-mPFC pathway preceding LOC. These data suggest that LOC might be triggered by sequential activities in the hippocampus, thalamus and mPFC, while wide-spread activity increases in other cortical regions commonly observed during anesthesia-induced unconsciousness might be a consequence, rather than a cause of LOC. Taken together, our study identifies a cascade of neural events unfolding as the brain transitions into unconsciousness, offering critical insight into the systems-level neural mechanisms underpinning LOC.

Discovery of a PROTAC degrader for METTL3-METTL14 complex.

N6-methyladenosine (m6A) methylation is the most abundant type of RNA modification that is mainly catalyzed by the METTL3-METTL14 methyltransferase complex. This complex has been linked to multiple cancers and is considered a promising therapeutic target for acute myeloid leukemia (AML). However, only a few METTL3 inhibitors targeting the catalytic activity were developed recently. Here, we present the discovery of WD6305 as the potent and selective proteolysis-targeting chimera (PROTAC) degrader of METTL3-METTL14 complex. WD6305 suppresses m6A modification and the proliferation of AML cells, and promotes apoptosis much more effectively than its parent inhibitor. WD6305 also affects a variety of signaling pathways related to the development and proliferation of AML. Collectively, our study reveals PROTAC degradation of METTL3-METTL14 complex as a potential anti-leukemic strategy and provides desirable chemical tool for further understanding METTL3-METTL14 protein functions.

Bioactivity and influence on colonic microbiota of polyphenols from noni (Morinda citrifolia L.) fruit under simulated gastrointestinal digestion.

Noni (Morinda citrifolia L.) is a tropical fruit rich in bioactive compounds. Little is known about its polyphenol composition at different ripeness levels and digestive characteristics. Here, we studied changes in polyphenols and antioxidant activity as noni ripened. Rutin and kaempferol-3-O-rutinoside were found in high amounts in noni, with antioxidant capacity increasing as it ripened. Under simulated digestion, polyphenols were gradually released from the oral to gastrointestinal phases, partially decomposing in the small intestine due to their instability. Conversely, fiber-bound phenols were released during colonic fermentation, leading to high bioaccessible antioxidant activity. Additionally, noni consumption affected the intestinal microbiome by reducing the Firmicutes/Bacteroidetes ratio and increasing bacteria with prebiotic properties like Prevotella and Ruminococcus. These findings demonstrate that polyphenols significantly contribute to the health benefits of noni fruit by providing absorbable antioxidants and improving the structure of the intestinal microbiome.

Protective Effect of Artocarpus heterophyllus Lam. (Jackfruit) Polysaccharides on Liver Injury Induced by Cyclophosphamide in Mice.

In recent years, Artocarpus heterophyllus Lam. (jackfruit) polysaccharides (namely JFP-Ps) have attracted much attention due to their multiple biological activities. This study aimed to explore the protective effects and the underlying mechanisms of JFP-Ps on cyclophosphamide (Cp)-induced liver damage. The protective effect of JFP-Ps was evaluated using HE staining, antioxidant testing, enzyme-linked immunosorbent assay (ELISA), real-time quantitative polymerase chain reaction (RT-qPCR), Western blot and ultra-performance liquid chromatography equipped with quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS/MS) metabolomics analysis. The results showed that Cp caused pathological liver damage, activated oxidative stress and downregulated cytokine expression, while JFP-Ps treatment was found to exert antioxidant effects and play immune regulatory roles through mitogen-activated protein kinase/nuclear factor-κB (MAPK/NF-κB) related inflammation and cell apoptosis pathways to protect the Cp-induced liver injury. Metabolomic results showed that the liver-protective effects of JFP-Ps were mainly related to aminoacyl transfer ribonucleic acid (tRNA) biosynthesis, sphingolipid metabolism, purine metabolism and the citrate cycle. These results indicate that JFP-Ps have great potential application in alleviating liver injury.

Discovery of a potent and selective covalent threonine tyrosine kinase (TTK) inhibitor.

Threonine tyrosine kinase (TTK) is a critical component of the spindle assembly checkpoint and plays a pivotal role in mitosis. TTK has been identified as a potential therapeutic target for human cancers. Here, we describe our design, synthesis and evaluation of a class of covalent TTK inhibitors, exemplified by 16 (SYL1073). Compound 16 potently inhibits TTK kinase with an IC50 of 0.016 µM and displays improved selectivity in a panel of kinases. Mass spectrometry analysis reveals that 16 covalently binds to the C604 cysteine residue in the hinge region of the TTK kinase domain. Furthermore, 16 achieves strong potency in inhibiting the growth of various human cancer cell lines, outperforming its relative reversible inhibitor, and eliciting robust downstream effects. Taken together, compound 16 provides a valuable lead compound for further optimization toward the development of drug for treatment of human cancers.

Study of unripe and inferior banana flours pre-gelatinized by four different physical methods.

This study aimed to prepare the pre-gelatinized banana flours and compare the effects of four physical treatment methods (autoclaving, microwave, ultrasound, and heat-moisture) on the digestive and structural characteristics of unripe and inferior banana flours. After the four physical treatments, the resistant starch (RS) content values of unripe and inferior banana flours were decreased from 96.85% (RS2) to 28.99-48.37% (RS2 + RS3), while C∞ and k values were increased from 5.90% and 0.039 min-1 to 56.22-74.58% and 0.040-0.059 min-1, respectively. The gelatinization enthalpy (ΔHg) and I1047/1022 ratio (short-range ordered crystalline structures) were decreased from 15.19 J/g and 1.0139 to 12.01-13.72 J/g, 0.9275-0.9811, respectively. The relative crystallinity decreased from 36.25% to 21.69-26.30%, and the XRD patterns of ultrasound (UT) and heat-moisture (HMT) treatment flours maintained the C-type, but those samples pre-gelatinized by autoclave (AT) and microwave (MT) treatment were changed to C + V-type, and heat-moisture (HMT) treatment was changed to A-type. The surface of pre-gelatinized samples was rough, and MT and HMT showed large amorphous holes. The above changes in structure further confirmed the results of digestibility. According to the experimental results, UT was more suitable for processing unripe and inferior banana flours as UT had a higher RS content and thermal gelatinization temperatures, a lower degree and rate of hydrolysis, and a more crystalline structure. The study can provide a theoretical basis for developing and utilizing unripe and inferior banana flours.

Gastroprotective Effects of the Aqueous Extract of Finger Citron Pickled Products against Ethanol-Induced Gastric Damage: In Vitro and In Vivo Studies.

Finger citron pickled products (FCPP), as folk remedies, are famous in southern China for protecting gastric mucosa. However, the gastric mucosa protection of FCPP has not been reported yet, and its effective mechanism is unclear. In this study, the protective mechanism of FCPP aqueous extract on gastric mucosa was investigated in vitro and in vivo for the first time, using human gastric mucosa epithelial cells (GES-1) and acute alcoholic gastric ulcer rat model respectively. Furthermore, we also investigated the main substances in the aqueous extract that exert gastroprotective activity using a GES-1 scratch test and basic chemical composition analysis. FCPP aqueous extract was found to play a protective and reparative role in GES-1 by promoting the secretion of trefoil factor thyroid transcription factor 2 (TFF2) and inhibiting the secretion of tumor necrosis factor-α (TNF-α) in cells damaged by alcohol. The ulcer index of gastric tissue induced by alcohol was significantly decreased (p < 0.01) after pretreatment with FCPP aqueous extract, indicating that FCPP aqueous extract had a good protective effect on the stomach mucosa. Moreover, FCPP aqueous extract could increase superoxide dismutase (SOD) activity and inhibit malondialdehyde (MDA) content, exhibiting good antioxidant capacity. Aqueous extract of FCPP could also effectively inhibit the increase of cytokines TNF-α, interleukin-1ß (IL-1ß) and interleukin-6 (IL-6) in serum of rats, and promote the increase of anti-inflammatory cytokines interleukin-10 (IL-10) to some extent. Furthermore, FCPP aqueous extract could inhibit the expression of nuclear factor kappa-B (NF-κB/P65) protein, caspase-1 protein and IL-1ß protein in the gastric tissue of rats, while promoting the expression of IκBα protein, indicating that the gastric mucosa protection effects of FCPP aqueous extract were mainly dependent on the NF-κB/caspase-1/IL-1ß axis. The polysaccharides in FCPP aqueous extract might be the main components that exerted gastroprotective activity, as demonstrated by GES-1 cell scratch assay. This study confirmed that FCPP aqueous extract presented promising potential in protecting gastric mucosa and avoiding gastric ulcers, which could provide an experimental basis for further utilizing the medicinal value and developing new products of FCPP.

Proteinosomes via Self-Assembly of Thermoresponsive Miktoarm Polymer Protein Bioconjugates.

To fabricate nanoscale proteinosomes, thermoresponsive miktoarm polymer protein bioconjugates were prepared through highly efficient molecular recognition between the ß-cyclodextrin modified BSA (CD-BSA) and the adamantyl group anchored at the junction point of the thermoresponsive block copolymer poly(ethylene glycol)-b-poly(di(ethylene glycol) methyl ether methacrylate) (PEG-b-PDEGMA). PEG-b-PDEGMA was synthesized by the Passerini reaction of benzaldehyde-modified PEG, 2-bromo-2-methylpropionic acid, and 1-isocyanoadamantane, followed by the atom transfer radical polymerization of DEGMA. Two block copolymers with different chain lengths of PDEGMA were prepared, and both self-assembled into polymersomes at a temperature above their lower critical solution temperatures (LCST). The two copolymers can undergo molecular recognition with the CD-BSA and form miktoarm star-like bioconjugates. The bioconjugates self-assembled into ∼160 nm proteinosomes at a temperature above their LCSTs, and the miktoarm star-like structure has a great effect on the formation of the proteinosomes. Most of the secondary structure and esterase activity of BSA in the proteinosomes were maintained. The proteinosomes exhibited low toxicity to the 4T1 cells and could deliver model drug doxorubicin into the 4T1 cells.

Near Infrared-Activatable Methylene Blue Polypeptide Codelivery of the NO Prodrug via π-π Stacking for Cascade Reactive Oxygen Species Amplification-Mediated Photodynamic Therapy.

The application of photodynamic therapy (PDT) has attracted remarkable interest in cancer treatment because of the advantages of noninvasiveness and spatiotemporal selectivity. However, the PDT efficiency is considerably limited by photosensitizer (PS) quenching and severe hypoxia in solid tumors. Herein, a kind of near infrared (NIR)-activatable methylene blue (MB) peptide nanocarrier was developed for codelivery of nitric oxide (NO) prodrug JSK, expecting a cascade of reactive oxygen species (ROS) amplification-mediated antitumor PDT. In detail, MB was conjugated to water-soluble polyethylene glycol-polylysine (PEG-PLL) through NIR-photocleavable 10-N-carbamoyl bonds, and the subsequent amphiphilic conjugates (mPEG-PLL-MB) self-assembled into nanoparticles (NPs), which allowed JSK codelivery via π-π stacking interactions. MB in quenched state in mPEG-PLL-MB/JSK NPs could be photoactivated by NIR light locoregionally in a controlled manner due to the photocleavage of carbamoyl bonds. Apart from ROS production, assembly disturbance and even disintegration of mPEG-PLL-MB/JSK occurred along with MB activation that subsequently freed JSK, which was further triggered by intracellularly overexpressed glutathione (GSH) and glutathione S-transferase (GST) to sustain the release of NO. NO then served as a hypoxia relief agent through inhibition of cellular respiration to economize O2, cooperating with MB activation and GSH depletion, which synergistically enabled a cascade of ROS amplification to augment PDT for mitochondrial apoptosis-mediated tumor inhibition in vitro and in vivo. Therefore, this pioneering strategy of cascade amplification of ROS addressed the key issues of PS inactivation, hypoxia resistance, and ROS neutralization in a three-pronged approach, which hold great promise in efficient antitumor PDT.

Versatile Hydrogel Dressing with Skin Adaptiveness and Mild Photothermal Antibacterial Activity for Methicillin-Resistant Staphylococcus Aureus-Infected Dynamic Wound Healing.

Bacterial infection often induces chronic repair of wound healing owing to aggravated inflammation. Hydrogel dressing exhibiting intrinsic antibacterial activity may substantially reduce the use of antibiotics for infected wound management. Hence, a versatile hydrogel dressing (rGB/QCS/PDA-PAM) exhibiting skin adaptiveness on dynamic wounds and  mild photothermal antibacterial activity is developed for safe and efficient infected wound treatment. Phenylboronic acid-functionalized graphene (rGB) and oxadiazole-decorated quaternary carboxymethyl chitosan (QCS) are incorporated into a polydopamine-polyacrylamide (PDA-PAM) network with multiple covalent and noncovalent bonds, which conferred the hydrogel with flexible mechanical properties, strong tissue adhesion and excellent self-healing ability on the dynamic wounds. Moreover, the glycocalyx-mimicking phenylboronic acid on the surface of rGB enables the hydrogel to specifically capture bacteria. The enhanced membrane permeability of QCS enhanced bacterial vulnerability to photothermal therapy（PTT）, which is demonstrated by efficient mild PTT antibacteria against methicillin-resistant Staphylococcus aureus in vitro and in vivo at temperatures of <49.6 °C. Consequently, the hydrogel demonstrate accelerated tissue regeneration on MRSA-infected wound in vivo, with an intact epidermis, abundant collagen deposition and prominent angiogenesis. Therefore, rGB/QCS/PDA-PAM is a versatile hydrogel dressing exhibiting inherent antibacterial activity and has considerable potential in treating wounds infected with drug-resistant bacteria.

Effects of hydroxylation at C3' on the B ring and diglycosylation at C3 on the C ring on flavonols inhibition of α-glucosidase activity.

The structure-activity relationship and inhibitory mechanism of flavonols on α-glucosidase were studied by inhibition kinetics, multispectral study, and molecular docking. The flavonols of rutin, quercetin and kaempferol effectively inhibit the activity of α-glucosidase, among which quercetin and rutin showed the strongest and weakest inhibitory abilities, respectively. The inhibitory ability of flavonols was enhanced by hydroxylation at C3' of B ring, while it was weakened by diglycosylation at C3 of C ring. Remarkably, the quenching affinity and inhibitory ability of flavonols were inconsistent, which was different from the conclusions reported by some previous studies. This may be ascribed to the hydroxyl groups of C3' of B ring and C3 of C ring. Furthermore, three flavonols were spontaneously bound to α-glucosidase through hydrophobic interactions and hydrogen bonding, which caused the structure and hydrophobic microenvironment of α-glucosidase to change, resulting in significant inhibition of α-glucosidase by flavonols.

Adsorption Mechanism of Amidoxime Collector on the Flotation of Lepidolite: Experiment and DFT Calculation.

Lepidolite is an important mineral resource of lithium. With the increase in awareness of low-carbon and green travel, the demand for lithium has increased dramatically. Therefore, how to increase the output of lithium has to turn into high precedence. In this paper, amidoxime (DPA) was synthesized and used for the efficient collection of lepidolite. Dodecylamine (DA), a commonly used collector of lepidolite ore, was used for comparison. The collecting performances of DA and DPA for lepidolite were studied by the micro-flotation experiment, and the adsorption mechanism of DPA on lepidolite was verified by contact angle, zeta potential tests, FTIR spectra, and density functional theory (DFT) calculations. The results of flotation experiments showed that at the same collector dosage (3 × 10-4 mol/L), the recovery of lepidolite could reach 90%, while the recovery of lepidolite with DA was only 52.5%, and to achieve the maximum recovery of DA (77.5%), only half of the DPA was added. The contact angle test results showed that DPA could effectively improve the hydrophobicity of lepidolite than DA. FTIR spectra and zeta potential tests suggested that DPA molecules were adsorbed on the lepidolite surface by electrostatic attraction. DFT calculations revealed that DPA reacted with the nucleophilic reagent (lepidolite) by the reactive site of the -CH2NH(CH2)2C(NOH)N+H3 group and more easily absorbed on the surface of lepidolite than DA. Therefore, our new finding will provide an important prospect for the sustainable development and utilization of lithium resources.

A study of starch resources with high-amylose content from five Chinese mutant banana species.

Investigation on staple crop starch of new species has been becoming the research focus of scholars at present. Based on this, the physicochemical properties and microstructural characteristics of starches isolated from Chinese mutant Musa acuminata Colla acuminata and double balbisiana (MA), Musa double acuminata cv. Pisang Mas (MAM), Musa acuminata cv. Pisang Awak (MAA), and Musa Basjoo Siebold (MBS), and Musa double acuminata and balbisiana-Prata (MAP) were investigated. Results exhibited that all starches exhibited high content of amylose (34.04-42.59%). According to the particle size, they were divided into medium (MA, MAM) (14.54-17.71 µm) and large (MAA, MBS, MAP) (23.01-23.82 µm) group. The medium group with A-type crystallization showed higher peak viscosity (PV), final viscosity, gel fracturability and gel hardness. For large group with B-type crystallization, the compact particle morphology, higher degree of crystallinity, short range order, gelatinization enthalpy, pasting temperature, lower porosity, water absorption capacity (WAC) and oil absorption capacity were found. In addition, the medium group with higher PV and gel hardness could be used as food thickening or gelling agents. The large group with higher Rc, short-range order, lower porosity and WAC could be potential to become raw material for resistant starch. All results showed the amylose content, had significant effect on the microstructure and physicochemical properties of starch samples. Outcomes in this investigation might provide a basis of theoretical application for industrial food production.

Polysaccharides from Artocarpus heterophyllus Lam. (jackfruit) pulp improves intestinal barrier functions of high fat diet-induced obese rats.

Polysaccharides show protective effects on intestinal barrier function due to their effectiveness in mitigating oxidative damage, inflammation and probiotic effects. Little has been known about the effects of polysaccharides from Artocarpus heterophyllus Lam. pulp (jackfruit, JFP-Ps) on intestinal barrier function. This study aimed to investigate the effects of JFP-Ps on intestinal barrier function in high fat diet-induced obese rats. H&E staining and biochemical analysis were performed to measure the pathological and inflammatory state of the intestine as well as oxidative damage. Expression of the genes and proteins associated with intestinal health and inflammation were analyzed by RT-qPCR and western blots. Results showed that JFP-Ps promoted bowel movements and modified intestinal physiochemical environment by lowering fecal pH and increasing fecal water content. JFP-Ps also alleviated oxidative damage of the colon, relieved intestinal colonic inflammation, and regulated blood glucose transport in the small intestine. In addition, JFP-Ps modified intestinal physiological status through repairing intestinal mucosal damage and increasing the thickness of the mucus layer. Furthermore, JFP-Ps downregulated the inflammatory genes (TNF-α, IL-6) and up-regulated the free fatty acid receptors (GPR41 and GPR43) and tight junction protein (occludin). These results revealed that JFP-Ps showed a protective effect on intestinal function through enhancing the biological, mucosal, immune and mechanical barrier functions of the intestine, and activating SCFAs-GPR41/GPR43 related signaling pathways. JFP-Ps may be used as a promising phytochemical to improve human intestinal health.

Effectiveness and Safety of Thyroid Hormone Therapy in Patients with Dilated Cardiomyopathy: A Systematic Review and Meta-analysis of RCTs.

BACKGROUND: Previous research demonstrated that short-term treatment of dilated cardiomyopathy with thyroid hormones exerted beneficial hemodynamic effects when added to standard anti-heart failure therapy, but it remains debatable whether thyroid hormones can be used to treat dilated cardiomyopathy. Therefore, we conducted a meta-analysis to evaluate the effectiveness and safety of thyroid hormone treatment in patients with dilated cardiomyopathy. METHODS: The Cochrane Clinical Trials Registry database, PubMed, Embase, Chinese Biomedical Literature Database, China Academic Journals full-text database, Wanfang Database, China Science and Technology Journal Database, and Clinical Trials.gov were screened through 15 October, 2021. Randomized controlled clinical trials were selected based on study inclusion criteria. Two independent reviewers extracted the data and assessed study bias using the Cochrane risk of bias tool. For the data synthesis, the weighted mean difference was calculated using baseline and post-thyroid hormone treatment data. Random-effects models were used for the meta-analysis. The primary outcomes were left ventricular ejection fraction after a minimum follow-up of 1 week and adverse events. RESULTS: Ten of the 1149 published reports met the inclusion criteria (N = 608 randomized individuals). After reasonable use of thyroid hormone therapy, left ventricular ejection fraction increased (weighted mean difference, 3.94; 95% confidence interval 3.06-4.81; I2 = 0.00%), cardiac output increased, and left ventricular end-diastolic diameter decreased, but left ventricular mass index and thyroid function were unaffected. Adverse events were reported in the intervention group of two studies. The ten studies demonstrated a low risk of bias. CONCLUSIONS: Adding thyroid hormones to conventional anti-heart failure treatment in patients with DCM appears to be an effective and well tolerated therapeutic option. CLINICAL TRIAL REGISTRATION: The protocol was registered in the International Prospective Register of Systematic Reviews (PROSPERO) database (CRD42021286043).

The Effectiveness of Thyroid Hormone Replacement Therapy on Heart Failure and Low-Triiodothyronine Syndrome: An Updated Systematic Review and Meta-analysis of Randomized Controlled Trials.

OBJECTIVE: The purpose of this study was to conduct a systematic review and meta-analysis evaluating the role of thyroid hormone therapy in patients with heart failure and low-triiodothyronine syndrome. METHODS: The electronic databases PubMed, Embase, Cochrane Library, China National Knowledge Infrastructure, China Science and Technology Journal Database, Wanfang Database, and China Biology Medicine disc were systematically searched to identify eligible studies published before November 27, 2021. The mean difference was pooled for randomized controlled trials using a random-effects model. RESULTS: The meta-analysis showed that thyroid hormone treatment improved the left ventricular ejection fraction (weighted mean difference [WMD] 5.61, 95% confidence interval [CI]: 4.38 to 6.85, I2 = 63.12%, P < 0.01). The cardiac output improved with thyroid hormone therapy (WMD 0.65, 95% CI: 0.42 to 0.89, I2 = 84.28%, P < 0.01). The early-to-late diastolic transmitral flow velocity in the thyroid hormone group was also improved compared to the control group (WMD 0.29, 95% CI: 0.15 to 0.42, I2 = 95.08%, P < 0.01). The left ventricular diastolic dysfunction was decreased with thyroid hormone treatment (WMD -5.17, 95% CI: -7.47 to -2.88, I2 = 90.18%, P < 0.01). The brain natriuretic peptide decreased with thyroid hormone treatment (standardized mean difference -1.49, 95% CI: -2.15 to -0.84, I2 = 90.18%, P < 0.01). Noradrenaline decreased with thyroid hormone therapy (WMD -349.86, 95% CI: -401.05 to -298.67, I2 = 0%, P < 0.01). Free triiodothyronine increased with thyroid hormone treatment (standardized mean difference 2.18, 95% CI: 0.75 to 2.60, I2 = 98.20%, P < 0.01). CONCLUSION: This meta-analysis showed that thyroid hormone replacement therapy was effective in patients with heart failure and low-triiodothyronine syndrome.

Discovery of a potent and selective proteolysis targeting chimera (PROTAC) degrader of NSD3 histone methyltransferase.

Nuclear receptor binding SET domain protein 3 (NSD3) is an attractive potential target in the therapy for human cancers. Herein, we report the discovery of a series of small-molecule NSD3 degraders based on the proteolysis targeting chimera (PROTAC) strategy. The represented compound 8 induces NSD3 degradation with DC50 values of 1.43 and 0.94 µM in NCI-H1703 and A549 lung cancer cells, respectively, and shows selectivity over two other NSD proteins. 8 reduces histone H3 lysine 36 methylation and induces apoptosis and cell cycle arrest in lung cancer cells. Moreover, the RNA sequencing and immunohistochemistry assays showed that 8 downregulates NSD3-associated gene expression. Significantly, 8, but not 1 (a reported NSD3-PWWP antagonist) could inhibit the cell growth of NCI-H1703 and A549 cells. A single administration of 8 effectively decreases the NSD3 protein level in lung cancer xenograft models. Therefore, this study demonstrated that inducing NSD3 degradation is a more effective approach inhibiting the function of NSD3 than blocking the NSD3-PWWP domain, which may provide a potential therapeutic approach for lung cancer.

Variations of volatile flavour compounds in finger citron (Citrus medica L. var. sarcodactylis) pickling process revealed by E-nose, HS-SPME-GC-MS and HS-GC-IMS.

The pickled products of finger citron are famous in southern China for their unique taste and flavor. Although pickling process involves complex treatments including salting, desalting, sugaring, cooking and drying, extended shelf-life up to ten years after pickling can be achieved. In this study, the variations of volatile flavour components in the pickling process of finger citron were investigated by electronic nose (E-nose), headspace solid phase microextraction-gas chromatography-mass spectrometry (HS-SPME-GC-MS) and headspace-gas chromatography-ion mobility spectrometry (HS-GC-IMS). HS-SPME-GC-MS identified 85 substances, and HS-GC-IMS identified 81 substances, including terpenoids (21), aromatic hydrocarbons (11), alcohols (11), aldehydes (10), esters (7), phenols (6), acids (5), ethers (2), ketones (2), and other species (10). Linalool, limonene, (E)-3,7-dimethyl-1,3,6-octatriene, myrcene, 3-carene, ß-pinene, α-pinene, terpinolene, 1-methyl-4-(1-methylethyl)-1,4-cyclohexadiene, α-terpinene, (S)-ß-bisabolene, 1-isopropyl-2-methylbenzene and 1-methyl-4-(1-methylethenyl)-benzene were the stable substances at relatively high contents in finger citron at different pickling process. Salting and drying steps in the pickling process exerted greatest influence on the volatile components of finger citron. Salting promoted the generation of aldehydes, esters and acids, but led to the disappearance of alcohols, while drying promoted the generation of alcohols, phenols, aldehydes and acids at the expense of reduction in terpenoids. Our study revealed that the characteristic volatile compounds of finger citron pickled products was mainly formed by the biological reactions in the salting stage and thermal chemical transformations in the drying stage. This study also validated the suitability of E-nose combined with HS-SPME-GC-MS and HS-GC-IMS in tracking the changes of volatile components in finger citron during the pickling process.

Carbon-dot-supported atomically dispersed gold as a mitochondrial oxidative stress amplifier for cancer treatment.

Mitochondrial redox homeostasis, the balance between reactive oxygen species and antioxidants such as glutathione, plays critical roles in many biological processes, including biosynthesis and apoptosis, and thus is a potential target for cancer treatment. Here, we report a mitochondrial oxidative stress amplifier, MitoCAT-g, which consists of carbon-dot-supported atomically dispersed gold (CAT-g) with further surface modifications of triphenylphosphine and cinnamaldehyde. We find that the MitoCAT-g particles specifically target mitochondria and deplete mitochondrial glutathione with atomic economy, thus amplifying the reactive oxygen species damage caused by cinnamaldehyde and finally leading to apoptosis in cancer cells. We show that imaging-guided interventional injection of these particles potently inhibits tumour growth in subcutaneous and orthotopic patient-derived xenograft hepatocellular carcinoma models without adverse effects. Our study demonstrates that MitoCAT-g amplifies the oxidative stress in mitochondria and suppresses tumour growth in vivo, representing a promising agent for anticancer applications.