Neuroanatomy of lymphoid organs: Lessons learned from whole-tissue imaging studies.

Decades of extensive research have documented the presence of neural innervations of sensory, sympathetic, or parasympathetic origin in primary and secondary lymphoid organs. Such neural inputs can release neurotransmitters and neuropeptides to directly modulate the functions of various immune cells, which represents one of the essential aspects of the body's neuroimmune network. Notably, recent studies empowered by state-of-the-art imaging techniques have comprehensively assessed neural distribution patterns in BM, thymus, spleen, and LNs of rodents and humans, helping clarify several controversies lingering in the field. In addition, it has become evident that neural innervations in lymphoid organs are not static but undergo alterations in pathophysiological contexts. This review aims to update the current information on the neuroanatomy of lymphoid organs obtained through whole-tissue 3D imaging and genetic approaches, focusing on anatomical features that may designate the functional modulation of immune responses. Moreover, we discuss several critical questions that call for future research, which will advance our in-depth understanding of the importance and complexity of neural control of lymphoid organs.

Protopine protects chondrocytes from undergoing ferroptosis by activating Nrf2 pathway.

Osteoarthritis is a highly prevalent joint disease; however, effective treatments are lacking. Protopine (PTP) is an isoquinoline alkaloid with potent anti-inflammatory and antioxidant properties; however, it has not been studied in osteoarthritis. This study aimed to investigate whether PTP can effectively protect chondrocytes from ferroptosis. Primary mouse chondrocytes were treated with tert-butyl hydroperoxide (TBHP) to simulate oxidative stress in an in vitro model of osteoarthritis. Two concentrations of PTP (10 and 20 µg/mL) were validated for in vitro experiments. Cellular inflammation and metabolism were detected using RT-qPCR and western blotting (WB). Ferroptosis was assessed via WB, qPCR, reactive oxygen species (ROS) levels, lipid ROS, and immunofluorescence staining. In vitro, PTP significantly ameliorated chondrocyte inflammation and cytolytic metabolism and significantly suppressed chondrocyte ferroptosis through the activation of the Nrf2 pathway. The anterior cruciate ligament transection (ACLT) mouse model was used to validate the in vivo effects of PTP. The joint cartilage was assessed using the Osteoarthritis Research Society International (OARSI) score, Safranin O staining, and immunohistochemistry. The intra-articular administration of PTP alleviated cartilage inflammation and ferroptosis, as evidenced by the expression of MMP3, MMP13, COL2A1, GPX4, and Nrf2. Overall, we find that PTP exerted anti-ferroptosis and anti-inflammatory effects on chondrocytes to protect the articular cartilage.

Disentangling the relationships of body mass index and circulating sex hormone concentrations in mammographic density using Mendelian randomization.

PURPOSE: Mammographic density phenotypes, adjusted for age and body mass index (BMI), are strong predictors of breast cancer risk. BMI is associated with mammographic density measures, but the role of circulating sex hormone concentrations is less clear. We investigated the relationship between BMI, circulating sex hormone concentrations, and mammographic density phenotypes using Mendelian randomization (MR). METHODS: We applied two-sample MR approaches to assess the association between genetically predicted circulating concentrations of sex hormones [estradiol, testosterone, sex hormone-binding globulin (SHBG)], BMI, and mammographic density phenotypes (dense and non-dense area). We created instrumental variables from large European ancestry-based genome-wide association studies and applied estimates to mammographic density phenotypes in up to 14,000 women of European ancestry. We performed analyses overall and by menopausal status. RESULTS: Genetically predicted BMI was positively associated with non-dense area (IVW: ß = 1.79; 95% CI = 1.58, 2.00; p = 9.57 × 10-63) and inversely associated with dense area (IVW: ß = - 0.37; 95% CI = - 0.51,- 0.23; p = 4.7 × 10-7). We observed weak evidence for an association of circulating sex hormone concentrations with mammographic density phenotypes, specifically inverse associations between genetically predicted testosterone concentration and dense area (ß = - 0.22; 95% CI = - 0.38, - 0.053; p = 0.009) and between genetically predicted estradiol concentration and non-dense area (ß = - 3.32; 95% CI = - 5.83, - 0.82; p = 0.009), although results were not consistent across a range of MR approaches. CONCLUSION: Our findings support a positive causal association between BMI and mammographic non-dense area and an inverse association between BMI and dense area. Evidence was weaker and inconsistent for a causal effect of circulating sex hormone concentrations on mammographic density phenotypes. Based on our findings, associations between circulating sex hormone concentrations and mammographic density phenotypes are weak at best.

Patients with chronic hepatitis B who have persistently normal alanine aminotransferase or aged < 30 years may exhibit significant histologic damage.

BACKGROUND: The timing of antiviral therapy for chronic hepatitis B (CHB) patients with normal alanine transaminase (ALT) or aged < 30 years is still undetermined. We aimed to elucidate the correlation between liver histology, age, and ALT level in CHB patients and analyze the histological characteristics of the liver among patients with persistently normal ALT or aged < 30 years. METHODS: A retrospective analysis was conducted on 697 treatment-naive CHB patients. Liver biopsies were performed, and significant histological damage was defined as the grade of liver inflammation ≥ G2 and/or fibrosis ≥ S2 based on the Scheuer scoring system. RESULTS: The liver inflammation grades and fibrosis stages correlated positively with age, ALT, AST, GGT levels and negatively with the counts of PLT (all p < 0.050) in HBeAg-positive patients. Higher ALT levels and lower PLT counts were independently associated with significant liver inflammation and fibrosis in both HBeAg-positive and HBeAg-negative patients. Furthermore, among those with persistently normal ALT levels, the incidence of significant liver inflammation and fibrosis were 66.1% and 53.7% in HBeAg-positive groups, and 63.0% and 55.5% in HBeAg-negative groups. Moreover, there was no significant difference in the prevalence of significant liver damage between patients aged < 30 years and those aged ≥ 30 years, in both HBeAg-positive (≥ G2 or ≥ S2: 63.8% vs. 75.8%, p = 0.276) and HBeAg-negative (≥ G2 or ≥ S2: 65.9% vs. 72.5%, p = 0.504) groups, among patients with persistently normal ALT levels. CONCLUSIONS: A considerable proportion of CHB patients with persistently normal ALT, including those below the age of 30 years, exhibited significant histological damage. This highlights the importance of initiating early antiviral therapy for HBV-infected individuals, even in the absence of elevated ALT levels.

Multi-center application of a convolutional neural network for preoperative detection of cavernous sinus invasion in pituitary adenomas.

OBJECTIVE: Cavernous sinus invasion (CSI) plays a pivotal role in determining management in pituitary adenomas. The study aimed to develop a Convolutional Neural Network (CNN) model to diagnose CSI in multiple centers. METHODS: A total of 729 cases were retrospectively obtained in five medical centers with (n = 543) or without CSI (n = 186) from January 2011 to December 2021. The CNN model was trained using T1-enhanced MRI from two pituitary centers of excellence (n = 647). The other three municipal centers (n = 82) as the external testing set were imported to evaluate the model performance. The area-under-the-receiver-operating-characteristic-curve values (AUC-ROC) analyses were employed to evaluate predicted performance. Gradient-weighted class activation mapping (Grad-CAM) was used to determine models' regions of interest. RESULTS: The CNN model achieved high diagnostic accuracy (0.89) in identifying CSI in the external testing set, with an AUC-ROC value of 0.92 (95% CI, 0.88-0.97), better than CSI clinical predictor of diameter (AUC-ROC: 0.75), length (AUC-ROC: 0.80), and the three kinds of dichotomizations of the Knosp grading system (AUC-ROC: 0.70-0.82). In cases with Knosp grade 3A (n = 24, CSI rate, 0.35), the accuracy the model accounted for 0.78, with sensitivity and specificity values of 0.72 and 0.78, respectively. According to the Grad-CAM results, the views of the model were confirmed around the sellar region with CSI. CONCLUSIONS: The deep learning model is capable of accurately identifying CSI and satisfactorily able to localize CSI in multicenters.

The use of individual-based FDG-PET volume of interest in predicting conversion from mild cognitive impairment to dementia.

BACKGROUND: Based on a longitudinal cohort design, the aim of this study was to investigate whether individual-based 18F fluorodeoxyglucose positron emission tomography (18F-FDG-PET) regional signals can predict dementia conversion in patients with mild cognitive impairment (MCI). METHODS: We included 44 MCI converters (MCI-C), 38 non-converters (MCI-NC), 42 patients with Alzheimer's disease with dementia, and 40 cognitively normal controls. Data from annual cognitive measurements, 3D T1 magnetic resonance imaging (MRI) scans, and 18F-FDG-PET scans were used for outcome analysis. An individual-based FDG-PET approach was applied using seven volumes of interest (VOIs), Z transformed using a normal FDG-PET template. Hypometabolism was defined as a Z score < -2 of regional standard uptake value ratio. For the longitudinal cognitive test scores, generalized estimating equations were used. A linear mixed-effects model was used to compare the temporal impact of cortical hypometabolism and cortical thickness degeneration. RESULTS: The clinical follow-up period was 6.6 ± 3.8 years (range 3.1 to 16.0 years). The trend of cognitive decline could differentiate MCI-C from MCI-NC after 3 years of follow-up. In the baseline 18F-FDG-PET scan of the patients with MCI, medial temporal lobe (MTL; 94.7% sensitivity, 80.5% specificity) and posterior cingulate cortex (PCC; 89.5% sensitivity, 73.1% specificity) hypometabolism predicted conversion with high accuracy. 18F-FDG-PET hypometabolism preceded dementia conversion at an interval of 3.70 ± 1.68 years and was earlier than volumetric changes, with the exception of the MTL. CONCLUSIONS: Our finding supports the use of individual-based 18F-FDG-PET analysis to predict MCI conversion to dementia. Reduced FDG-PET metabolism in the MTL and PCC were strongly associated with future cognitive decline in the MCI-C group. Changes in 18F-FDG-PET occurred 1 to 8 years prior to conversion to dementia. Progressive hypometabolism in the PCC, precuneus and lateral temporal lobe, but not MTL, preceded MRI findings at the MCI stage.

The association between fear of progression and medical coping strategies among people living with HIV: a cross-sectional study.

BACKGROUND: Due to the chronic nature of HIV, mental health has become a critical concern in people living with HIV (PLWHIV). However, little knowledge exists about the association between fear of progression (FoP) and medical coping modes (MCMs) in PLWHIV in China. METHODS: A cohort of 303 PLWHIV were consecutively enrolled and their demographic, clinical and psychological information was collected. The Fear of Progression Questionnaire-Short Form (FoP-Q-SF), Social Support Rating Scale (SSRS), Internalized HIV Stigma Scale (IHSS) and MCMs Questionnaire were utilized. RESULTS: Of the participants, 215 PLWHIV were classified into the low-level FoP group, and 88 were grouped into the high-level FoP group based on their FoP-Q-SF scores, according to the criteria for the classification of dysfunctional FoP in cancer patients. The high-level group had a higher proportion of acquired immunodeficiency syndrome (AIDS) stage (P = 0.005), lower education levels (P = 0.027) and lower income levels (P = 0.031). Additionally, the high-level group had lower scores in social support (P < 0.001) and its three dimensions, with total SSRS scores showing a negative correlation with two dimensions of FoP-Q-SF, namely physical health (r2 = 0.0409, P < 0.001) and social family (r2 = 0.0422, P < 0.001). Further, the high-level group had higher scores in four dimensions of internalized HIV stigma, and a positive relationship was found to exist between IHSS scores and FoP-Q-SF scores for physical health (r2 = 0.0960, P < 0.001) and social family (r2 = 0.0719, P < 0.001). Social support (OR = 0.929, P = 0.001), being at the AIDS stage (OR = 3.795, P = 0.001), and internalized HIV stigma (OR = 1.028, P < 0.001) were independent factors for FoP. Furthermore, intended MCMs were evaluated. FoP were positively correlated with avoidance scores (r2 = 0.0886, P < 0.001) and was validated as the only factor for the mode of confrontation (OR = 0.944, P = 0.001) and avoidance (OR = 1.059, P = 0.001) in multivariate analysis. CONCLUSION: The incidence of dysfunctional FoP in our study population was relatively high. High-level FoP was associated with poor social support, high-level internalized HIV stigma and a negative MCM among PLWHIV.

Bioactive 5/5/5/6 Four-Ring System Iridoids from Plumeria alba L.

Two rare 5/5/5/6 four-ring system iridoids, allamancins A and B (1 and 2) together with one known biogenetically related iridoid derivative, 3-O-methyallamancin (3) were isolated from the flowers of Plumeria alba L. The structures of these iridoid derivatives were determined by comprehensive spectroscopic analyses. The absolute configuration of 1 was confirmed by X-ray crystallographic analysis. The inhibitory activities of compounds 1-3 against nitric oxide (NO) production induced and three cancer cell lines were evaluated in vitro. Compounds 1 and 3 showed inhibitory activities on NO production with IC50 values of 18.3±0.12 and 22.1±0.14 µM, respectively. Compounds 1-3 showed moderate inhibitory activities against cancer cell lines of A549, Hela and MCF-7.

Wearable Dual-Signal NH3 Sensor with High Sensitivity for Non-invasive Diagnosis of Chronic Kidney Disease.

NH3 gas in human exhaled breath contains abundant physiological information related to human health, especially chronic kidney disease (CKD). Unfortunately, up to now, most wearable NH3 sensors show inevitable defects (low sensitivity, easy to be interfered by the environment, etc.), which may lead to misdiagnosis of CKD. To solve the above dilemma, a nanoporous, heterogeneous, and dual-signal (optical and electrical) wearable NH3 sensor mask is developed successfully. More specifically, a polyacrylonitrile/bromocresol green (PAN/BCG) nanofiber film as a visual NH3 sensor and a polyacrylonitrile/polyaniline/reduced graphene oxide (PAN/PANI/rGO) nanofiber film as a resistive NH3 sensor are constructed. Due to the high specific surface area and abundant NH3 binding sites of these two nanofiber films, they exhibit good NH3 sensing performance. However, although the visual NH3 sensor (PAN/BCG nanofiber film) is simple without the need of any detecting facilities and quite stable when temperature and humidity change, it shows poor sensitivity and resolution. In comparison, the resistive NH3 sensor (PAN/PANI/rGO nanofiber film) is of high sensitivity, fast response, and good resolution, but its electrical signal is easily interfered by the external environment (such as humidity, temperature, etc.). Considering that the sensing principles between a visual NH3 sensor and resistive NH3 sensor are significantly different, a wearable dual-signal NH3 sensor containing both a visual NH3 sensor and resistive NH3 sensor is further explored. Our data prove that the two sensing signals in this dual-signal NH3 sensor mask can not only work well without interference with each other but also complement each other to improve the sensing accuracy, indicating its potential application in non-invasive diagnosis of CKD.

Acyl-CoA dehydrogenase substrate promiscuity: Challenges and opportunities for development of substrate reduction therapy in disorders of valine and isoleucine metabolism.

Toxicity of accumulating substrates is a significant problem in several disorders of valine and isoleucine degradation notably short-chain enoyl-CoA hydratase (ECHS1 or crotonase) deficiency, 3-hydroxyisobutyryl-CoA hydrolase (HIBCH) deficiency, propionic acidemia (PA), and methylmalonic aciduria (MMA). Isobutyryl-CoA dehydrogenase (ACAD8) and short/branched-chain acyl-CoA dehydrogenase (SBCAD, ACADSB) function in the valine and isoleucine degradation pathways, respectively. Deficiencies of these acyl-CoA dehydrogenase (ACAD) enzymes are considered biochemical abnormalities with limited or no clinical consequences. We investigated whether substrate reduction therapy through inhibition of ACAD8 and SBCAD can limit the accumulation of toxic metabolic intermediates in disorders of valine and isoleucine metabolism. Using analysis of acylcarnitine isomers, we show that 2-methylenecyclopropaneacetic acid (MCPA) inhibited SBCAD, isovaleryl-CoA dehydrogenase, short-chain acyl-CoA dehydrogenase and medium-chain acyl-CoA dehydrogenase, but not ACAD8. MCPA treatment of wild-type and PA HEK-293 cells caused a pronounced decrease in C3-carnitine. Furthermore, deletion of ACADSB in HEK-293 cells led to an equally strong decrease in C3-carnitine when compared to wild-type cells. Deletion of ECHS1 in HEK-293 cells caused a defect in lipoylation of the E2 component of the pyruvate dehydrogenase complex, which was not rescued by ACAD8 deletion. MCPA was able to rescue lipoylation in ECHS1 KO cells, but only in cells with prior ACAD8 deletion. SBCAD was not the sole ACAD responsible for this compensation, which indicates substantial promiscuity of ACADs in HEK-293 cells for the isobutyryl-CoA substrate. Substrate promiscuity appeared less prominent for 2-methylbutyryl-CoA at least in HEK-293 cells. We suggest that pharmacological inhibition of SBCAD to treat PA should be investigated further.

A genome-wide association study of mammographic texture variation.

BACKGROUND: Breast parenchymal texture features, including grayscale variation (V), capture the patterns of texture variation on a mammogram and are associated with breast cancer risk, independent of mammographic density (MD). However, our knowledge on the genetic basis of these texture features is limited. METHODS: We conducted a genome-wide association study of V in 7040 European-ancestry women. V assessments were generated from digitized film mammograms. We used linear regression to test the single-nucleotide polymorphism (SNP)-phenotype associations adjusting for age, body mass index (BMI), MD phenotypes, and the top four genetic principal components. We further calculated genetic correlations and performed SNP-set tests of V with MD, breast cancer risk, and other breast cancer risk factors. RESULTS: We identified three genome-wide significant loci associated with V: rs138141444 (6q24.1) in ECT2L, rs79670367 (8q24.22) in LINC01591, and rs113174754 (12q22) near PGAM1P5. 6q24.1 and 8q24.22 have not previously been associated with MD phenotypes or breast cancer risk, while 12q22 is a known locus for both MD and breast cancer risk. Among known MD and breast cancer risk SNPs, we identified four variants that were associated with V at the Bonferroni-corrected thresholds accounting for the number of SNPs tested: rs335189 (5q23.2) in PRDM6, rs13256025 (8p21.2) in EBF2, rs11836164 (12p12.1) near SSPN, and rs17817449 (16q12.2) in FTO. We observed significant genetic correlations between V and mammographic dense area (rg = 0.79, P = 5.91 × 10-5), percent density (rg = 0.73, P = 1.00 × 10-4), and adult BMI (rg = - 0.36, P = 3.88 × 10-7). Additional significant relationships were observed for non-dense area (z = - 4.14, P = 3.42 × 10-5), estrogen receptor-positive breast cancer (z = 3.41, P = 6.41 × 10-4), and childhood body fatness (z = - 4.91, P = 9.05 × 10-7) from the SNP-set tests. CONCLUSIONS: These findings provide new insights into the genetic basis of mammographic texture variation and their associations with MD, breast cancer risk, and other breast cancer risk factors.

Genome-wide and transcriptome-wide association studies of mammographic density phenotypes reveal novel loci.

BACKGROUND: Mammographic density (MD) phenotypes, including percent density (PMD), area of dense tissue (DA), and area of non-dense tissue (NDA), are associated with breast cancer risk. Twin studies suggest that MD phenotypes are highly heritable. However, only a small proportion of their variance is explained by identified genetic variants. METHODS: We conducted a genome-wide association study, as well as a transcriptome-wide association study (TWAS), of age- and BMI-adjusted DA, NDA, and PMD in up to 27,900 European-ancestry women from the MODE/BCAC consortia. RESULTS: We identified 28 genome-wide significant loci for MD phenotypes, including nine novel signals (5q11.2, 5q14.1, 5q31.1, 5q33.3, 5q35.1, 7p11.2, 8q24.13, 12p11.2, 16q12.2). Further, 45% of all known breast cancer SNPs were associated with at least one MD phenotype at p < 0.05. TWAS further identified two novel genes (SHOX2 and CRISPLD2) whose genetically predicted expression was significantly associated with MD phenotypes. CONCLUSIONS: Our findings provided novel insight into the genetic background of MD phenotypes, and further demonstrated their shared genetic basis with breast cancer.

Highly coherent, flat, and broadband time-stretched swept source based on extra-cavity spectral shaping assisted by a booster semiconductor optical amplifier.

We demonstrate a flat broadband time-stretched swept source based on extra-cavity spectral shaping. By adjusting the polarization-dependent gain profile and driving current of the booster optical amplifier (BOA), extra-cavity spectral shaping is optimized to generate output with a 1-dB bandwidth of ∼100 nm, 3-dB bandwidth of ∼140 nm and output power of ∼21.4 mW. The short-term and long-term stabilities are characterized. The average cross correlation of 183,485 round trips is 0.9997 with a standard deviation of 2×10-5, indicating high single-shot spectral similarity and high coherence. The noise floor of relative spectral energy jitter is -141.7 dB/Hz, indicating a high short-term spectral energy stability. The proposed highly stable flat broadband time-stretched swept source is applied to an optical coherence tomography (OCT) system. The axial resolution is 10.8 µm. The proposed swept source can serve as excellent light sources in ultra-fast coherent detection systems for high precision sensing and imaging.

Mutual dynamics between synchronous solitons in a bidirectional mode-locked fiber laser.

In this Letter, the mutual dynamics between synchronous solitons in a bidirectional mode-locked fiber laser are studied via dispersive Fourier transform methodology. We explore the spectral evolution and the statistical correlations between solitons with bidirectional propagation, indicating the low and high mutual linear dependences of the spectral energy jitters in stable and breathing mode-locking states, respectively. Moreover, to the best of our knowledge, the oscillating and sliding phase dynamics are experimentally revealed by the interference between bidirectional breathing solitons in ultrafast fiber lasers for the first time. Our findings enrich the understanding of the internal mutual dynamics between bidirectional solitons, which guides the extension of their potential applications, such as Sagnac-effect-based optical sensing.

Diagnostic value of circulating genetically abnormal cells to support computed tomography for benign and malignant pulmonary nodules.

BACKGROUND: The accuracy of CT and tumour markers in screening lung cancer needs to be improved. Computer-aided diagnosis has been reported to effectively improve the diagnostic accuracy of imaging data, and recent studies have shown that circulating genetically abnormal cell (CAC) has the potential to become a novel marker of lung cancer. The purpose of this research is explore new ways of lung cancer screening. METHODS: From May 2020 to April 2021, patients with pulmonary nodules who had received CAC examination within one week before surgery or biopsy at First Affiliated Hospital of Zhengzhou University were enrolled. CAC counts, CT scan images, serum tumour marker (CEA, CYFRA21-1, NSE) levels and demographic characteristics of the patients were collected for analysis. CT were uploaded to the Pulmonary Nodules Artificial Intelligence Diagnostic System (PNAIDS) to assess the malignancy probability of nodules. We compared diagnosis based on PNAIDS, CAC, Mayo Clinic Model, tumour markers alone and their combination. The combination models were built through logistic regression, and was compared through the area under (AUC) the ROC curve. RESULTS: A total of 93 of 111 patients were included. The AUC of PNAIDS was 0.696, which increased to 0.847 when combined with CAC. The sensitivity (SE), specificity (SP), and positive (PPV) and negative (NPV) predictive values of the combined model were 61.0%, 94.1%, 94.7% and 58.2%, respectively. In addition, we evaluated the diagnostic value of CAC, which showed an AUC of 0.779, an SE of 76.3%, an SP of 64.7%, a PPV of 78.9%, and an NPV of 61.1%, higher than those of any single serum tumour marker and Mayo Clinic Model. The combination of PNAIDS and CAC exhibited significantly higher AUC values than the PNAIDS (P = 0.009) or the CAC (P = 0.047) indicator alone. However, including additional tumour markers did not significantly alter the performance of CAC and PNAIDS. CONCLUSIONS: CAC had a higher diagnostic value than traditional tumour markers in early-stage lung cancer and a supportive value for PNAIDS in the diagnosis of cancer based on lung nodules. The results of this study offer a new mode of screening for early-stage lung cancer using lung nodules.

Effectiveness of antiviral treatment in HBeAg-negative chronic hepatitis B patients with normal or mildly elevated alanine aminotransferase: a retrospective study.

BACKGROUND: There are inadequate data and no histological evidence regarding the effects of antiviral treatment for hepatitis B e-antigen (HBeAg)-negative chronic hepatitis B (CHB) patients with normal or mildly elevated alanine aminotransferase (ALT). This study investigated the effects of antiviral treatment on these patients. METHODS: We retrospectively analysed the outcomes of antiviral treatment for HBeAg-negative CHB patients with normal or mildly elevated ALT who were treated with nucleoside/nucleotide analogues (NAs) for up to 96 weeks. RESULTS: A total of 128 patients were enrolled; 74 patients had normal ALT and 54 patients had mildly elevated ALT. The total cumulative rates of viral suppression were 64.06%, 81.97%, and 96.39%, at weeks 24, 48, and 96, respectively. The cumulative rates of viral suppression for the normal and mildly elevated ALT groups were 67.85% and 58.97%, 86.39% and 76.31%, and 93.13% and 97.04% at weeks 24, 48, and 96, respectively. The serum HBV DNA levels at week 12 and hepatitis B surface antigen (HBsAg) levels at week 24 were significant predictors of the 96-week virological response. Of the 128 patients, 54 with normal ALT and 33 with mildly elevated ALT underwent FibroScan at baseline. Significant fibrosis (F ≥ 2) was found in 44.4% (n = 24) and 51.5% (n = 17) of the patients in the normal ALT group and mildly elevated ALT group, respectively. Compared with the values at baseline, liver stiffness values significantly decreased at week 48 (8.12 kPa vs. 6.57 kPa; p < 0.001) and week 96 (8.87 kPa vs. 6.43 kPa; p < 0.001), respectively. CONCLUSIONS: HBeAg-negative CHB patients with normal ALT could benefit from antiviral therapy with NAs, similar to patients with mildly elevated ALT. Antiviral treatment is strongly recommended for HBeAg-negative CHB patients with normal ALT. Additionally, significant liver fibrosis is not rare in HBeAg-negative CHB patients with ALT less than two-times the upper limit of normal, and FibroScan should be performed regularly for these patients.

Murine deficiency of peroxisomal L-bifunctional protein (EHHADH) causes medium-chain 3-hydroxydicarboxylic aciduria and perturbs hepatic cholesterol homeostasis.

Peroxisomes play an essential role in the ß-oxidation of dicarboxylic acids (DCAs), which are metabolites formed upon ω-oxidation of fatty acids. Genetic evidence linking transporters and enzymes to specific DCA ß-oxidation steps is generally lacking. Moreover, the physiological functions of DCA metabolism remain largely unknown. In this study, we aimed to characterize the DCA ß-oxidation pathway in human cells, and to evaluate the biological role of DCA metabolism using mice deficient in the peroxisomal L-bifunctional protein (Ehhadh KO mice). In vitro experiments using HEK-293 KO cell lines demonstrate that ABCD3 and ACOX1 are essential in DCA ß-oxidation, whereas both the bifunctional proteins (EHHADH and HSD17B4) and the thiolases (ACAA1 and SCPx) have overlapping functions and their contribution may depend on expression level. We also show that medium-chain 3-hydroxydicarboxylic aciduria is a prominent feature of EHHADH deficiency in mice most notably upon inhibition of mitochondrial fatty acid oxidation. Using stable isotope tracing methodology, we confirmed that products of peroxisomal DCA ß-oxidation can be transported to mitochondria for further metabolism. Finally, we show that, in liver, Ehhadh KO mice have increased mRNA and protein expression of cholesterol biosynthesis enzymes with decreased (in females) or similar (in males) rate of cholesterol synthesis. We conclude that EHHADH plays an essential role in the metabolism of medium-chain DCAs and postulate that peroxisomal DCA ß-oxidation is a regulator of hepatic cholesterol biosynthesis.

Peach Kernel Extracts Inhibit Lipopolysaccharide-Induced Activation of HSC-T6 Hepatic Stellate Cells.

There is an important role for hepatic stellate cells (HSCs) in liver fibrosis. As it stands, many traditional Chinese medicine formulations can effectively improve liver fibrosis, whether it is clinically used or in animal studies; however, the efficacy and mechanism of the main formulations remain unclear, including the peach kernel, which contains numerous phytochemicals with a wide range of biological activities. The purpose of this study was to investigate peach kernel's anti-liver fibrosis effects. In this study, peach kernel extracts inhibited lipopolysaccharide (LPS) activation in HSC-T6 cells and the expression of α-smooth muscle actin and connective tissue growth factor induced by LPS in HSC-T6 cells. Furthermore, peach kernel extracts inhibited signal transducers involving protein kinase B and mitogen-activated protein kinase, which regulate downstream genes associated with inflammation. As a result, peach kernel extracts inhibited inflammatory responses and subsequently inhibited LPS-induced transformation of activated HSC-T6 cells.

Laminaria japonica Peptides Suppress Liver Cancer by Inducing Apoptosis: Possible Signaling Pathways and Mechanism.

The anticancer properties of Laminaria japonica peptides (LJPs) have never been studied. Here, we extracted LJPs from fresh seaweed and explored their anti-liver cancer activity (in vivo and in vitro). LJPs were isolated/purified by HPLC-ESI-MS. HepG2 cell apoptosis and cell cycle were evaluated. MTT assays were used to examine the cytotoxicity of LJPs. Caspase activation of caspases 3 and 9, cleaved caspases 3 and 9, and cleaved PARP was examined by Western blotting. The PI3K/AKT pathway and the phosphorylation states of MAPKs (p38 and JNK) were examined. We found that the LJP-1 peptide had the most antiproliferative activity in H22 cells in vitro. LJP-1 blocked H22 cells in the G0/G1 phase, accompanied by inhibition of cyclin expression. LJP-1 induced apoptosis through caspase activation and regulation of the ASK1/MAPK pathway. Concurrent in vivo studies demonstrated that LJP-1 significantly inhibited tumor growth and induced tumor cell apoptosis/necrosis. In conclusion, LJPs, particularly LJP-1, exert strong inhibitory effects on liver cancer growth in vivo and in vitro. LJP-1 induces HCC cell apoptosis through the caspase-dependent pathway and G0/G1 arrest. LJP-1 induces caspase-dependent apoptosis, in part by inhibiting PI3K, MAPK signaling pathways, and cell cycle proteins. LJP-1 has the potential to be a novel candidate for human liver cancer therapeutics.

Nangibotide attenuates osteoarthritis by inhibiting osteoblast apoptosis and TGF-ß activity in subchondral bone.

Osteoarthritis (OA) is a chronic joint disorder that causes cartilage degradation and subchondral bone abnormalities. Nangibotide, also known as LR12, is a dodecapeptide with considerable anti-inflammatory properties, but its significance in OA is uncertain. The aim of the study was to determine whether nangibotide could attenuate the progression of OA, and elucidate the underlying mechanism. In vitro experiments showed that nangibotide strongly inhibited TNF-α-induced osteogenic reduction, significantly enhanced osteoblast proliferation and prevented apoptosis in MC3T3-E1 cells. Male C57BL/6 J mice aged 2 months were randomly allocated to three groups: sham, ACLT, and ACLT with nangibotide therapy. Nangibotide suppressed ACLT-induced cartilage degradation and MMP-13 expression. MicroCT analysis revealed that nangibotide attenuated in vivo subchondral bone loss induced by ACLT. Histomorphometry results showed that nangibotide attenuated ACLT-induced osteoblast inhibition; TUNEL assays and immunohistochemical staining of cleaved-caspase3 further confirmed the in vivo anti-apoptotic effect of nangibotide on osteoblasts. Furthermore, we found that nangibotide exerted protective effects by suppressing TGF-ß signaling mediated by Smad2/3 to restore coupled bone remodeling in the subchondral bone. In conclusion, the findings suggest that nangibotide might exert a protective effect on the bone-cartilage unit and maybe an alternative treatment option for OA.