Theoretical trends in the dynamics simulations of molecular machines across multiple scales.

Over the past few decades, molecular machines have been extensively studied, since they are composed of single molecules for functional materials capable of responding to external stimuli, enabling motion at scales ranging from the microscopic to the macroscopic level within molecular aggregates. This advancement holds the potential to efficiently transform external resources into mechanical movement, achieved through precise control of conformational changes in stimuli-responsive materials. However, the underlying mechanism that links microscopic and macroscopic motions remains unclear, demanding computational development associated with simulating the construction of molecular machines from single molecules. This bottleneck has impeded the design of more efficient functional materials. Advancements in theoretical simulations have successfully been developed in various computational models to unveil the operational mechanisms of stimulus-responsive molecular machines, which could help us reduce the costs in experimental trial-and-error procedures. It opens doors to the computer-aided design of innovative functional materials. In this perspective, we have reviewed theoretical approaches employed in simulating dynamic processes involving conformational changes in molecular machines, spanning different scales and environmental conditions. In addition, we have highlighted current challenges and anticipated future trends in the collective control of aggregates within molecular machines. Our goal is to provide a comprehensive overview of recent theoretical advancements in the field of molecular machines, offering valuable insights for the design of novel smart materials.

Kaempferol and nicotiflorin ameliorated alcohol-induced liver injury in mice by miR-138-5p/SIRT1/FXR and gut microbiota.

Aims: Excessive alcohol consumption can lead to alcoholic liver diseases (ALDs). Tetrastigma hemsleyanum Diels et Gilg is a rare Chinese medicinal herb. Tetrastigma hemsleyanum Diels et Gilg has been validated to be highly effective for treating hepatitis. Kaempferol and nicotiflorin are two highly representative flavonoids, which have exhibit therapeutic effects on liver disease. Therefore, the protective mechanism of kaempferol and nicotiflorin on alcohol-induced liver injury were investigated. Main methods: Forty mice were used in this study. After treatment of Kaempferol and nicotiflorin, serum and liver were collected and used for determination of biochemical indicators, H&E staining, and molecular detection. The interaction of miRNAs from serum extracellular vehicles (EVs) with mRNAs and 16S rRNA sequencing of gut microbiota were also investigated. Key findings: The results showed that kaempferol and nicotiflorins significantly ameliorated alcohol-induced liver damage and observably regulated gut microbiota. Specifically, the levels of malondialdehyde (MDA) and CYP2E1 in the liver significantly reduced, and the activity of superoxide dismutase (SOD) and glutathione (GSH) in the liver evidently increased. They also significantly relieved liver oxidative stress and lipid accumulation by suppressing miR-138-5p expression, inversely enhancing deacetylase silencing information regulator 2 related enzyme-1 (SIRT1) levels and then decreasing farnesoid X receptor (FXR) acetylation, which then modulated Nrf2 and SREBP-1c signaling pathways to regulate oxidative stress and lipid metabolism induced by alcohol. Significance: Kaempferol and nicotiflorin reduced alcohol-induced liver damage by enhancing alcohol metabolism and reducing oxidative stress and lipid metabolism. The intestinal microorganism disorder was also ameliorated after oral kaempferol and nicotiflorin.

Preparation of microgels loaded with lycopene/NMN and their protective mechanism against acute liver injury.

This study aimed to enhance the stability and bioavailability of lycopene (LYC) and nicotinamide mononucleotide (NMN) by incorporating them into porous microgels after loading LYC into liposomes. The particle size, zeta potential, encapsulation rate (%), scanning electron microscopy images, and stability and release kinetics characteristics in simulating digestion confirmed that the microgels had high LYC and NMN encapsulation rates (99.11% ± 0.12% and 68.98% ± 0.26%, respectively) and good stability and release characteristics. The protective effect and potential mechanism of microgels loaded with LYC and NMN on lipopolysaccharide (LPS)-induced acute liver injury in C57BL/6 mice were investigated by intragastric administration for 28 days prior to LPS exposure. The results showed that the microgels loaded with LYC and NMN significantly ameliorated LPS-induced liver injury and reduced the inflammatory response and oxidative stress. In addition, LYC and NMN can not only act on the Toll-like receptor 4 (TLR4)/MD2 complex but also regulate TLR4-related miRNAs (miR-145a-5p and miR-217-5p) in serum extracellular vesicles, thereby synergistically inhibiting the TLR4/NF-κB signaling pathway. In addition, the microgels loaded with LYC and NMN were able to enrich beneficial bacteria that produced short-chain fatty acids and reduce harmful bacteria. In conclusion, LYC and NMN protected against LPS-induced acute liver injury via inhibition of oxidative stress and inflammation, as well as regulating the gut microbiota.

Modular Design of Biodegradable Ionizable Lipids for Improved mRNA Delivery and Precise Cancer Metastasis Delineation In Vivo.

Lipid nanoparticles (LNPs) represent the most clinically advanced nonviral mRNA delivery vehicles; however, the full potential of the LNP platform is greatly hampered by inadequate endosomal escape capability. Herein, we rationally introduce a disulfide bond-bridged ester linker to modularly synthesize a library of 96 linker-degradable ionizable lipids (LDILs) for improved mRNA delivery in vivo. The top-performing LDILs are composed of one 4A3 amino headgroup, four disulfide bond-bridged linkers, and four 10-carbon tail chains, whose unique GSH-responsive cone-shaped architectures endow optimized 4A3-SCC-10 and 4A3-SCC-PH lipids with superior endosomal escape and rapid mRNA release abilities, outperforming their parent lipids 4A3-SC-10/PH without a disulfide bond and control lipids 4A3-SSC-10/PH with a disulfide bond in the tail. Notably, compared to DLin-MC3-DMA via systematic administration, 4A3-SCC-10- and 4A3-SCC-PH-formulated LNPs significantly improved mRNA delivery in livers by 87-fold and 176-fold, respectively. Moreover, 4A3-SCC-PH LNPs enabled the highly efficient gene editing of 99% hepatocytes at a low Cre mRNA dose in tdTomato mice following intravenous administration. Meanwhile, 4A3-SCC-PH LNPs were able to selectively deliver firefly luciferase mRNA and facilitate luciferase expression in tumor cells after intraperitoneal injection, further improving cancer metastasis delineation and surgery via bioluminescence imaging. We envision that the chemistry adopted here can be further extended to develop new biodegradable ionizable lipids for broad applications such as gene editing and cancer immunotherapy.

Ultrafast Photocontrolled Rotation in a Molecular Motor Investigated by Machine Learning-Based Nonadiabatic Dynamics Simulations.

The thermal helix inversion (THI) of the overcrowded alkene-based molecular motors determines the speed of the unidirectional rotation due to the high reaction barrier in the ground state, in comparison with the ultrafast photoreaction process. Recently, a phosphine-based motor has achieved all-photochemical rotation experimentally, promising to be controlled without a thermal step. However, the mechanism of this photochemical reaction has not yet been fully revealed. The comprehensive computational studies on photoisomerization still resort to nonadiabatic molecular dynamics (NAMD) simulations based on electronic structure calculations, which remains a high computational cost for large systems such as molecular motors. Machine learning (ML) has become an accelerating tool in NAMD simulations recently, where excited-state potential energy surfaces (PESs) are constructed analytically with high accuracy, providing an efficient approach for simulations in photochemistry. Herein the reaction pathway is explored by a spin-flip time-dependent density functional theory (SF-TDDFT) approach in combination with ML-based NAMD simulations. According to our computational simulations, we notice that one of the key factors of fulfilling all-photochemical rotation in the phosphine-based motor is that the excitation energies of four isomers are similar. Additionally, a shortcut photoinduced transformation between unstable isomers replaces the THI step, which shares the conical intersection (CI) with photoisomerization. In this study, we provide a practical approach to speed up the NAMD simulations in photochemical reactions for a large system that could be extended to other complex systems.

The characteristics of oncological clinical trials investigating the synergistic effect of radiotherapy and immune checkpoint inhibitors: a cross-sectional study.

Background: The combined use of radiotherapy (RT) and immune checkpoint inhibitors (ICIs) is a promising strategy in the treatment of cancer patients. We sought to comprehensively summarize the characteristics of oncological trials investigating the synergistic effect of RT and ICIs registered at ClinicalTrials.gov. Methods: In this cross-sectional study, oncological trials investigating the synergistic effect of RT and ICIs registered at ClinicalTrials.gov from database inception to November 30, 2021 were retrieved. The characteristics of the included trials were assessed. Results: Overall, 403 registered trials were identified for analysis. Of these trials, 393 (97.5%) were interventional trials and 10 (2.5%) were observational trials. The top 3 most-studied conditions were gastrointestinal cancer (25.8%), head and neck cancer (18.6%), and non-small cell lung cancer (NSCLC) (17.9%). Approximately, 60.0% of the trials comprised ≤50 participants and 22.6% of the trials comprised >100 participants. More than half of the registered trials were prospective phase 2 trials (54.3%). In relation to trial location, 39.7% of the trials were conducted in the United States, which was the most common registered area, followed by China (33.7%) and Europe (19.4%). In relation to the radiation fractionation, the conventional fractionation size of 1.8-2.0 Gy was comparable to the ultra-hypofractionation size of ≥5 Gy (46.4% vs. 32.8%), and the most commonly used ultra-hypofractionation regimen was 24 Gy/3 Fx (24%), followed by 25 Gy/5 Fx (11%) and 30 Gy/5 Fx (11%). Additionally, the most commonly used ICI in the registered trials was pembrolizumab (20.1%), followed by durvalumab (11.4%) and nivolumab (9.2%). Among all the registered trials, only 4% of the trials had been completed, but 61.5% of the completed trials had reported their results on ClinicalTrials.gov. The conventional fractionation trials were more likely to be phase 3 trials, located in China, and performed in patients with head and neck cancer or gynecological cancer (all P values <0.05), while the ultra-hypofractionation trials were more likely to be phase 1 trials, stopped early, located in the United States, and performed in patients with lung cancer (all P values <0.05). Conclusions: The number of prospective trials investigating the synergistic effect of RT and ICIs registered at ClinicalTrials.gov has increased significantly over the past decade. The ultra-hypofractionation size of the registered trials varies, but the 24 Gy/3 Fx regimen is commonly used. The clinical results of registered trials examining the synergistic effect of RT in combination with ICIs, specifically in terms of ultra-hypofractionation, remain limited.

Effect of granular activated carbon adsorption and size of microbial aggregates in inoculum on stimulating direct interspecies electron transfer during anaerobic digestion of fat, oil, and grease.

To investigate the effect of granular activated carbon (GAC) adsorption and size of microbial aggregates in inoculum on stimulating direct interspecies electron transfer (DIET) during anaerobic digestion of fat, oil, and grease (FOG), seed sludge was divided into two inocula (big (>0.85 mm)/small (0.15-0.85 mm)) for FOG digestion with/without GAC. More long-chain fatty acids (LCFAs) were adsorbed on GAC in the reactor with small aggregates than that with big aggregates, corresponding to 57 % and 10 % decreased methane production, respectively. Adsorption of unsaturated LCFAs (e.g., oleic acid) on GAC was found to reduce LCFA bioavailability, hinder DIET via GAC, and change community structure. Compared to pre-adsorption of oleic acid on GAC, pre-attachment of microbes on GAC resulted in 5.6-fold higher methane yield for oleic acid digestion. Together, competition of LCFA adsorption between GAC and microbial aggregates is essential for enhanced methane recovery from FOG digestion via GAC-induced DIET.

Preparation of microgel co-loaded with nuciferine and epigallocatechin-3-gallate for the regulation of lipid metabolism.

This study aims to enhance the stability and bioavailability of nuciferine (NF) and epigallocatechin-3-gallate (EGCG) by loading NF into liposomes and then incorporating the liposomes and EGCG into porous microgels (NFEG-microgel) prepared with chitosan and proanthocyanidin. Analysis of particle size (0.5-3.0 µm), electron microscopy, rheology, stability, and simulated gastrointestinal release confirmed that the prepared microgels had high encapsulation rate and good stability and release characteristics. Intervention experiments were performed by orally administering NFEG-microgel to high-fat diet rats to evaluate its efficacy and regulatory mechanism for blood lipid metabolism. NFEG-microgel intervention significantly reduced the body weight and serum lipid level, and the mechanism was related to the expression regulation of key genes involved in lipid metabolism and miRNAs (miR-126a-5p and miR-30b-5p) in serum extracellular vesicles. In addition, NFEG-microgel improved the diversity of gut microbiota by enriching short-chain fatty acids (SCFA)-producing bacteria and reducing harmful bacteria, suggesting that it can ameliorate lipid metabolism by regulating the intestinal flora community in rats.

Induction mechanism of cigarette smoke components (CSCs) on dyslipidemia and hepatic steatosis in rats.

OBJECTIVE: The purpose of this study was to explore the effect of cigarette smoke component (CSC) exposure on serum lipid levels in rats and the underlying molecular mechanism. METHODS: Male SPF-grade SD rats were randomly divided into a control group and a CSC exposure group, with the CSC group being exposed to CSC for 6 weeks. RT-PCR and Western blotting methods were used to detect lipid metabolism gene expression in rats, and 16S RNA gene sequencing was used to detect the gut microbiota in the rat cecum. Rat serum exosomes were prepared and identified, and the interaction of exosomal miR-291a-3p and miR-126a-5p with AMPK and CYP7A1 was detected by a dual luciferase reporter gene assay (DLRG). RESULTS: Serum indicators, including cholesterol levels and trimethylamine oxide (TMAO) content, were significantly affected in the CSC exposure group compared with the control group (P < 0.05), and the expression levels of adenylate-activated protein kinase (AMPK), acetyl-coenzyme A carboxylase (ACC) and HMG-CoA reductase (HMG-CoAR) genes were significantly increased (P < 0.05) in the liver, while the expression level of cholesterol 7α-hydroxylase (CYP7A1) was markedly decreased (P < 0.01). 16S rRNA gene sequencing of the gut microbiota in the rat cecum showed that the abundance of Firmicutes in the CSC group increased significantly at the phylum level, while the abundances of Bacteroidota and Spirochaetota were reduced significantly (P < 0.01). The relative abundance of Romboutsia, Turicibacter, and Clostridium sensu stricto increased significantly (P < 0.01), and the relative abundance of Prevotella, Muribaculaceae_norank, Lachnospiraceae NK4A136 group, Roseburia, Treponema, and Ruminococcus significantly decreased (P < 0.01) at the genus level. In addition, the exosome miR-291a-3p and miR-126a-5p levels were markedly regulated by CSC exposure (P < 0.01). The interactions of miR-291a-3p and miR-126a-5p with AMPK and CYP7A1 mRNA were also validated by the DLRG method. CONCLUSIONS: In summary, the rat dyslipidemia induced by CSC exposure may be related to the interference of gut microbiota structure and interaction of miRNAs from serum exosomes with target mRNAs, which further regulated AMPK-ACC/CYP7A1 signaling in rats.

BOIMPY-Based NIR-II Fluorophore with High Brightness and Long Absorption beyond 1000 nm for In Vivo Bioimaging: Synergistic Steric Regulation Strategy.

Fluorescence imaging in the second near-infrared (NIR-II, 1000-1700 nm) region holds great promise for in vivo bioimaging. However, it is challenging to develop a brilliant donor-acceptor-donor (D-A-D) type NIR-II fluorophore with maximal absorption beyond 1000 nm in aqueous solution. Herein, we report a bright D-A-D type BOIMPY-based NIR-II dye (NK1143) with peak absorption/emission at 1005/1143 nm for in vivo bioimaging. Co-assembly of NK1143, SC12 (intermolecular steric hindrance modulator), and DSPE-PEG2000 effectively inhibits H-aggregation of NK1143 in aqueous solution and enhances the brightness simultaneously up to 53-fold by leveraging synergistic steric regulation strategy. Notably, this strategy allows for deep optical penetration of 8 mm and high-resolution blood vessels imaging in vivo, displaying high signal-to-background ratio of 7.8/1 under 980 nm excitation. More importantly, the BOIMPY-based nanoprobe can passively target and clearly visualize broad types of tumor xenografts, further improving intraoperative NIR-II fluorescence-guided resection of tiny metastases of less than 1 mm. This work provides an effective strategy for the development of BOIMPY-based NIR-II organic fluorophores with broad applications.

Enhanced direct interspecies electron transfer and methane production during anaerobic digestion of fat, oil, and grease by coupling carbon-based conductive materials and exogenous hydrogen.

To investigate the combination of carbon-based conductive materials and exogenous hydrogen (EH2) on methane recovery from fat, oil, and grease (FOG), granular activated carbon (GAC) and carbon cloth (CC) were chosen to collaborate with EH2, resulting in increased methane production by 59 % and 84 %, respectively. Further digestion of long chain fatty acids (LCFAs) confirms that enhanced direct interspecies electron transfer (DIET) was achieved in the reactors with GAC/CC + EH2 than those with GAC/CC only. Other evidences (such as increased microbial population and rapid degradation of volatile fatty acids) were found to support the role of GAC/CC + EH2 in promotion of DIET. Significant change of microbial community was observed using GAC/CC + EH2, which was mainly attributed to the enrichment of electrogenic species (such as Spirochaetaceae, Syntrophomonas palmitatica, and Methanosaeta), leading to some changes in metabolic pathways during acidogenesis and methanogenesis. Together, enhanced DIET was achieved by GAC/CC + EH2, thus improving the methane recovery from FOG.

Three Birds with One Stone: Acceptor Engineering of Hemicyanine Dye with NIR-II Emission for Synergistic Photodynamic and Photothermal Anticancer Therapy.

It is challenging to develop a near-infrared (NIR) small molecular photosensitizer for synergistic phototherapy in deep tissues. Herein, first, a heavy-atom-free NIR hemicyanine photosensitizer (BHcy) for 808 nm light-mediated synergistic photodynamic therapy/photothermal therapy (PDT/PTT) anticancer therapy by leveraging the acceptor engineering strategy is reported. This strategy endows BHcy with a more planar and larger π-conjugated structure, resulting in long NIR absorption/emission at 770/915-1200 nm as well as enhanced singlet oxygen (1 O2 ) generation ability and photothermal effect, which is ascribed to the reduced energy levels of excited singlet/triplet states and the promoted intersystem crossing process. Notably, BHcy-based nanoparticles (BHcy-NPs) exhibit efficient 1 O2 yield (12.9%) and high photothermal conversion efficiency (55.1%). More importantly, BHcy-NPs are able to significantly kill cancer cells by destroying main organelles and inhibit tumor growth in vivo after a single irradiation. Overall, this study provides a strategy to design new heavy-atom-free PDT/PTT agents for potential clinical applications.

Bichromatic Imaging with Hemicyanine Fluorophores Enables Simultaneous Visualization of Non-alcoholic Fatty Liver Disease and Metastatic Intestinal Cancer.

Simultaneous detection of different diseases via a single fluorophore is challenging. We herein report a bichromatic fluorophore named Cy-914 for the simultaneous diagnosis of non-alcoholic fatty liver disease (NAFLD) and metastatic intestinal cancer by leveraging its NIR-I/NIR-II dual-color imaging capability. Cy-914 with a pKa of 6.98 exhibits high sensitivity to pH and viscosity, showing turn-on NIR-I fluorescence at 795 nm in an acidic tumor microenvironment, meanwhile displaying intense NIR-II fluorescence at 914/1030 nm under neutral to slightly basic viscous conditions. Notably, Cy-914 could sensitively and noninvasively monitor viscosity variations in the progression of NAFLD. More importantly, it was able to simultaneously visualize NAFLD (ex/em = 808/1000-1700 nm) and intestinal metastases (ex/em = 570/810-875 nm) in two independent channels without spectral cross interference after topical spraying, further improving fluorescence-guided surgery of tiny metastases less than 3 mm. This strategy may provide an understanding for developing multi-color fluorophores for multi-disease diagnosis.

In Situ Programming of Nanovaccines for Lymph Node-Targeted Delivery and Cancer Immunotherapy.

In situ cancer vaccines consisting of antigens and adjuvants are a promising cancer treatment modality; however, the convenient manufacture of vaccines in vivo and their efficient delivery to lymph nodes (LNs) remains a major challenge. Herein, we outline a facile approach to simultaneously achieve the in situ programming of vaccines via two synergetic nanomedicines, Tu-NPFN and Ln-NPR848. Tu-NPFN (∼100 nm) generated a large number of antigens under an alternating magnetic field, and Ln-NPR848 (∼35 nm) encapsulating adjuvant R848 captured a portion of generated antigens for the manufacture of nanovaccines in situ and LN-targeted delivery, which significantly promoted the uptake and maturation of dendritic cells to initiate potent anticancer immune responses. Notably, combined with an anti-CTLA4 antibody (aCTLA-4), this therapy completely eradicated distant tumors in some mice and exerted a long-term immune memory effect on tumor metastasis. This study provides a generalizable strategy for in situ cancer vaccination.

Temporal specificity of IL-6 knockout in enhancing the thermogenic capability of brown adipose tissue

Although interleukin-6 (IL-6) has been regarded as a homeostatic regulator of fat metabolism, its role in brown adipose thermogenesis remains to be further clarified. By using wild-type (WT) and IL-6-knockout (KO) mice, this study aims to investigate whether IL-6 regulates the thermogenic capability of brown adipose tissue (BAT) at both young and elderly stages. We demonstrated that IL-6 KO enhances BAT thermogenesis at a young age, as evidenced by the increased mRNA and protein expression levels of thermogenic genes, and the elevated interscapular surface temperature. The IL-6-KO enhancement of BAT thermogenesis is associated with improved respiratory exchange ratio (RER) and glucose homeostasis at young stages. However, these improvements disappear in elderly KO mice, which is likely attributable to the highly increased expression of other inflammatory cytokines, such as Tnfα, Il-1β, and Il-10. Our findings indicate that the lack of IL-6 has a temporal-specific contribution to the promotion of BAT thermogenesis. (AU)

GATA1 regulates the microRNA­328­3p/PIM1 axis via circular RNA ITGB1 to promote renal ischemia/reperfusion injury in HK­2 cells.

Acute kidney injury (AKI) is caused by renal ischemia/reperfusion injury (IRI) during kidney transplantation. The levels of both circular RNAs (circRNAs) and microRNAs (miRNAs/miR) appear to be critical for AKI detection. While several RNA interactions in AKI have been found, the regulatory mechanisms between the molecules remain to be fully elucidated. In the present study, miRNA expression profiling analysis was conducted using an online dataset to identify the differentially expressed miRNAs in rats with IRI. miR­328­3p was also found to be downregulated in human kidney­2 (HK­2) cells subjected to hypoxia/reperfusion (H/R), and its overexpression targeting pim­1 proto­oncogene (PIM1) resulted in an increased viability and a reduced apoptosis, as well as in the decreased expression of inflammatory factors upon H/R exposure. Putative targets and circRNAs of miR­328­3p were identified using publically available databases. The inhibition of circRNA integrin beta 1 (ITGB1; circITGB1) suppressed the inflammatory response induced by H/R by sponging miR­328­3p in HK­2 cells. Furthermore, a sequence of the functional ITGB1 promoter was studied for transcription factor GATA binding protein 1 (GATA1) binding sites. GATA1 binds to the ITGB1 promoter, leading to the expression of circITGB1. On the whole, the findings of the present study revealed a regulatory pathway modulating miR­328­3p in IRI, demonstrating that the GATA1­mediated regulation of circITGB1 enhanced the H/R­induced inflammatory response via the miR­328­3p/PIM1 axis.

Clinicopathological significance of tubulointerstitial CD68 macrophages in proliferative lupus nephritis.

OBJECTIVES: Tubulointerstitial macrophage plays a pathogenic role in renal damage of lupus nephritis (LN). However, the clinical and pathological role of these CD68 macrophages has not been fully described. The aim of the present study is to decipher the correlation between clinicopathological features and tubulointerstitial CD68 macrophages in 76 proliferative LN patients and further evaluate the prognostic significance of tubulointerstitial CD68 macrophages. METHODS: Tubulointerstitial CD68 macrophages were quantitated by standard histochemical staining. The correlation between the number of tubulointerstitial CD68 macrophages and clinicopathological features was analyzed by Spearman's correlation analysis. Factors potentially affecting renal prognosis were further evaluated by Cox regression analysis. RESULTS: Among the 76 proliferative LN cases, the number of CD68 macrophage infiltrates was positively correlated with serum creatinine (SCr) level, the proportion of glomeruli sclerosis and focal segmental sclerosis, tubulointerstitial inflammation, and chronicity indices, while negatively correlated with the glomerular filtration rate. During a mean follow-up period of 45 months, 5 patients (6.6%) progressed to dialysis, and 3 patents (3.9%) had a twofold increase in SCr. Multivariate Cox regression analysis showed that the number of tubulointerstitial CD68 macrophages was an independent variable associated with poor renal outcomes (HR = 1.002, P = 0.012). The optimal cutoff value of tubulointerstitial CD68 macrophages was 340/mm2 in our study with 87.5% sensitivity and 61.8% specificity to predict end-stage renal disease within 4 years. CONCLUSION: The number of tubulointerstitial CD68 macrophages was positively linked to poor prognosis of LN. Urgent immunosuppression should be considered in LN patients with abundant tubulointerstitial CD68 macrophages. Key Points • Tubulointerstitial CD68 macrophage infiltrates are positively correlated with clinicohistologic impairment in proliferative lupus nephritis. • The positive association between the number of tubulointerstitial CD68 macrophages and poor renal outcome of lupus nephritis patients were observed. • Urgent immunosuppression and monitor are required when abundant tubulointerstitial CD68 macrophage infiltrates are detected.

The regulation of hsacirc_004413 promotes proliferation and drug resistance of gastric cancer cells by acting as a competing endogenous RNA for miR-145-5p.

Background: Whether circRAN, which acts as a microRNA sponge, plays a role in 5-fluorouracil (5-Fu) resistant gastric cancer has not been reported. In this study, a 5-Fu resistant cell line with an IC50 of 16.59 µM was constructed. Methods: Using comparative analysis of circRNA in the transcriptomics of resistant and sensitive strains, 31 differentially expressed circRNAs were detected, and the microRNA interacting with them was predicted. Results: Hsacirc_004413 was selected for verification in drug resistant and sensitive cells. By interfering with hsacirc_004413 using antisense RNA, the sensitivity of drug resistant cells to 5-Fu was significantly promoted, and the apoptosis and necrosis of the cells were significantly increased. In sensitive cells, inhibition by inhibitors enhanced the resistance of cells to 5-Fu. We hypothesize that hsacirc_004413 makes gastric cancer cells resistant to 5-Fu mainly through adsorption of miR-145-5p.

Temporal specificity of IL-6 knockout in enhancing the thermogenic capability of brown adipose tissue.

Although interleukin-6 (IL-6) has been regarded as a homeostatic regulator of fat metabolism, its role in brown adipose thermogenesis remains to be further clarified. By using wild-type (WT) and IL-6-knockout (KO) mice, this study aims to investigate whether IL-6 regulates the thermogenic capability of brown adipose tissue (BAT) at both young and elderly stages. We demonstrated that IL-6 KO enhances BAT thermogenesis at a young age, as evidenced by the increased mRNA and protein expression levels of thermogenic genes, and the elevated interscapular surface temperature. The IL-6-KO enhancement of BAT thermogenesis is associated with improved respiratory exchange ratio (RER) and glucose homeostasis at young stages. However, these improvements disappear in elderly KO mice, which is likely attributable to the highly increased expression of other inflammatory cytokines, such as Tnfα, Il-1ß, and Il-10. Our findings indicate that the lack of IL-6 has a temporal-specific contribution to the promotion of BAT thermogenesis.