Lung mesenchymal cells elicit lipid storage in neutrophils that fuel breast cancer lung metastasis.

Acquisition of a lipid-laden phenotype by immune cells has been defined in infectious diseases and atherosclerosis but remains largely uncharacterized in cancer. Here, in breast cancer models, we found that neutrophils are induced to accumulate neutral lipids upon interaction with resident mesenchymal cells in the premetastatic lung. Lung mesenchymal cells elicit this process through repressing the adipose triglyceride lipase (ATGL) activity in neutrophils in prostaglandin E2-dependent and -independent manners. In vivo, neutrophil-specific deletion of genes encoding ATGL or ATGL inhibitory factors altered neutrophil lipid profiles and breast tumor lung metastasis in mice. Mechanistically, lipids stored in lung neutrophils are transported to metastatic tumor cells through a macropinocytosis-lysosome pathway, endowing tumor cells with augmented survival and proliferative capacities. Pharmacological inhibition of macropinocytosis significantly reduced metastatic colonization by breast tumor cells in vivo. Collectively, our work reveals that neutrophils serve as an energy reservoir to fuel breast cancer lung metastasis.

Lung fibroblasts facilitate pre-metastatic niche formation by remodeling the local immune microenvironment.

Primary tumors are drivers of pre-metastatic niche formation, but the coordination by the secondary organ toward metastatic dissemination is underappreciated. Here, by single-cell RNA sequencing and immunofluorescence, we identified a population of cyclooxygenase 2 (COX-2)-expressing adventitial fibroblasts that remodeled the lung immune microenvironment. At steady state, fibroblasts in the lungs produced prostaglandin E2 (PGE2), which drove dysfunctional dendritic cells (DCs) and suppressive monocytes. This lung-intrinsic stromal program was propagated by tumor-associated inflammation, particularly the pro-inflammatory cytokine interleukin-1ß, supporting a pre-metastatic niche. Genetic ablation of Ptgs2 (encoding COX-2) in fibroblasts was sufficient to reverse the immune-suppressive phenotypes of lung-resident myeloid cells, resulting in heightened immune activation and diminished lung metastasis in multiple breast cancer models. Moreover, the anti-metastatic activity of DC-based therapy and PD-1 blockade was improved by fibroblast-specific Ptgs2 deletion or dual inhibition of PGE2 receptors EP2 and EP4. Collectively, lung-resident fibroblasts reshape the local immune landscape to facilitate breast cancer metastasis.

Early onset of pathological polyploidization and cellular senescence in hepatocytes lacking RAD51 creates a pro-fibrotic and pro-tumorigenic inflammatory microenvironment.

BACKGROUND AND AIMS: RAD51 recombinase (RAD51) is a highly conserved DNA repair protein and is indispensable for embryonic viability. As a result, the role of RAD51 in liver development and function is unknown. Our aim was to characterize the function of RAD51 in postnatal liver development. APPROACH AND RESULTS: RAD51 is highly expressed during liver development and during regeneration following hepatectomy and hepatic injury, and is also elevated in chronic liver diseases. We generated a hepatocyte-specific Rad51 deletion mouse model using Alb -Cre ( Rad51 -conditional knockout (CKO)) and Adeno-associated virus 8-thyroxine-binding globulin-cyclization recombination enzyme to evaluate the function of RAD51 in liver development and regeneration. The phenotype in Rad51 -CKO mice is dependent on CRE dosage, with Rad51fl/fl ; Alb -Cre +/+ manifesting a more severe phenotype than the Rad51fl/fl ; Alb -Cre +/- mice. RAD51 deletion in postnatal hepatocytes results in aborted mitosis and early onset of pathological polyploidization that is associated with oxidative stress and cellular senescence. Remarkable liver fibrosis occurs spontaneously as early as in 3-month-old Rad51fl/fl ; Alb -Cre +/+ mice. While liver regeneration is compromised in Rad51 -CKO mice, they are more tolerant of carbon tetrachloride-induced hepatic injury and resistant to diethylnitrosamine/carbon tetrachloride-induced HCC. A chronic inflammatory microenvironment created by the senescent hepatocytes appears to activate ductular reaction the transdifferentiation of cholangiocytes to hepatocytes. The newly derived RAD51 functional immature hepatocytes proliferate vigorously, acquire increased malignancy, and eventually give rise to HCC. CONCLUSIONS: Our results demonstrate a novel function of RAD51 in liver development, homeostasis, and tumorigenesis. The Rad51 -CKO mice represent a unique genetic model for premature liver senescence, fibrosis, and hepatocellular carcinogenesis.

Laser-activable murine ferritin nanocage for chemo-photothermal therapy of colorectal cancer.

Chemotherapy, as a conventional strategy for tumor therapy, often leads to unsatisfied therapeutic effect due to the multi-drug resistance and the serious side effects. Herein, we genetically engineered a thermal-responsive murine Ferritin (mHFn) to specifically deliver mitoxantrone (MTO, a chemotherapeutic and photothermal agent) to tumor tissue for the chemotherapy and photothermal combined therapy of colorectal cancer, thanks to the high affinity of mHFn to transferrin receptor that highly expressed on tumor cells. The thermal-sensitive channels on mHFn allowed the effective encapsulation of MTO in vitro and the laser-controlled release of MTO in vivo. Upon irradiation with a 660 nm laser, the raised temperature triggered the opening of the thermal-sensitive channel in mHFn nanocage, resulting in the controlled and rapid release of MTO. Consequently, a significant amount of reactive oxygen species was generated, causing mitochondrial collapse and tumor cell death. The photothermal-sensitive controlled release, low systemic cytotoxicity, and excellent synergistic tumor eradication ability in vivo made mHFn@MTO a promising candidate for chemo-photothermal combination therapy against colorectal cancer.

Epithelial Barrier in the Nasal Mucosa, Related Risk Factors and Diseases.

As the first line of defense against risk factors, the nasal epithelial barrier maintains homeostasis in nasal mucosa. The composition of the epithelial barrier contains physical, chemical, immune, and microbiological barriers. Together, these barriers form the nasal defense against irritations. Risk factors from both internal and external environments can disrupt them. External risk factors contain allergens containing proteases, bacteria, virus, particulate matter, diesel exhaust particles, and cigarette smoke. In the meantime, inflammatory cytokines also increase the load on the barrier. Taking into account the role of the epithelial barrier in the nasal mucosa, some studies focus on the treatment of allergic rhinitis (AR) and chronic rhinosinusitis (CRS) by restoring the epithelial barrier, and some progress has been made. Among the therapeutic approaches, histone deacetylase (HDAC) inhibitor and steroid corticosteroids are considered two of the more studied categories, and their roles in repairing barriers have been demonstrated in AR and CRS. The underlying mechanism of HDAC inhibitor may be related to the transcription factor p63. And the protection of corticosteroids may be associated with the allergic disease susceptibility gene, protocadherin-1. Notably, manipulation of the microbiological barrier also has a positive effect on AR and CRS. Lactococcus and probiotics are two categories that are worth being explored continuously. We here review and discuss the compositions and risk factors of the nasal epithelial barrier. Furthermore, some novel and promising approaches to restore the defective barrier in nasal allergic diseases were mentioned.

Effect of Gushen shetuo decoction in improving motor and non-motor symptoms and the expression of PERK, ATF4 and CHOP in patients with Parkinson's disease.

This study aims to observe the therapeutic effect of Gushen Shetuo decoction on Parkinson's disease (PD), so as to provide reference for clinical practice. In order to demonstrate the clinical value of Gushen Shetuo Decoction, we selected 80 patients with PD for the study. Among them, 38 patients received the Gushen Shetuo decoction (research group), and 42 patients received Levodopa and Benserazide Hydrochloride Tablets (control group). There was no difference in Non-Motor Symptoms Scale (NMSS) scores between the research group and the control group (P>0. 05). However, the scores of motor complications in Movement Disorder Society-sponsored revision of the Parkinson's Disease Rating Scale (MDS-UPDRS) and those of Drooling Severity and Frequency Scale (DSFS) in the research group were lower than those in the control group (P<0. 05). Subsequently, we established PD model rats, and after Gushen Shetuo Decoction gavage treatment, we found that rats in the intervention group had increased mobility (P<0. 05), as well as notably improved pathological damage of substantia nigra and striatum. Also, the expression of PERK, ATF4 and CHOP in the brain tissues of rats in the intervention group was lower than those in the control group (P<0. 05). These results confirm that Gushen Shetuo decoction effectively improved the drooling of patients with PD and showed high safety.

Socially Assistive Robots for People Living with Dementia in Long-Term Facilities: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

BACKGROUND AND OBJECTIVE: The purpose of our study was to explore the immediate and long-term effects of socially assistive robots (SARs) on neuropsychiatric symptoms (NPSs), behavioral and psychological symptoms of dementia (BPSD), positive emotional experiences, and social interaction in older people living with dementia. METHODS: We set keywords and used Boolean operators to search the CINAHL, Cochrane Library, EMBASE, IEEE Digital Library, MEDLINE, PsycINFO, PubMed, Web of Science, Scopus, and Chinese Electronic Periodical Service from inception to February 2022 for randomized controlled trials. The Cochrane Collaboration bias assessment tool was used to assess article quality, and RevMan 5.4.1 software was used to conduct the meta-analysis. RESULTS: A total of 14 studies were included in the meta-analysis. SARs can help people living with dementia reduce their NPS of depression and anxiety, provide happiness from positive emotional experiences, and improve their social interaction through conversation. However, there was no significant improvement in agitation behavior, overall BPSD, or quality of life in people living with dementia. In follow-up, it was found that the effect of SRT was limited. CONCLUSION: SARs can reduce depression and increase positive emotions in people living with dementia. They may also reduce the burden on healthcare workers during the COVID-19 pandemic. This research was registered on PROSPERO CRD42020169340.

The effect of research on life satisfaction in middle-aged and older adults: physical disability and physical activity as a parallel and serial mediation analysis.

BACKGROUND AND OBJECTIVE: Maintaining the life satisfaction of frail middle-aged and older adults when they experience physical disability, lower activity status, or complex conditions that are related to each other is now an urgent issue. Therefore, the purpose of this study was to provide evidence for the impact of frailty in middle-aged and older adults on life satisfaction under the simultaneous occurrence and correlation of physical disability and physical activity status. METHODS: Data from the 2015 Taiwan Longitudinal Study in Ageing (TLSA) were analyzed by PROCESS in SPSS to explore three different mediation models (N = 4,421). The first was a parallel mediation model for exploring life satisfaction in middle-aged and older adults with frailty through physical disability or physical activity. The second was a serial mediation model for examining physical disability and physical activity in causal chains linked with a specific direction of flow and to test all combinations. The third was a moderated mediation model for testing whether the indirect effect of frailty status on life satisfaction through physical disability or physical activity was moderated by age stratification. RESULTS: Physical disability and physical activity partially mediated the relationship between frailty status and life satisfaction (IEOVERALL = -0.196, 95% CI: -0.255 to -0.139). The causal path with the highest indirect effect was found to be that between frailty and physical disability; increased frailty led to higher physical disability, which in turn affected physical activity, leading to lower life satisfaction (IE = 0.013, 95% CI: 0.008 to 0.019). The different stratifications by age significantly increased the mediating effect of physical activity (Index of Moderated Mediation = -0.107, SE = 0.052, 95% CI: -0.208 to -0.005) but did not reduce the mediating effect of physical disability. CONCLUSION: This study provides evidence that physical activity and physical disability influence the development of frailty. It also has a significant impact on the life satisfaction of middle-aged and older adults.

Prevalence and risk factors of hearing loss among the middle-aged and older population in China: a systematic review and meta-analysis.

PURPOSE: This paper was aimed at estimating the prevalence and risk factors of hearing loss (HL) among the middle-aged and elderly in China. METHODS: Databases including the CQVIP (VIP) Database, Chinese National Knowledge Infrastructure (CNKI), China Biology Medicine disc (CBMdisc), Wanfang, PubMed, Web of Science, Excerpta Medica Database (Embase) and the Cochrane Library were comprehensively searched. In this review, random-effect models were used for pooling the prevalence of HL and the odds ratios (ORs) of potential risk factors. RESULTS: 34 studies were included in the meta-analysis. HL among the middle-aged and elderly in China had a pooled prevalence of 45% (95% confidence interval (CI) 40-51%). There were significant differences in the prevalence of HL between males and females (47% vs. 42%), between different screening methods by self-report and pure-tone audiometry (44% vs. 46%), between the middle-aged and the elderly (18% vs. 52%), and between the uneducated and the educated (49% vs. 36%). In urban areas, the prevalence was slightly higher than that in rural areas (50% vs. 48%). The findings suggested that the middle-aged and elderly in the South Central China region (61%, 95% CI 45-78%) and Northwest China (57%, 95% CI 55-58%) were more likely to develop HL. In addition, it was confirmed that advanced age, being male, noise exposure history, hypertension and hyperglycemia were related to a higher prevalence of HL among middle-aged and older adults. CONCLUSION: The prevalence of HL among the middle-aged and older population in China is 45%, nearly half of the total population. It is urgent to take great efforts to raise people's awareness of HL prevention and early hearing screening.

Lipid metabolism and neutrophil function.

Neutrophils are an essential part of the innate immune system, playing a critical role in the control of infectious diseases, maintenance of tissue homeostasis and regulation of tumorigenesis. However, their functional importance has often been overlooked due to the conception that they are short-lived and unable to proliferate. Recent studies indicate that the functions of neutrophils are diverse and can be influenced by cellular metabolisms, including that governing lipid homeostasis. Here, we review how lipids, especially lipid droplets, in neutrophils are dynamically regulated in different pathophysiological contexts, with a specific focus on the key regulators involved in lipid metabolism. We also describe how alterations in lipid metabolism are intertwined with different signaling pathways orchestrating neutrophil functions during pathogen defense, tissue repair and tumor metastasis.

Prevalence and affective correlates of subjective cognitive decline in patients with de novo Parkinson's disease.

OBJECTIVES: The novel concept of subjective cognitive decline (SCD) in Parkinson's disease (PD) refers to subjective cognitive impairment without concurrent objective cognitive deficits. This study aimed to determine the prevalence and affective correlates of SCD in de novo PD patients. MATERIALS AND METHODS: A total of 139 de novo PD patients underwent comprehensive neuropsychological evaluation. PD patients with SCD (PD-SCD) did not meet the diagnostic criteria for mild cognitive impairment in PD (PD-MCI) based on the Movement Disorder Society Level II Criteria and were defined by a Domain-5 Score ≥1 on the Non-Motor Symptoms Questionnaire. Affective symptoms were measured using the Hamilton Depression Scale (HAMD) and Hamilton Anxiety Scale (HAMA). RESULTS: In de novo PD cohort, the prevalence of SCD was 28.1%. PD-SCD patients performed significantly better than PD-MCI patients on tests of five cognitive domains. The more commonly affected domains in PD-SCD patients were memory (28.2%) and attention/working memory (25.6%). Multivariable linear regression analysis revealed that PD-SCD was significantly associated with both HAMD (ß = 4.518, 95% CI = 0.754-8.281, p = .019) and HAMA scores (ß = 4.259, 95% CI = 1.054-7.464, p = .010). Furthermore, binary logistic regression analysis revealed that higher HAMD (OR = 1.128, 95% CI = 1.019-1.249, p = .020) and HAMA scores (OR = 1.176, 95% CI = 1.030-1.343, p = .017) increased the risk of PD-SCD. CONCLUSIONS: Our findings suggest that SCD is highly prevalent in de novo PD patients. The presence of PD-SCD is suggestive of an underlying affective disorder.

Structures, biosynthesis, and bioactivities of prodiginine natural products.

Prodiginines are a large family of microbial secondary metabolites with a core structure of tripyrrole rings. They exhibit not only diverse chemical structures but also rich biological activities, such as anti-cancer, anti-microbial, anti-algae, anti-parasitic, pesticides, and UV radiation resistance. The preferred cytotoxicity to cancer cells rather than normal cells indicates a good biological selectivity and safety, which makes the prodiginines promising candidates for drug development and novel additives for food processing. Until now, 33 prodiginine natural products have been identified in various bacteria, including Serratia, Hahella, Pseudoalteromonas, Vibrio, Zooshikella, Streptomyces, and Actinomadura. However, most efforts are still focused on the star molecule prodigiosin, while little yet is known about other prodiginine members, which retards the research and application of prodiginine compounds. To gain insight into the prodiginine family, we reviewed the recent discoveries on their chemical structures, biosynthesis, biological activities, and mechanisms of action. We believe this article will provide a guideline for new research on prodiginines, such as the discovery of new congeners and drug development. KEY POINTS: • The prodiginines are a large family of natural products with a core structure of tripyrrole rings and exhibit various bioactivities. • The prodiginines have a widespread distribution among many environmental microbes and diverse biosynthetic pathways, indicating important ecological roles and a great potential for new congeners. • The potent biological activities and good selectivity of action make prodiginines good lead compounds for drug development.

Discovery of New Secondary Metabolites from Marine Bacteria Hahella Based on an Omics Strategy.

Hahella is one characteristic genus under the Hahellaceae family and shows a good potential for synthesizing new natural products. In this study, we examined the distribution of the secondary metabolite biosynthetic gene cluster (SMBGC) under Hahella with anti-SMASH. The results derived from five genomes released 70 SMBGCs. On average, each strain contains 12 gene clusters, and the most abundant ones (45.7%) are from the family of non-ribosomal peptide synthetase (NRPS) and non-ribosomal peptide synthetase hybrid with polyketide synthase (NRPS/PKS), indicating a great potential to find bioactive compounds. The comparison of SMBGC between H. chejuensis and other species showed that H. chejuensis contained two times more gene clusters than H. ganghwensis. One strain, designed as NBU794, was isolated from the mangrove soil of Dongzhai Port in Haikou (China) by iChip. The 16S rRNA gene of NBU794 exhibited 99% identity to H. chejuensis KCTC 2396 and clustered with the H. chejuensis clade on the phylogenetic trees. Genome mining on strain NBU794 released 17 SMBGCs and two groups of bioactive compounds, which are chejuenolide A-C and nine prodiginines derivatives. The prodiginines derivatives include the well-known lead compound prodigiosin and two new compounds, 2-methyl-3-pentyl-4-O-methyl-prodiginine and 2-methyl-3-octyl-prodiginine, which were identified through fragmentation analysis based on LC-MS/MS. The anti-microbial activity assay showed prodigiosin and 2-methyl-3-heptyl-prodiginine exhibited the best performance in inhibiting Escherichia coli, Salmonella paratyphi B, MASA Staphylococcus aureus, Bacillus subtilis, and Candida albicans. Moreover, the yield of prodigiosin in H. chejuensis NBU794 was also evaluated, which could reach 1.40 g/L under the non-optimized condition and increase to 5.83 g/L in the modified ISP4 medium with macroporous adsorption beads added, indicating that NBU794 is a promising source of prodigiosin.

308-nm excimer lamp with 0.03% tacrolimus ointment is safe and effective to treat children with non-segmental vitiligo.

Introduction: A 308-nm excimer lamp combined with topical medicines has been used to treat vitiligo. However, few studies have evaluated its efficacy and influencing factors in children. Aim: We investigated the clinical effects and factors influencing the effectiveness of a 308-nm excimer lamp combined with 0.03% tacrolimus ointment in treating children with non-segmental vitiligo. Material and methods: A retrospective interventional case-series study was performed on 73 patients with non-segmental vitiligo treated with combination therapy. The duration of treatment ranged from 1 to 24 months, and the total number of treatments ranged from 4 to 78 sessions. We evaluated different treatment factors, including the number of treatments with a 308-nm excimer lamp, location, dose, disease course, and adverse reactions. Results: Overall, 105 leukodermas were treated: 36.2% had disappeared completely. The efficiency rate was 81.9% after a median treatment duration of 10.5 months. The treatment was most effective for the face and neck. Patients with a short disease duration showed a better response (disease duration shorter than 12 months). Reported adverse reactions were mild. Conclusions: Treatment using a 308-nm excimer lamp and 0.03% tacrolimus ointment is a safe and valuable treatment for children with non-segmental vitiligo.

Aryl hydrocarbon receptor (AhR) regulates adipocyte differentiation by assembling CRL4B ubiquitin ligase to target PPARγ for proteasomal degradation.

Peroxisome proliferator-activated receptor γ (PPARγ) is the central regulator of adipogenesis, and its dysregulation is linked to obesity and metabolic diseases. Identification of the factors that regulate PPARγ expression and activity is therefore crucial for combating obesity. Aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor with a known role in xenobiotic detoxification. Recent studies have suggested that AhR also plays essential roles in energy metabolism. However, the detailed mechanisms remain unclear. We previously reported that experiments with adipocyte-specific Cullin 4b (Cul4b)-knockout mice showed that CUL4B suppresses adipogenesis by targeting PPARγ. Here, using immunoprecipitation, ubiquitination, real-time PCR, and GST-pulldown assays, we report that AhR functions as the substrate receptor in CUL4B-RING E3 ubiquitin ligase (CRL4B) complex and is required for recruiting PPARγ. AhR overexpression reduced PPARγ stability and suppressed adipocyte differentiation, and AhR knockdown stimulated adipocyte differentiation in 3T3-L1 cells. Furthermore, we found that two lysine sites on residues 268 and 293 in PPARγ are targeted for CRL4B-mediated ubiquitination, indicating cross-talk between acetylation and ubiquitination. Our findings establish a critical role of AhR in regulating PPARγ stability and suggest that the AhR-PPARγ interaction may represent a potential therapeutic target for managing metabolic diseases arising from PPARγ dysfunction.

Numb directs the subcellular localization of EAAT3 through binding the YxNxxF motif.

Excitatory amino acid transporter type 3 (EAAT3, also known as SLC1A1) is a high-affinity, Na(+)-dependent glutamate carrier that localizes primarily within the cell and at the apical plasma membrane. Although previous studies have reported proteins and sequence regions involved in EAAT3 trafficking, the detailed molecular mechanism by which EAAT3 is distributed to the correct location still remains elusive. Here, we identify that the YVNGGF sequence in the C-terminus of EAAT3 is responsible for its intracellular localization and apical sorting in rat hepatoma cells CRL1601 and Madin-Darby canine kidney (MDCK) cells, respectively. We further demonstrate that Numb, a clathrin adaptor protein, directly binds the YVNGGF motif and regulates the localization of EAAT3. Mutation of Y503, N505 and F508 within the YVNGGF motif to alanine residues or silencing Numb by use of small interfering RNA (siRNA) results in the aberrant localization of EAAT3. Moreover, both Numb and the YVNGGF motif mediate EAAT3 endocytosis in CRL1601 cells. In summary, our study suggests that Numb is a pivotal adaptor protein that mediates the subcellular localization of EAAT3 through binding the YxNxxF (where x stands for any amino acid) motif.

Identification and characterization of NPC1L1 variants in Uygur and Kazakh with extreme low-density lipoprotein cholesterol.

BACKGROUND: Plasma levels of low-density lipoprotein cholesterol (LDL-C) are a major risk factor for cardiovascular disease and are influenced by both heredity and dietary habits. The Niemann-Pick C1 like 1 (NPC1L1) protein mediates efficient dietary cholesterol absorption and contributes to variations in human LDL-C levels. METHODS: In the present study, using high throughput sequencing we identified three non-synonymous (NS) variations and 64 synonymous variations in the NPC1L1 gene from subsets of Chinese Han, Uygur and Kazakh populations with high or low LDL-C. Subsequently, three NS variations encoding R174H, V177I and V1284L substitutions were observed only in Uygur and Kazakh individuals with limited maximal plasma LDL-C levels. RESULTS: In further experiments, we investigated cholesterol-regulated recycling and glycosylation and stability of these NS NPC1L1 variants. However, no significant differences between WT and variant NPC1L1 proteins were observed using in vivo assays in mouse livers with adenovirus-mediated expression, demonstrating that none of the three NPC1L1 NS variants caused decreased uptake of biliary cholesterol. CONCLUSIONS: Simultaneously, these data indicate that R174H, V177I and V1284L NPC1L1 variations in high or low LDL-C individuals may not directly influence cholesterol absorption by NPC1L1.

The clathrin adaptor proteins ARH, Dab2, and numb play distinct roles in Niemann-Pick C1-Like 1 versus low density lipoprotein receptor-mediated cholesterol uptake.

The uptake of circulating low density lipoproteins (LDL) is mediated by LDL receptor (LDLR) through clathrin-dependent endocytosis. At the early stage of this process, adaptor proteins ARH and Dab2 specifically bind the endocytic signal motif in LDLR and recruit clathrin/AP2 to initiate internalization. On the other hand, intestinal cholesterol is absorbed by Niemann-Pick C1-Like 1 (NPC1L1) through clathrin-dependent endocytosis. Another adaptor protein, Numb recognizes the endocytic motif in NPC1L1 C terminus and couples NPC1L1 to endocytic machinery. The ARH, Dab2, and Numb proteins contain a homogeneous phosphotyrosine binding (PTB) domain that directly binds endocytic motifs. Because ARH, Dab2, and Numb are all PTB domain family members, the emerging mystery is whether these adaptors act complementally in LDLR and NPC1L1 endocytosis. Here, we found that ARH and Dab2 did not bind NPC1L1 and were not required for NPC1L1 internalization. Similarly, Numb lacked the ability to interact with the LDLR C terminus and was dispensable for LDL uptake. Only the Numb isoforms with shorter PTB domain could facilitate NPC1L1 endocytosis. Besides the reported function in intestinal cholesterol absorption, Numb also mediated cholesterol reabsorption from bile in liver. We further identified a Numb variant with G595D substitution in humans of low blood LDL-cholesterol. The G595D substitution impaired NPC1L1 internalization and cholesterol reabsorption, due to attenuating affinity of Numb to clathrin/AP2. These results demonstrate that Numb specifically regulates NPC1L1-mediated cholesterol absorption both in human intestine and liver, distinct from ARH and Dab2, which selectively participate in LDLR-mediated LDL uptake.

Prognostic Significance of CDCP1 Expression in Colorectal Cancer and Effect of Its Inhibition on Invasion and Migration.

BACKGROUND: To assess the correlations and functions of complement C1r/C1s, Uegf, Bmp1 domain-containing protein-1 (CDCP1) in identifying colorectal cancer (CRC) patients who are at high risk for metastasis. METHODS: Tumor specimens from 101 patients were analyzed by real-time polymerase chain reaction to detect CDCP1 expression. CDCP1 expression plasmids and shRNA were used to knock down CDCP1 expression in this study to investigate migratory and invasive abilities by Boyden chambers. The mRNA expression profiles in shCDCP1 transfectants were compared to those in control cells by conducting microarray analysis. Its downstream effectors were also invested in this study. RESULTS: CRC patients with a high CDCP1 expression had a statistically significant lower overall survival and disease-free survival compared to those exhibiting low CDCP1 expression. In vitro, knock-down CDCP1 expression significantly decreased migratory and invasive abilities in HCT116. Aberrant expression of CDCP1 increased cancer cell migration and invasion. By using integrated genomics, we identified ROCK1 (rho-associated, coiled-coil-containing protein kinase 1 pseudogene 1) as a downstream effector in CDCP1-mediated migration and as an invasion mediator. Clinically, ROCK1 and CDCP1 mRNA expression exhibited a strong positive correlation in CRC patient samples. CONCLUSIONS: Our results implicated CDCP1 as a key regulator of CRC migration and invasion, and suggest that it is a useful prognostic factor for patients with CRC. Improved identification of a high-risk subset of early metastatic patients may guide indications of individualized treatment in clinical practice.

Effects of mind-body exercise on perimenopausal and postmenopausal women: a systematic review and meta-analysis.

IMPORTANCE: The increasing attention to the management of perimenopausal and postmenopausal women parallels the growth of the aging population. Although hormone therapy is commonly used to alleviate menopausal symptoms, it carries a potential risk of cancer. Recently, mind-body exercises have emerged as innovative approaches for improving menopausal symptoms and bone health. However, research findings have needed to be more consistent, highlighting the significance of this study's systematic review of mind-body exercise effects on perimenopausal and postmenopausal women. OBJECTIVE: This study aims to evaluate the impact of mind-body exercises, including tai chi, yoga, Pilates, qigong, baduanjin, and mindfulness-based stress reduction, on bone mineral density, sleep quality, anxiety, depression, and fatigue among perimenopausal and postmenopausal women. EVIDENCE REVIEW: Four electronic databases-PubMed, Embase, Cochrane Central Register of Controlled Trials, and Web of Science-were systematically searched from inception until July 2023. The search focused exclusively on randomized controlled trials to examine the impact of mind-body exercise interventions on perimenopausal and postmenopausal women. The methodological quality of the included studies was evaluated using the Cochrane Bias Risk Assessment tool. FINDINGS: A total of 11 randomized controlled trials, comprising 1,005 participants, were included in the analysis. Traditional meta-analysis indicated that mind-body exercise significantly enhanced bone mineral density in perimenopausal and postmenopausal women compared with control groups, with a standardized mean difference (SMD) of 0.41 (95% CI, 0.17 to 0.66; P = 0.001, I2 = 7%). In addition, significant improvements were observed in sleep quality (SMD, -0.48; 95% CI, -0.78 to -0.17; P = 0.002, I2 = 76%), anxiety reduction (SMD, -0.80; 95% CI, -1.23 to -0.38; P = 0.0002, I2 = 84%), depressive mood (SMD, -0.80; 95% CI, -1.17 to -0.44; P < 0.0001, I2 = 79%), and fatigue (SMD, -0.67; 95% CI, -0.97 to -0.37; P < 0.0001, I2 = 0%). CONCLUSIONS AND RELEVANCE: The findings of this meta-analysis demonstrate that mind-body exercise positively influences bone mineral density, sleep quality, anxiety, depression, and fatigue among perimenopausal and postmenopausal women.