The zinc finger protein Miz1 suppresses liver tumorigenesis by restricting hepatocyte-driven macrophage activation and inflammation.

Chronic inflammation plays a central role in hepatocellular carcinoma (HCC), but the contribution of hepatocytes to tumor-associated inflammation is not clear. Here, we report that the zinc finger transcription factor Miz1 restricted hepatocyte-driven inflammation to suppress HCC, independently of its transcriptional activity. Miz1 was downregulated in HCC mouse models and a substantial fraction of HCC patients. Hepatocyte-specific Miz1 deletion in mice generated a distinct sub-group of hepatocytes that produced pro-inflammatory cytokines and chemokines, which skewed the polarization of the tumor-infiltrating macrophages toward pro-inflammatory phenotypes to promote HCC. Mechanistically, Miz1 sequestrated the oncoprotein metadherin (MTDH), preventing MTDH from promoting transcription factor nuclear factor κB (NF-κB) activation. A distinct sub-group of pro-inflammatory cytokine-producing hepatocytes was also seen in a subset of HCC patients. In addition, Miz1 expression inversely correated with disease recurrence and poor prognosis in HCC patients. Our findings identify Miz1 as a tumor suppressor that prevents hepatocytes from driving inflammation in HCC.

NT-3 contributes to chemotherapy-induced neuropathic pain through TrkC-mediated CCL2 elevation in DRG neurons.

Cancer patients undergoing treatment with antineoplastic drugs often experience chemotherapy-induced neuropathic pain (CINP), and the therapeutic options for managing CINP are limited. Here, we show that systemic paclitaxel administration upregulates the expression of neurotrophin-3 (Nt3) mRNA and NT3 protein in the neurons of dorsal root ganglia (DRG), but not in the spinal cord. Blocking NT3 upregulation attenuates paclitaxel-induced mechanical, heat, and cold nociceptive hypersensitivities and spontaneous pain without altering acute pain and locomotor activity in male and female mice. Conversely, mimicking this increase produces enhanced responses to mechanical, heat, and cold stimuli and spontaneous pain in naive male and female mice. Mechanistically, NT3 triggers tropomyosin receptor kinase C (TrkC) activation and participates in the paclitaxel-induced increases of C-C chemokine ligand 2 (Ccl2) mRNA and CCL2 protein in the DRG. Given that CCL2 is an endogenous initiator of CINP and that Nt3 mRNA co-expresses with TrkC and Ccl2 mRNAs in DRG neurons, NT3 likely contributes to CINP through TrkC-mediated activation of the Ccl2 gene in DRG neurons. NT3 may be thus a potential target for CINP treatment.

Quantum Hall effect based on Weyl orbits in Cd3As2.

Discovered decades ago, the quantum Hall effect remains one of the most studied phenomena in condensed matter physics and is relevant for research areas such as topological phases, strong electron correlations and quantum computing1-5. The quantized electron transport that is characteristic of the quantum Hall effect typically originates from chiral edge states-ballistic conducting channels that emerge when two-dimensional electron systems are subjected to large magnetic fields2. However, whether the quantum Hall effect can be extended to higher dimensions without simply stacking two-dimensional systems is unknown. Here we report evidence of a new type of quantum Hall effect, based on Weyl orbits in nanostructures of the three-dimensional topological semimetal Cd3As2. The Weyl orbits consist of Fermi arcs (open arc-like surface states) on opposite surfaces of the sample connected by one-dimensional chiral Landau levels along the magnetic field through the bulk6,7. This transport through the bulk results in an additional contribution (compared to stacked two-dimensional systems and which depends on the sample thickness) to the quantum phase of the Weyl orbit. Consequently, chiral states can emerge even in the bulk. To measure these quantum phase shifts and search for the associated chiral modes in the bulk, we conduct transport experiments using wedge-shaped Cd3As2 nanostructures with variable thickness. We find that the quantum Hall transport is strongly modulated by the sample thickness. The dependence of the Landau levels on the magnitude and direction of the magnetic field and on the sample thickness agrees with theoretical predictions based on the modified Lifshitz-Onsager relation for the Weyl orbits. Nanostructures of topological semimetals thus provide a way of exploring quantum Hall physics in three-dimensional materials with enhanced tunability.

FUS Contributes to Nerve Injury-Induced Nociceptive Hypersensitivity by Activating NF-κB Pathway in Primary Sensory Neurons.

Dysregulation of pain-associated genes in the dorsal root ganglion (DRG) is considered to be a molecular basis of neuropathic pain genesis. Fused in sarcoma (FUS), a DNA/RNA-binding protein, is a critical regulator of gene expression. However, whether it contributes to neuropathic pain is unknown. This study showed that peripheral nerve injury caused by the fourth lumbar (L4) spinal nerve ligation (SNL) or chronic constriction injury (CCI) of the sciatic nerve produced a marked increase in the expression of FUS protein in injured DRG neurons. Blocking this increase through microinjection of the adeno-associated virus (AAV) 5-expressing Fus shRNA into the ipsilateral L4 DRG mitigated the SNL-induced nociceptive hypersensitivities in both male and female mice. This microinjection also alleviated the SNL-induced increases in the levels of phosphorylated extracellular signal-regulated kinase 1/2 (p-ERK1/2) and glial fibrillary acidic protein (GFAP) in the ipsilateral L4 dorsal horn. Furthermore, mimicking this increase through microinjection of AAV5 expressing full-length Fus mRNA into unilateral L3/4 DRGs produced the elevations in the levels of p-ERK1/2 and GFAP in the dorsal horn, enhanced responses to mechanical, heat and cold stimuli, and induced the spontaneous pain on the ipsilateral side of both male and female mice in the absence of SNL. Mechanistically, the increased FUS activated the NF-κB signaling pathway by promoting the translocation of p65 into the nucleus and phosphorylation of p65 in the nucleus from injured DRG neurons. Our results indicate that DRG FUS contributes to neuropathic pain likely through the activation of NF-κB in primary sensory neurons.SIGNIFICANCE STATEMENT In the present study, we reported that fused in sarcoma (FUS), a DNA/RNA-binding protein, is upregulated in injured dorsal root ganglion (DRG) following peripheral nerve injury. This upregulation is responsible for nerve injury-induced translocation of p65 into the nucleus and phosphorylation of p65 in the nucleus from injured DRG neurons. Because blocking this upregulation alleviates nerve injury-induced nociceptive hypersensitivity, DRG FUS participates in neuropathic pain likely through the activation of NF-κB in primary sensory neurons. FUS may be a potential target for neuropathic pain management.

Schwann cell-derived extracellular vesicles promote memory impairment associated with chronic neuropathic pain.

BACKGROUND: The pathogenesis of memory impairment, a common complication of chronic neuropathic pain (CNP), has not been fully elucidated. Schwann cell (SC)-derived extracellular vesicles (EVs) contribute to remote organ injury. Here, we showed that SC-EVs may mediate pathological communication between SCs and hippocampal neurons in the context of CNP. METHODS: We used an adeno-associated virus harboring the SC-specific promoter Mpz and expressing the CD63-GFP gene to track SC-EVs transport. microRNA (miRNA) expression profiles of EVs and gain-of-function and loss-of-function regulatory experiments revealed that miR-142-5p was the main cargo of SC-EVs. Next, luciferase reporter gene and phenotyping experiments confirmed the direct targets of miR-142-5p. RESULTS: The contents and granule sizes of plasma EVs were significantly greater in rats with chronic sciatic nerve constriction injury (CCI)than in sham rats. Administration of the EV biogenesis inhibitor GW4869 ameliorated memory impairment in CCI rats and reversed CCI-associated dendritic spine damage. Notably, during CCI stress, SC-EVs could be transferred into the brain through the circulation and accumulate in the hippocampal CA1-CA3 regions. miR-142-5p was the main cargo wrapped in SC-EVs and mediated the development of CCI-associated memory impairment. Furthermore, α-actinin-4 (ACTN4), ELAV-like protein 4 (ELAVL4) and ubiquitin-specific peptidase 9 X-linked (USP9X) were demonstrated to be important downstream target genes for miR-142-5p-mediated regulation of dendritic spine damage in hippocampal neurons from CCI rats. CONCLUSION: Together, these findings suggest that SCs-EVs and/or their cargo miR-142-5p may be potential therapeutic targets for memory impairment associated with CNP.

Topological Lifshitz transition and one-dimensional Weyl mode in HfTe5.

Landau band crossings typically stem from the intra-band evolution of electronic states in magnetic fields and enhance the interaction effect in their vicinity. Here in the extreme quantum limit of topological insulator HfTe5, we report the observation of a topological Lifshitz transition from inter-band Landau level crossings using magneto-infrared spectroscopy. By tracking the Landau level transitions, we demonstrate that band inversion drives the zeroth Landau bands to cross with each other after 4.5 T and forms a one-dimensional Weyl mode with the fundamental gap persistently closed. The unusual reduction of the zeroth Landau level transition activity suggests a topological Lifshitz transition at 21 T, which shifts the Weyl mode close to the Fermi level. As a result, a broad and asymmetric absorption feature emerges due to the Pauli blocking effect in one dimension, along with a distinctive negative magneto-resistivity. Our results provide a strategy for realizing one-dimensional Weyl quasiparticles in bulk crystals.

Assessing the causal relationship between 731 immunophenotypes and the risk of lung cancer: a bidirectional mendelian randomization study.

BACKGROUND: Previous studies have observed a link between immunophenotypes and lung cancer, both of which are closely associated with genetic factors. However, the causal relationship between them remains unclear. METHODS: Bidirectional Mendelian randomization (MR) was performed on publicly available genome-wide association study (GWAS) summary statistics to analyze the causal relationships between 731 immunophenotypes and lung cancer. Sensitivity analyses were conducted to verify the robustness, heterogeneity, and potential horizontal pleiotropy of our findings. RESULTS: Following Bonferroni adjustment, CD14- CD16+ monocyte (OR = 0.930, 95%CI 0.900-0.960, P = 8.648 × 10- 6, PBonferroni = 0.006) and CD27 on CD24+ CD27+ B cells (OR = 1.036, 95%CI 1.020-1.053, P = 1.595 × 10 - 5, PBonferroni = 0.012) were identified as having a causal role in lung cancer via the inverse variance weighted (IVW) method. At a more relaxed threshold, CD27 on IgD+ CD24+ B cell (OR = 1.035, 95%CI 1.017-1.053, P = 8.666 × 10- 5, PBonferroni = 0.063) and CD27 on switched memory B cell (OR = 1.037, 95%CI 1.018-1.056, P = 1.154 × 10- 4, PBonferroni = 0.084) were further identified. No statistically significant effects of lung cancer on immunophenotypes were found. CONCLUSIONS: The elevated level of CD14- CD16+ monocytes was a protective factor against lung cancer. Conversely, CD27 on CD24+ CD27+ B cell was a risk factor. CD27 on class-switched memory B cells and IgD+ CD24+ B cells were potential risk factors for lung cancer. This research enhanced our comprehension of the interplay between immune responses and lung cancer risk. Additionally, these findings offer valuable perspectives for the development of immunologically oriented therapeutic strategies.

Combined treatment of human mesenchymal stem cells and green tea extract on retinal ganglion cell regeneration in rats after optic nerve injury.

Retinal ganglion cell (RGC) death and axonal loss cause irreversible vision loss upon optic nerve (ON) injury. We have independently demonstrated that mesenchymal stem cells (MSCs) and green tea extract (GTE) promote RGC survival and axonal regeneration in rats with ON injury. Here we aimed to evaluate the combined treatment effect of human bone marrow-derived MSCs (hBM-MSCs) and GTE on RGC survival and axonal regeneration after ON injury. Combined treatment of hBM-MSCs and GTE promoted RGC survival and neurite outgrowth/axonal regeneration in ex vivo retinal explant culture and in rats after ON injury. GTE increased Stat3 activation in the retina after combined treatment, and enhanced brain-derived neurotrophic factor secretion from hBM-MSCs. Treatment of 10 µg/mL GTE would not induce hBM-MSC apoptosis, but inhibited their proliferation, migration, and adipogenic and osteogenic differentiation in vitro with reducing matrix metalloproteinase secretions. In summary, this study revealed that GTE can enhance RGC protective effect of hBM-MSCs, suggesting that stem cell priming could be a prospective strategy enhancing the properties of stem cells for ON injury treatment.

A sensory neuron-specific long non-coding RNA reduces neuropathic pain by rescuing KCNN1 expression.

Nerve injury to peripheral somatosensory system causes refractory neuropathic pain. Maladaptive changes of gene expression in primary sensory neurons are considered molecular basis of this disorder. Long non-coding RNAs (lncRNAs) are key regulators of gene transcription; however, their significance in neuropathic pain remains largely elusive.Here, we reported a novel lncRNA, named sensory neuron-specific lncRNA (SS-lncRNA), for its expression exclusively in dorsal root ganglion (DRG) and trigeminal ganglion. SS-lncRNA was predominantly expressed in small DRG neurons and significantly downregulated due to a reduction of early B cell transcription factor 1 in injured DRG after nerve injury. Rescuing this downregulation reversed a decrease of the calcium-activated potassium channel subfamily N member 1 (KCNN1) in injured DRG and alleviated nerve injury-induced nociceptive hypersensitivity. Conversely, DRG downregulation of SS-lncRNA reduced the expression of KCNN1, decreased total potassium currents and afterhyperpolarization currents and increased excitability in DRG neurons and produced neuropathic pain symptoms.Mechanistically, downregulated SS-lncRNA resulted in the reductions of its binding to Kcnn1 promoter and heterogeneous nuclear ribonucleoprotein M (hnRNPM), consequent recruitment of less hnRNPM to the Kcnn1 promoter and silence of Kcnn1 gene transcription in injured DRG.These findings indicate that SS-lncRNA may relieve neuropathic pain through hnRNPM-mediated KCNN1 rescue in injured DRG and offer a novel therapeutic strategy specific for this disorder.

Lack of causal association between epilepsy and dementia: A Mendelian randomization analysis.

OBJECTIVE: Epidemiological studies have reported an association between epilepsy and dementia. However, the causal relationship between epilepsy and the risk of dementia is not clear. We aimed to inspect the causal effect of epilepsy on memory loss and dementia. METHODS: We analyzed summary data of epilepsy, memory loss, and dementia from the genome-wide association study (GWAS) using the two-sample Mendelian randomization (MR) method. We used the estimated odds ratio of memory loss and dementia associated with each of the genetically defined traits to infer evidence for a causal relationship with the following exposures: all epilepsy, focal epilepsy (including focal epilepsy with hippocampal sclerosis, lesion-negative focal epilepsy, and focal epilepsy with other lesions), and genetic generalized epilepsy (including childhood absence epilepsy, generalized tonic-clonic seizures alone, Juvenile absence epilepsy, and Juvenile myoclonic epilepsy). RESULTS: According to the result of MR using the inverse variance weighted method (IVW), we found that genetically predicted epilepsy did not causally increase the risk of memory loss and dementia (p > 0.05). Results of the MR-Egger and weighted median method were consistent with the IVW method. CONCLUSIONS: No evidence has been found to support the notion that epilepsy can result in memory loss and dementia. The associations observed in epidemiological studies could be attributed, in part, to confounding or nongenetic determinants.

Fourteen new 2-benzylbenzofuran glycosides with cardioprotective activity from Heterosmilax yunnanensis.

Fourteen new 2-benzylbenzofuran O-glycosides (1-13, 15) and one new key precursor, diarylacetone (14) were isolated from the roots of Heterosmilax yunnanensis Gagnep, which all have characteristic 2,3,4-O-trisubstituted benzyl. Their structures were elucidated by 1D and 2D NMR, HRESIMS, UV and IR. The isolated compounds were assessed for their cardioprotective activities and compounds 1, 3 and 6 could significantly improve cardiomyocytes viability. Moreover, the mechanistic study revealed that these three compounds could significantly decrease intracellular ROS levels and maintain mitochondrial homeostasis upon hypoxia inducement. Consequently, 1, 3 and 6 might serve as potential lead compounds to prevent myocardial ischemia.

Targeted therapy for rare lung cancers: Status, challenges, and prospects.

Lung cancer causes the most cancer-related deaths worldwide. In recent years, molecular and immunohistochemical techniques have rapidly developed, further inaugurating an era of personalized medicine for lung cancer. The rare subset of lung cancers accounts for approximately 10%, each displaying distinct clinical characteristics. Treatments for rare lung cancers are mainly based on evidence from common counterparts, which may lead to unsolid clinical benefits considering intertumoral heterogeneity. The increasing knowledge of molecular profiling of rare lung cancers has made targeting genetic alterations and immune checkpoints a powerful strategy. Additionally, cellular therapy has emerged as a promising way to target tumor cells. In this review, we first discuss the current status of targeted therapy and preclinical models for rare lung cancers, as well as provide mutational profiles by integrating the results of existing cohorts. Finally, we point out the challenges and future directions for developing targeted agents for rare lung cancer.

Agonist of growth hormone-releasing hormone enhances retinal ganglion cell protection induced by macrophages after optic nerve injury.

Optic neuropathies are leading causes of irreversible visual impairment and blindness, currently affecting more than 100 million people worldwide. Glaucoma is a group of optic neuropathies attributed to progressive degeneration of retinal ganglion cells (RGCs). We have previously demonstrated an increase in survival of RGCs by the activation of macrophages, whereas the inhibition of macrophages was involved in the alleviation on endotoxin-induced inflammation by antagonist of growth hormone-releasing hormone (GHRH). Herein, we hypothesized that GHRH receptor (GHRH-R) signaling could be involved in the survival of RGCs mediated by inflammation. We found the expression of GHRH-R in RGCs of adult rat retina. After optic nerve crush, subcutaneous application of GHRH agonist MR-409 or antagonist MIA-602 promoted the survival of RGCs. Both the GHRH agonist and antagonist increased the phosphorylation of Akt in the retina, but only agonist MR-409 promoted microglia activation in the retina. The antagonist MIA-602 reduced significantly the expression of inflammation-related genes Il1b, Il6, and Tnf Moreover, agonist MR-409 further enhanced the promotion of RGC survival by lens injury or zymosan-induced macrophage activation, whereas antagonist MIA-602 attenuated the enhancement in RGC survival. Our findings reveal the protective effect of agonistic analogs of GHRH on RGCs in rats after optic nerve injury and its additive effect to macrophage activation, indicating a therapeutic potential of GHRH agonists for the protection of RGCs against optic neuropathies especially in glaucoma.

Six new iridoid glycosides from the whole plants of Hedyotis diffusa.

Six new iridoid glycosides were isolated from the ethyl acetate fraction of the whole plants of Hedyotis diffusa Willd. They were identified as E-6-O-p-methoxycinnamoyl-10-O-acetyl scandoside acid methyl ester (1), Z-6-O-p-methoxycinnamoyl-10-O-acetyl scandoside acid methyl ester (2), E-6-O-caffeoyl scandoside methyl ester (3), E-6-O-p-coumaroyl-6'-O-acetyl scandoside methyl ester (4), Z-6-O-p-coumaroyl-6'-O-acetyl scandoside methyl ester (5), and E-6-O-p-coumaroyl-4'-O-acetyl scandoside methyl ester (6). The structures of them were elucidated based on unambiguous spectroscopic data (UV, IR, HRESIMS, and NMR). They were screened for anti-inflammatory effect, antioxidant effect, antitumor effect, and neuroprotective effect and did not show potent activities.

Three new flavonoids from the roots of Sophora tonkinensis.

Three new flavonoids including two isoflavanones sophortones A and B (1 and 2), and one chalcone sophortone C (3) were isolated from the roots of Sophora tonkinensis. Their structures were established by UV, IR, HRESIMS, and NMR data. The absolute configurations of 1 and 2 were determined by electronic circular dichroism (ECD) calculations.

Whole-brain neural connectivity to cholinergic neurons in the nucleus basalis of Meynert.

The cholinergic neurons in the nucleus basalis of Meynert (NBM) are a key structure in cognition, the dysfunction of which is associated with various neurological disorders, especially dementias. However, the whole-brain neural connectivity to cholinergic neurons in the NBM remains to be further and comprehensively researched. Using virus-based, specific, retrograde, and anterograde tracing, we illustrated the monosynaptic inputs and axon projections of NBM cholinergic neurons in choline acetyltransferase (ChAT)-Cre transgenic mice. Our results showed that NBM cholinergic neurons received mainly inputs from the caudate putamen and the posterior limb of the anterior commissure in the subcortex. Moreover, the majority of cholinergic terminals from the NBM were observed in the cortex mantle, including the motor cortex, sensory cortex, and visual cortex. Interestingly, although NBM cholinergic neurons received input projections from the caudate putamen, interstitial nucleus of the posterior limb of the anterior commissure, and central amygdaloid nucleus, NBM cholinergic neurons sparsely sent axon projection to innervate these areas. Furthermore, primary motor cortex, secondary motor cortex, and primary somatosensory cortex received abundant inputs from the NBM but sent few outputs to the NBM. Taken together, our results reveal the detailed and specific connectivity of cholinergic neurons of the NBM and provide a neuroanatomic foundation for further studies to explore the important physiological functions of NBM cholinergic neurons.

Contribution of activating lateral hypothalamus-lateral habenula circuit to nerve trauma-induced neuropathic pain in mice.

Neuropathic pain, a severe clinical symptom, significantly affects the quality of life in the patients. The molecular mechanisms underlying neuropathic pain have been the focus of research in recent decades; however, the neuronal circuit-mediated mechanisms associated with this disorder remain poorly understood. Here, we report that a projection from the lateral hypothalamus (LH) glutamatergic neurons to the lateral habenula (LHb), an excitatory LH-LHb neuronal circuit, participates in nerve injury-induced nociceptive hypersensitivity. LH glutamatergic neurons are activated and display enhanced responses to normally non-noxious stimuli following chronic constriction injury. Chemogenetic inhibition of LH glutamatergic neurons or excitatory LH-LHb circuit blocked CCI-induced nociceptive hypersensitivity. Activation of the LH-LHb circuit led to augmented responses to mechanical and thermal stimuli in mice without nerve injury. These findings suggest that LH neurons and their triggered LH-LHb circuit participate in central mechanisms underlying neuropathic pain and may be targets for the treatment of this disorder.

A histidine-rich fusion tag enables real-time monitoring of recombinant protein expression by Pauly reaction-based colorimetric assay.

Commercially available recombinant expression systems always use fusion tags to facilitate target protein purification and SDS-PAGE analysis followed by Coomassie Brilliant Blue (CBB) staining is the classical method to validate the expression level of target protein, which is time-consuming, although not very laborious. Previously, we found that a histidine-rich elastin-like polypeptide (HRELP) tag could make its fusion proteins being quickly and specifically stained with Pauly's reagent. In this study, we designed a Pauly reaction-based colorimetric assay to real-time monitoring of the expression level of recombinant protein tagged HRELP and found that the absorption value of post-induction E. coli cells stained with Pauly's reagent correlated well with both the band intensity of the target protein from Pauly's reagent-stained and CBB-stained gels. Moreover, we found the colorimetric assay could also be helpful to roughly estimate the expression efficiency by using a poly-histidine-tagged protein, which has only 1.17% histidine residue. In our opinion, Pauly reaction-based colorimetric assay could significantly shorten the time to validate the over-expression of recombinant protein tagged with either HRELP or poly-histidine. And HRELP seemed to be an ideal fusion tag for it can not only facilitate protein purification but also simplify protein detection.

Primary open-angle glaucoma risk prediction with ABCA1 and LOC102723944 variants and their genotype-phenotype correlations in southern Chinese population.

Glaucoma is a leading cause of irreversible visual impairment and blindness worldwide. Previous genome-wide association studies have identified caveolin-1 (CAV1), ATP-binding cassette A1 (ABCA1), and forkhead box C1 (FOXC1) loci associated with primary open angle glaucoma (POAG), a major subtype of glaucoma. This study aimed to fine map the association pattern of FOXC1 locus with POAG and determine the correlations of FOXC1, ABCA1, and CAV1 variants with ocular and lipidemic parameters in southern Chinese population. In total, 1291 unrelated Han Chinese subjects were recruited, including 301 high-tension glaucoma (HTG), 126 normal-tension glaucoma (NTG), and 864 control subjects. Twelve variants in FOXC1 locus, and two variants in ABCA1 and CAV1 genes, were genotyped by TaqMan assays. Genetic risk score and genotype-phenotype correlation analyses were conducted. In the FOXC1 locus, LOC102723944 rs6596830, rather than previously reported rs2745572, showed significant association with POAG (P = 8.61 × 10-4, odds ratio (OR) = 0.75) and HTG (P = 3.68 × 10-3, OR = 0.75). ABCA1 rs2487032 was also significantly associated with POAG (P = 3.00 × 10-5, OR = 0.70) and HTG (P = 2.08 × 10-4, OR = 0.70). Joint analysis showed that carriers of homozygous non-protective alleles of ABCA1 rs2487032 and LOC102723944 rs6596830 had 2.99-fold higher risk of POAG (P = 1.27 × 10-3) when compared to those carrying homozygous non-risk alleles. Patients with POAG carrying ABCA1 rs2487032 G allele had higher HDL cholesterol, and those with LOC102723944 rs6596830 A allele had lower LDL. This study revealed individual and joint association of ABCA1 and LOC102723944 variants with POAG in southern Chinese population. Subjects carrying non-protective alleles had increased risk to POAG, and corresponding genotypes would affect the lipid profiles.

Dedifferentiation-associated inflammatory factors of long-term expanded human hepatocytes exacerbate their elimination by macrophages during liver engraftment.

BACKGROUND AND AIMS: Hepatocyte transplantation has been demonstrated to be effective to treat liver metabolic disease and acute liver failure. Nevertheless, the shortage of donor hepatocytes restrained its application in clinics. To expand human hepatocytes at a large scale, several dedifferentiation-based protocols have been established, including proliferating human hepatocytes (ProliHH). However, the decreased transplantation efficiency of these cells after long-term expansion largely impedes their application. APPROACH AND RESULTS: We found that accompanied with dedifferentiation, long-term cultured ProliHH (lc-ProliHH) up-regulated a panel of chemokines and cytokines related to innate immunity, which were referred to as dedifferentiation-associated inflammatory factors (DAIF). DAIF elicited excessive macrophage responses, accounting for the elimination of lc-ProliHH specifically during engraftment. Two possible strategies to increase ProliHH transplantation were then characterized. Blockage of innate immune response by dexamethasone reverted the engraftment and repopulation of lc-ProliHH to a level comparable to primary hepatocytes, resulting in improved liver function and a better survival of fumarylacetoacetate hydrolase-deficient mice. Alternatively, rematuration of lc-ProliHH as organoids reduced the expression of DAIF and led to markedly improved engraftment. CONCLUSIONS: These results revealed that lc-ProliHH triggers exacerbated macrophage activation by DAIF and provided potential solutions for clinical transplantation of lc-ProliHH.