Estrogen restores disordered lipid metabolism in visceral fat of prediabetic mice.

BACKGROUND: Visceral obesity is increasingly prevalent among adolescents and young adults and is commonly recognized as a risk factor for type 2 diabetes. Estrogen [17ß-estradiol (E2)] is known to offer protection against obesity via diverse me-chanisms, while its specific effects on visceral adipose tissue (VAT) remain to be fully elucidated. AIM: To investigate the impact of E2 on the gene expression profile within VAT of a mouse model of prediabetes. METHODS: Metabolic parameters were collected, encompassing body weight, weights of visceral and subcutaneous adipose tissues (VAT and SAT), random blood glucose levels, glucose tolerance, insulin tolerance, and overall body composition. The gene expression profiles of VAT were quantified utilizing the Whole Mouse Genome Oligo Microarray and subsequently analyzed through Agilent Feature Extraction software. Functional and pathway analyses were conducted employing Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses, respectively. RESULTS: Feeding a high-fat diet (HFD) moderately increased the weights of both VAT and SAT, but this increase was mitigated by the protective effect of endogenous E2. Conversely, ovariectomy (OVX) led to a significant increase in VAT weight and the VAT/SAT weight ratio, and this increase was also reversed with E2 treatment. Notably, OVX diminished the expression of genes involved in lipid metabolism compared to HFD feeding alone, signaling a widespread reduction in lipid metabolic activity, which was completely counteracted by E2 administration. This study provides a comprehensive insight into E2's local and direct protective effects against visceral adiposity in VAT at the gene level. CONCLUSION: In conclusion, the present study demonstrated that the HFD-induced over-nutritional challenge disrupted the gene expression profile of visceral fat, leading to a universally decreased lipid metabolic status in E2 deficient mice. E2 treatment effectively reversed this condition, shedding light on the mechanistic role and therapeutic potential of E2 in combating visceral obesity.

An ultrasound-based histogram analysis model for prediction of tumour stroma ratio in pleomorphic adenoma of the salivary gland.

OBJECTIVES: Preoperative identification of different stromal subtypes of pleomorphic adenoma (PA) of the salivary gland is crucial for making treatment decisions. We aimed to develop and validate a model based on histogram analysis (HA) of ultrasound (US) images for predicting tumour stroma ratio (TSR) in salivary gland PA. METHODS: A total of 219 PA patients were divided into low-TSR (stroma-low) and high-TSR (stroma-high) groups and enrolled in a training cohort (n = 151) and a validation cohort (n = 68). The least absolute shrinkage and selection operator regression algorithm was used to screen the most optimal clinical, US, and HA features. The selected features were entered into multivariable logistic regression analyses for further selection of independent predictors. Different models, including the nomogram model, the clinic-US (Clin + US) model, and the HA model, were built based on independent predictors using logistic regression. The performance levels of the models were evaluated and validated on the training and validation cohorts. RESULTS: Lesion size, shape, cystic areas, vascularity, HA_mean, and HA_skewness were identified as independent predictors for constructing the nomogram model. The nomogram model incorporating the clinical, US, and HA features achieved areas under the curve of 0.839 and 0.852 in the training and validation cohorts, respectively, demonstrating good predictive performance and calibration. Decision curve analysis and clinical impact curves further confirmed its clinical usefulness. CONCLUSIONS: The nomogram model we developed offers a practical tool for preoperative TSR prediction in PA, potentially enhancing clinical decision-making.

Genome-wide identification of the N6-methyladenosine regulatory genes reveals NtFIP37B increases drought resistance of tobacco (Nicotiana tabacum L.).

BACKGROUND: N6-methyladenosine (m6A) is one of the common internal RNA modifications found in eukaryotes. The m6A modification can regulate various biological processes in organisms through the modulation of alternative splicing, alternative polyadenylation, folding, translation, localization, transport, and decay of multiple types of RNA, without altering the nucleotide sequence. The three components involved in m6A modification, namely writer, eraser, and reader, mediate the abundance of RNA m6A modification through complex collaborative actions. Currently, research on m6A regulatory genes in plants is still in its infancy. RESULTS: In this study, we identified 52 candidate m6A regulatory genes in common tobacco (Nicotiana tabacum L.). Gene structure, conserved domains, and motif analysis showed structural and functional diversity among different subgroups of tobacco m6A regulatory genes. The amplification of m6A regulatory genes were mainly driven by polyploidization and dispersed duplication, and duplicated genes evolved through purified selection. Based on the potential regulatory network and expression pattern analysis of m6A regulatory genes, a significant number of m6A regulatory genes might play important roles in growth, development, and stress response processes. Furthermore, we have confirmed the critical role of NtFIP37B, an m6A writer gene in tobacco, in enhancing drought resistance. CONCLUSIONS: This study provides useful information for better understanding the evolution of m6A regulatory genes and the role of m6A modification in tobacco stress response, and lays the foundation for further elucidating the function of m6A regulatory genes in tobacco.

Genome-wide identification and analysis of WD40 proteins reveal that NtTTG1 enhances drought tolerance in tobacco (Nicotiana tabacum).

BACKGROUND: WD40 proteins, which are highly prevalent in eukaryotes, play important roles in plant development and stress responses. However, systematic identification and exploration of WD40 proteins in tobacco have not yet been conducted. RESULTS: In this study, a total of 399 WD40 regulatory genes were identified in common tobacco (Nicotiana tabacum). Gene structure and motif analysis revealed structural and functional diversity among different clades of tobacco WD40 regulatory genes. The expansion of tobacco WD40 regulatory genes was mainly driven by segmental duplication and purifying selection. A potential regulatory network of NtWD40s suggested that NtWD40s might be regulated by miRNAs and transcription factors in various biological processes. Expression pattern analysis via transcriptome analysis and qRT-PCR revealed that many NtWD40s exhibited tissue-specific expression patterns and might be involved in various biotic and abiotic stresses. Furthermore, we have validated the critical role of NtTTG1, which was located in the nuclei of trichome cells, in enhancing the drought tolerance of tobacco plants. CONCLUSIONS: Our study provides comprehensive information to better understand the evolution of WD40 regulatory genes and their roles in different stress responses in tobacco.

A nomogram based on ultrasound scoring system for differentiating between immunoglobulin G4-related sialadenitis and primary Sjögren syndrome.

OBJECTIVES: Accurate distinguishing between immunoglobulin G4-related sialadenitis (IgG4-RS) and primary Sjögren syndrome (pSS) is crucial due to their different treatment approaches. This study aimed to construct and validate a nomogram based on the ultrasound (US) scoring system for the differentiation of IgG4-RS and pSS. METHODS: A total of 193 patients with a clinical diagnosis of IgG4-RS or pSS treated at our institution were enrolled in the training cohort (n = 135; IgG4-RS = 28, pSS = 107) and the validation cohort (n = 58; IgG4-RS = 15, pSS = 43). The least absolute shrinkage and selection operator regression algorithm was utilized to screen the most optimal clinical features and US scoring parameters. A model for the differential diagnosis of IgG4-RS or pSS was built using logistic regression and visualized as a nomogram. The performance levels of the nomogram model were evaluated and validated in both the training and validation cohorts. RESULTS: The nomogram incorporating clinical features and US scoring parameters showed better predictive value in differentiating IgG4-RS from pSS, with the area under the curves of 0.947 and 0.958 for the training cohort and the validation cohort, respectively. Decision curve analysis demonstrated that the nomogram was clinically useful. CONCLUSIONS: A nomogram based on the US scoring system showed favourable predictive efficacy in differentiating IgG4-RS from pSS. It has the potential to aid in clinical decision-making.

A Novel Multi-Functional Fluorescence Probe for the Detection of Al3+/Zn2+/Cd2+ and its Practical Applications.

A novel multi-functional fluorescence probe HMIC based on hydrazide Schiff base has been successfully synthesized and characterized. It can distinguish Al3+/Zn2+/Cd2+ in ethanol, in which fluorescence emission with different colors (blue for Al3+, orange for Zn2+, and green for Cd2+) were presented. The limits of detection of HMIC towards three ions were calculated from the titration curve as 7.70 × 10- 9 M, 4.64 × 10- 9 M, and 1.35 × 10- 8 M, respectively. The structures of HMIC and its complexes were investigated using UV-Vis spectra, Job's plot, infrared spectra, mass spectrometry, 1H-NMR and DFT calculations. Practical application studies have also demonstrated that HMIC can be applied to real samples with a low impact of potential interferents. Cytotoxicity and cellular imaging assays have shown that HMIC has good cellular permeability and potential antitumor effects. Interestingly, HMIC can image Al3+, Zn2+ and Cd2+ in the cells with different fluorescence signals.

Impact of PNPLA3 I148M on alpha-1 antitrypsin deficiency-dependent liver disease progression.

BACKGROUND AND AIMS: Genetic risk factors are major determinants of chronic liver disease (CLD) progression. Patatin-like phospholipase domain-containing protein 3 (PNPLA3) I148M polymorphism and alpha-1 antitrypsin (AAT) E342K variant, termed PiZ, are major modifiers of metabolic CLD. Both variants are known to affect metabolic CLD through increased endoplasmic reticulum stress, but their combined effect on CLD progression remains largely unknown. Here, we aimed to test our working hypothesis that their combined incidence triggers CLD disease progression. APPROACH AND RESULTS: We showed that patients with PiZZ/PNPLA3 I148M from the European alpha-1-antitrypsin deficiency (AATD) liver consortium and the UK Biobank had a trend towards higher liver enzymes, but no increased liver fat accumulation was evident between subgroups. After generating transgenic mice that overexpress the PiZ variant and simultaneously harbor the PNPLA3 I148M knockin (designated as PiZ/PNPLA3 I148M ), we observed that animals with PiZ and PiZ/PNPLA3 I148M showed increased liver enzymes compared to controls during aging. However, no significant difference between PiZ and PiZ/PNPLA3 I148M groups was observed, with no increased liver fat accumulation over time. To further study the impact on CLD progression, a Western-styled diet was administered, which resulted in increased fat accumulation and fibrosis in PiZ and PiZ/PNPLA3 I148M livers compared to controls, but the additional presence of PNPLA3 I148M had no impact on liver phenotype. Notably, the PiZ variant protected PNPLA3 I148M mice from liver damage and obesity after Western-styled diet feeding. CONCLUSION: Our results demonstrate that the PNPLA3 polymorphism in the absence of additional metabolic risk factors is insufficient to drive the development of advanced liver disease in severe AATD.

The Gene Expression Profiles Associated with Maternal Nicotine Exposure in the Liver of Offspring Mice.

This study aims to investigate the effect of maternal nicotine exposure on the gene expression profiles in the liver of offspring mice. Pregnant mice were subcutaneously injected with either saline vehicle or nicotine twice a day on gestational days 11-21. Total RNA from the liver samples which collected from the offspring mice of postnatal day 7 and 21 was subjected to RNA sequencing. Gene Ontology (GO) functional enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) signaling pathway enrichment analysis were conducted to identify the functions of differentially expressed genes (DEGs). Four genes were selected for further validation by quantitative reverse transcription polymerase chain reaction (qRT-PCR). A total of 448 DEGs and 186 DEGs were identified on postnatal day 7 and 21, respectively. GO analysis revealed that the DEGs on postnatal day 7 mainly participated in the biological functions of cell growth and proliferation, and the DEGs on postnatal day 21 mainly participated in ion transport/activity. KEGG enrichment analysis showed that the DEGs on postnatal day 7 were mainly enriched in the cell cycle, cytokine-cytokine receptor interactions, hypertrophic cardiomyopathy, and the p53 signaling pathway, while the DEGs on postnatal day 21 were mainly enriched in neuroactive ligand-receptor interactions, the calcium signaling pathway, retinol metabolism, and axon guidance. The qRT-PCR results were consistent with the RNA sequencing data. The DEGs may affect the growth of liver in early postnatal period while may affect ion transport/activity in late postnatal period.

Ultrasound characteristics of breast fibromatosis mimicking carcinoma.

PURPOSE: To explore the value of ultrasound (US) characteristics in diagnosing breast fibromatosis (BF) and evaluate their differences from breast carcinoma. METHODS: A total of 121 patients with BF (n = 24, 29 lesions) or invasive ductal carcinoma (IDC) (n = 97, 102 lesions) of the breast were included. Their clinical and US findings were recorded and analyzed. RESULTS: The mean age of BF was younger than that of IDC (28.75 ± 5.55 vs. 50.19 ± 9.87, p < 0.001). The mean size of the BF was smaller than that of IDC (2.09 ± 0.91 vs. 2.71 ± 1.20, p = 0.011). Compared to IDC, BF had more frequency of posterior echo attenuation (p < 0.001), less frequency of peripheral hyperechoic halo (p = 0.002), calcification (p = 0.001), US reported axillary lymph node positive (p = 0.025), and grade 2-3 vascularity (p < 0.001). The Breast Imaging Reporting and Data System categorized BF at a lower level than IDC (p < 0.001). After adjusting for age, the peripheral hyperechoic halo, posterior echo feature, and vascularity could independently identify the differences between these two entities. CONCLUSION: Some differences were observed between BF and IDC in terms of patient age, lesion size, and US characteristics.

Resveratrol inhibits autophagy and promotes apoptosis in uveal melanoma cells via miR-512-3P/DUSPl axis / 中国药理学通报

Aim To investigate the regulatory role and mechanism of resveratrol in inhibiting autophagy and promoting apoptosis in choroidal melanoma cells. Methods Choroidal melanoma cells (MUM2B) were divided into control and experimental groups, and treated with different concentrations of resveratrol (0, 10, 20,40,60,80 μmol ·L

Metasurface-driven polarization-division multiplexing of PCSEL for optical communications.

Free-space optical communications hold promising advantages, including a large bandwidth, access to license-free spectrum, high data rates, quick and simple deployment, low power consumption, and relaxed quality requirements. Nevertheless, key technical challenges remain, such as a higher transmission efficiency, a lower transmission loss, and a smaller form factor of optical systems. Here, we demonstrate the viability of circular-polarization-multiplexed multi-channel optical communication using metasurfaces alongside a photonic-crystal surface-emitting laser (PCSEL) light source at wavelength of 940 nm. Through the light manipulation with metasurface, we split the linearly polarized incidence into left and right circular polarizations with desired diffraction angles. Such orthogonal polarization states provide a paradigm of polarization division multiplexing technique for light communication. The PCSEL light source maintains a low divergence angle of about 0.373 degrees after passing through an ultra-thin metasurface without further bulky collimator or light guide, making end-to-end (E2E) and device-to-device (D2D) communications available in a compact form. Both light source and modulated polarized light exhibit a - 3 dB bandwidth over 500 MHz, with successful 1 Gbit/s transmission demonstrated in eye diagrams. Our results affirm that metasurface effectively boosts transmission capacity without compromising the light source's inherent properties. Future metasurface designs could expand channel capacity, and its integration with PCSEL monolithically holds promise for reducing interface losses, thereby enhancing efficiency.

Effects of variable-temperature heat reservoirs on performance of irreversible Carnot refrigerator with heat recovery.

The outlet temperature of the heat recovery reservoir is an important parameter in the design of refrigeration with heat recovery systems. In this paper the second law of thermodynamics has been applied to an irreversible Carnot refrigerator with heat recovery (CRHR) coupled to variable-temperature heat reservoirs. The refrigerating rate, input power, refrigeration coefficient, heat recovery coefficient, comprehensive coefficient of performance and exergy efficiency are chosen as the objective functions. The design rule chosen for this study is that the heat transfer area should be constrained. The mathematical expressions for assessing performance parameters with respect to area ratio, were derived for this study. These expressions are transcendental equations. The numerical solution method was employed to calculate the approximate solutions of the optimum performance parameters in a numerical example. The results indicate that the increase in the outlet temperature of heat recovery reservoir could lead to a rise in the maximum value of refrigerating rate and minimum value of input power; also it will lead to the decline in the maximum value of refrigeration coefficient, heat recovery coefficient, comprehensive coefficient and the exergy efficiency. When the ratio of heat recovery heat exchanger area to the summation of high temperature heat exchanger area and the heat recovery heat exchanger area is 1.0, the performance coefficients would attain their limit values and all of the condensing heat could be recycled. Our findings are helpful to the design and optimization to inform preparation of standard relating to the development of refrigerator with heat recovery.

Pyroptosis is involved in maternal nicotine exposure-induced metabolic associated fatty liver disease progression in offspring mice.

We have investigated whether inflammasomes and pyroptosis are activated in maternal nicotine exposure (MNE) offspring mice and whether they are involved in MNE-promoted metabolic associated fatty liver disease (MAFLD) in adult offspring. We injected pregnant mice subcutaneously with saline vehicle or nicotine twice a day on gestational days 11-21. Offspring mice from both groups were fed with a normal diet (ND) or a high-fat diet (HFD) for 6 months at postnatal day 21 to develop the MAFLD model. Serum biochemical indices were analyzed, and liver histology was performed. The expression levels of inflammasome and pyroptosis proteins were detected by western blot. We found MNE significantly aggravated the injury of MAFLD in adult offspring mice. MNE activated inflammasomes and pyroptosis in both infant and adult offspring mice. HFD treatment activated inflammasomes but not pyroptosis at 3 months, while it showed no effect at 6 months. However, pyroptosis was more severe in MNE-HFD mice than in MNE-ND mice at 6 months. Taken together, our data suggest MNE promotes MAFLD progression in adult offspring mice. MNE also induces NLRP3 and NLRP6 inflammasome activation and pyroptosis in both infant and adult offspring mice, which may be involved in MNE-promoted progression of MAFLD.

JNKs protect from cholestatic liver disease progression by modulating Apelin signalling.

Background & Aims: Cholestatic liver injury is associated with c-Jun N-terminal kinases (JNK) activation in distinct cell types. Its hepatocyte-specific function during cholestasis, however, has not yet been established. Therefore, in our present study, we investigated the role of JNK1/2 during cholestasis and dissected its hepatocyte-specific function. Methods: A cohort of patients with primary biliary cholangitis (n = 29) and primary sclerosing cholangitis (n = 37) was examined. Wild-type, hepatocyte-specific knockout mice for Jnk2 (Jnk2Δhepa) or Jnk1 and Jnk2 (Jnk1Δhepa/2Δhepa) were generated. Mice were subjected to bile duct ligation (BDL) or carbon tetrachloride (CCl4) treatment. Finally, Apelin signalling was blocked using a specific inhibitor. As an interventional approach, Jnk1/2 were silenced in wild-type mice using lipid nanoparticles for small interfering RNA delivery. Results: JNK activation was increased in liver specimens from patients with chronic cholestasis (primary biliary cholangitis and primary sclerosing cholangitis) and in livers of Mdr2-/- and BDL-treated animals. In Jnk1Δhepa/2Δhepa animals, serum transaminases increased after BDL, and liver histology demonstrated enhanced cell death, compensatory proliferation, hepatic fibrogenesis, and inflammation. Furthermore, microarray analysis revealed that hepatocytic Jnk1/2 ablation induces JNK-target genes involved in oxidative stress and Apelin signalling after BDL. Consequently, blocking Apelin signalling attenuated BDL-induced liver injury and fibrosis in Jnk1Δhepa/2Δhepa mice. Finally, we established an interventional small interfering RNA approach of selective Jnk1/2 targeting in hepatocytes in vivo, further demonstrating the essential protective role of Jnk1/2 during cholestasis. Conclusions: Jnk1 and Jnk2 work together to protect hepatocytes from cholestatic liver disease by controlling Apelin signalling. Dual modification of JNK signalling in hepatocytes is feasible, and enhancing its expression might be an attractive therapeutic approach for cholestatic liver disease. Impact and Implications: The cell-specific function of Jnk genes during cholestasis has not been explicitly explored. In this study, we showed that combined Jnk1/2, but not Jnk2 deficiency, in hepatocytes exacerbates liver damage and fibrosis by enhancing Apelin signalling, which contributes to cholestasis progression. Combined cell-specific Jnk targeting may be a new molecular strategy for treating cholestatic liver disease.

A nomogram incorporating clinical, conventional ultrasound and shear wave elastography findings for distinguishing pleomorphic adenoma from Warthin's tumor of the major salivary glands.

OBJECTIVE: Pre-operative differentiation between pleomorphic adenoma (PA) and Warthin's tumor (WT) of the major salivary glands is crucial for treatment decisions. The purpose of this study was to develop and validate a nomogram incorporating clinical, conventional ultrasound (CUS) and shear wave elastography (SWE) features to differentiate PA from WT. METHODS: A total of 113 patients with histological diagnosis of PA or WT of the major salivary glands treated at Fujian Medical University Union Hospital were enrolled in training cohort (n = 75; PA = 41, WT = 34) and validation cohort (n = 38; PA = 22, WT = 16). The least absolute shrinkage and selection operator (LASSO) regression algorithm was used for screening the most optimal clinical, CUS, and SWE features. Different models, including the nomogram model, clinic-CUS (Clin+CUS) and SWE model, were built using logistic regression. The performance levels of the models were evaluated and validated on the training and validation cohorts, and then compared among the three models. RESULTS: The nomogram incorporating the clinical, CUS and SWE features showed favorable predictive value for differentiating PA from WT, with the area under the curves (AUCs) of 0.947 and 0.903 for the training cohort and validation cohort, respectively. Decision curve analysis showed that the nomogram model outperformed the Clin+CUS model and SWE model in terms of clinical usefulness. CONCLUSIONS: The nomogram had good performance in distinguishing major salivary PA from WT and held potential for optimizing the clinical decision-making process.

Colitis ameliorates cholestatic liver disease via suppression of bile acid synthesis.

Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease characterized by chronic inflammation and progressive fibrosis of the biliary tree. The majority of PSC patients suffer from concomitant inflammatory bowel disease (IBD), which has been suggested to promote disease development and progression. However, the molecular mechanisms by which intestinal inflammation may aggravate cholestatic liver disease remain incompletely understood. Here, we employ an IBD-PSC mouse model to investigate the impact of colitis on bile acid metabolism and cholestatic liver injury. Unexpectedly, intestinal inflammation and barrier impairment improve acute cholestatic liver injury and result in reduced liver fibrosis in a chronic colitis model. This phenotype is independent of colitis-induced alterations of microbial bile acid metabolism but mediated via hepatocellular NF-κB activation by lipopolysaccharide (LPS), which suppresses bile acid metabolism in-vitro and in-vivo. This study identifies a colitis-triggered protective circuit suppressing cholestatic liver disease and encourages multi-organ treatment strategies for PSC.

Contrast-Enhanced Ultrasound Imaging: Novel Method for the Evaluation of Chronic Alcohol-Induced Testicular Damage.

OBJECTIVE: The goals of this study were to determine whether contrast-enhanced ultrasound (CEUS) imaging could be used for assessment of chronic alcohol-induced testicular damage (CAITD) and to explore the relationships between the laboratory and pathological findings of CAITD and the quantitative parameters of CEUS. METHODS: Thirty-six rabbits were randomly divided into a chronic ethanol exposure (CEE) group and negative control (NC) group, which were further randomly divided into six groups with equal numbers of rabbits by period of exposure (30 d, 60 d, 90 d). All rabbits underwent conventional US and CEUS imaging at the end of the induction period. Blood and histological specimens were collected for laboratory and pathological examination. RESULTS: The peak intensity (PI) and area under the curve (AUC) for the CEUS parameters decreased as CAITD progressed (p < 0.05). Both PI and AUC were positively correlated with the Johnsen score (r= 0.945 and 0.898, respectively, all p values <0.001) and the mean epithelium thickness of the seminiferous tubule (METST) (r= 0.927 and 0.881, respectively, all p values <0.001) of the testis, and negatively correlated with the serum levels of endothelin-1 (ET-1) (r = -0.940 and -0.899, respectively, all p values <0.001) and nitric oxide (NO) (r = -0.894 and -0.954, respectively, all p values <0.001), as well as the testicular tissue content of malondialdehyde (MDA) (r = -0.894 and -0.945, respectively, all p values <0.001). CONCLUSION: CEUS imaging can be used for monitoring organ perfusion of the testis to quantify the development of CAITD.

Intermittent Fasting Primes the Tumor Microenvironment and Improves Nanomedicine Delivery in Hepatocellular Carcinoma.

Fasting has many health benefits, including reduced chemotherapy toxicity and improved efficacy. It is unclear how fasting affects the tumor microenvironment (TME) and tumor-targeted drug delivery. Here the effects of intermittent (IF) and short-term (STF) fasting are investigated on tumor growth, TME composition, and liposome delivery in allogeneic hepatocellular carcinoma (HCC) mouse models. To this end, mice are inoculated either subcutaneously or intrahepatically with Hep-55.1C cells and subjected to IF for 24 d or to STF for 1 d. IF but not STF significantly slows down tumor growth. IF increases tumor vascularization and decreases collagen density, resulting in improved liposome delivery. In vitro, fasting furthermore promotes the tumor cell uptake of liposomes. These results demonstrate that IF shapes the TME in HCC towards enhanced drug delivery. Finally, when combining IF with liposomal doxorubicin treatment, the antitumor efficacy of nanochemotherapy is found to be increased, while systemic side effects are reduced. Altogether, these findings exemplify that the beneficial effects of fasting on anticancer therapy outcomes go beyond modulating metabolism at the molecular level.

Long-term hypercaloric diet exacerbates metabolic liver disease in PNPLA3 I148M animals.

BACKGROUND & AIMS: Nonalcoholic fatty liver disease (NAFLD) is a major health burden associated with the metabolic syndrome leading to liver fibrosis, cirrhosis and ultimately liver cancer. In humans, the PNPLA3 I148M polymorphism of the phospholipase patatin-like phospholipid domain containing protein 3 (PNPLA3) has a well-documented impact on metabolic liver disease. In this study, we used a mouse model mimicking the human PNPLA3 I148M polymorphism in a long-term high fat diet (HFD) experiment to better define its role for NAFLD progression. METHODS: Male mice bearing wild-type Pnpla3 (Pnpla3WT ), or the human polymorphism PNPLA3 I148M (Pnpla3148M/M ) were subjected to HFD feeding for 24 and 52 weeks. Further analysis concerning basic phenotype, inflammation, proliferation and cell death, fibrosis and microbiota were performed in each time point. RESULTS: After 52 weeks HFD Pnpla3148M/M animals had more liver fibrosis, enhanced numbers of inflammatory cells as well as increased Kupffer cell activity. Increased hepatocyte cell turnover and ductular proliferation were evident in HFD Pnpla3148M/M livers. Microbiome diversity was decreased after HFD feeding, changes were influenced by HFD feeding (36%) and the PNPLA3 I148M genotype (12%). Pnpla3148M/M mice had more faecal bile acids. RNA-sequencing of liver tissue defined an HFD-associated signature, and a Pnpla3148M/M specific pattern, which suggests Kupffer cell and monocytes-derived macrophages as significant drivers of liver disease progression in Pnpla3148M/M animals. CONCLUSION: With long-term HFD feeding, mice with the PNPLA3 I148M genotype show exacerbated NAFLD. This finding is linked to PNPLA3 I148M-specific changes in microbiota composition and liver gene expression showing a stronger inflammatory response leading to enhanced liver fibrosis progression.

A novel digital biomarker of sarcopenia in frail elderly: New combination of gait parameters under dual-task walking.

Background: Frailty caused by deterioration in multiple physiological systems has led to a significant increase in adverse events such as falls, disability, and death in frail older people. Similar to frailty, sarcopenia, defined as loss of skeletal muscle mass and strength, is tightly related to mobility disorders, falls, and fractures. With population aging, co-occurrences of frailty and sarcopenia are increasingly common in the elderly, which are more deleterious for the health and independence of older adults. But the high similarity and overlap between the frailty and sarcopenia increase the difficulty of early recognition of frailty with sarcopenia. The purpose of this study is to use detailed gait assessment to determine the more convenient and sensitive digital biomarker of sarcopenia in the frail population. Methods: Ninety-five frail elderly people (age = 86 ± 7 years old, BMI, and body mass index = 23.21 ± 3.40 kg/m2) were screened out by the evaluation of Fried criteria. Then, 41 participants (46%) were identified with sarcopenia, and 51 participants (54%) were identified without sarcopenia. Using a validated wearable platform, participants' gait performance was evaluated under single-task and dual-task (DT). Participants walked back and forth on the 7-m-long trail for 2 min at a habitual speed. Gait parameters of interest include cadence, gait cycle duration, step duration, gait speed, variability of gait speed, stride length, turn duration, and steps in turn. Results: Our results showed that compared with the frail elderly without sarcopenia, the gait performance of the sarcopenic group in single-task and dual-task walking was worse. Overall, the parameters with high performance were the gait speed (DT) (OR 0.914; 95% CI 0.868-0.962) and turn duration (DT) (OR 7.907; 95% CI 2.401-26.039) under dual-task conditions, and the AUC in distinguishing between frail older adults with and without sarcopenia was 0.688 and 0.736, respectively. Turn duration in dual-task testing had larger observed effect than gait speed to identify sarcopenia in the frail population, this result remained significant even after controlling for potential confounds. When gait speed (DT) and turn duration (DT) were combined in the model, AUC increased from 0.688 to 0.763. Conclusion: This study shows that gait speed and turn duration under dual-task are good predictors of sarcopenia in frail elderly, and turn duration (DT) has a better predictive ability. The gait speed (DT) combined with turn duration (DT) is a potential gait digital Biomarker of sarcopenia in the frail elderly. Dual-task gait assessment and detailed gait indexes provide important value for identification of sarcopenia in frail elderly people.