To follow‐up on our previous report that acarbose (ACA), a drug that blocks postprandial glucose spikes, increases mouse lifespan, we studied ACA at three doses: 400, 1,000 (the original dose), and ...2,500 ppm, using genetically heterogeneous mice at three sites. Each dose led to a significant change (by log‐rank test) in both sexes, with larger effects in males, consistent with the original report. There were no significant differences among the three doses. The two higher doses produced 16% or 17% increases in median longevity of males, but only 4% or 5% increases in females. Age at the 90th percentile was increased significantly (8%–11%) in males at each dose, but was significantly increased (3%) in females only at 1,000 ppm. The sex effect on longevity is not explained simply by weight or fat mass, which were reduced by ACA more in females than in males. ACA at 1,000 ppm reduced lung tumors in males, diminished liver degeneration in both sexes and glomerulosclerosis in females, reduced blood glucose responses to refeeding in males, and improved rotarod performance in aging females, but not males. Three other interventions were also tested: ursolic acid, 2‐(2‐hydroxyphenyl) benzothiazole (HBX), and INT‐767; none of these affected lifespan at the doses tested. The acarbose results confirm and extend our original report, prompt further attention to the effects of transient periods of high blood glucose on aging and the diseases of aging, including cancer, and should motivate studies of acarbose and other glucose‐control drugs in humans.
Globally, plastics are used in various products. Concerns regarding the human body's exposure to plastics and environmental pollution have increased with increased plastic use. Microplastics can be ...detected in the atmosphere, leading to potential human health risks through inhalation; however, the toxic effects of microplastic inhalation are poorly understood. In this study, we examined the pulmonary toxicity of polystyrene (PS), polypropylene (PP), and polyvinyl chloride (PVC) in C57BL/6, BALB/c, and ICR mice strains. Mice were intratracheally instilled with 5 mg/kg of PS, PP, or PVC daily for two weeks. PS stimulation increased inflammatory cells in the bronchoalveolar lavage fluid (BALF) of C57BL/6 and ICR mice. Histopathological analysis of PS-instilled C57BL/6 and PP-instilled ICR mice showed inflammatory cell infiltration. PS increased the NLR family pyrin domain containing 3 (NLRP3) inflammasome components in the lung tissue of C57BL/6 and ICR mice, while PS-instilled BALB/c mice remained unchanged. PS stimulation increased inflammatory cytokines, including IL-1β and IL-6, in BALF of C57BL/6 mice. PP-instilled ICR mice showed increased NLRP3, ASC, and Caspase-1 in the lung tissue compared to the control groups and increased IL-1β levels in BALF. These results could provide baseline data for understanding the pulmonary toxicity of microplastic inhalation.
Background & Aims The secretory protein Slit2 and its receptor Robo1 are believed to regulate cell growth and migration. Here, we aimed to determine whether Slit2-Robo1 signaling mediates the ...pathogenesis of liver fibrosis. Methods Serum levels of Slit2 in patients with liver fibrosis were determined by ELISA. Liver fibrosis was induced in wild-type (WT), Slit2 transgenic ( Slit2 -Tg) and Robo1+/− Robo2+/− double heterozygotes ( Robo1/2+/− ) mice by carbon tetrachloride (CCl4 ). The functional contributions of Slit2-Robo1 signaling in liver fibrosis and activation of hepatic stellate cells (HSCs) were investigated using primary mouse HSCs and human HSC cell line LX-2. Results Significantly increased serum Slit2 levels and hepatic expression of Slit2 and Robo1 were observed in patients with liver fibrosis. Compared to WT mice, Slit2 -Tg mice were much more vulnerable to CCl4 -induced liver injury and more readily develop liver fibrosis. Development of hepatic fibrosis in Slit2 -Tg mice was associated with a stronger hepatic expression of collagen I and α-smooth muscle actin (α-SMA). However, liver injury and hepatic expression of collagen I and α-SMA were attenuated in CCl4 -treated Robo1/2+/− mice in response to CCl4 exposure. In vitro , Robo1 neutralizing antibody R5 and Robo1 siRNA downregulated phosphorylation of Smad2, Smad3, PI3K, and AKT in HSCs independent of TGF-β1. R5 and Robo1 siRNA also inhibited the expression of α-SMA by HSCs. Finally, the protective effect of R5 on the CCl4 -induced liver injury and fibrosis was further verified in mice. Conclusions Slit2-Robo1 signaling promotes liver injury and fibrosis through activation of HSCs.
Metastasis has been considered as the terminal step of tumor progression. However, recent genomic studies suggest that many metastases are initiated by further spread of other metastases. ...Nevertheless, the corresponding pre-clinical models are lacking, and underlying mechanisms are elusive. Using several approaches, including parabiosis and an evolving barcode system, we demonstrated that the bone microenvironment facilitates breast and prostate cancer cells to further metastasize and establish multi-organ secondary metastases. We uncovered that this metastasis-promoting effect is driven by epigenetic reprogramming that confers stem cell-like properties on cancer cells disseminated from bone lesions. Furthermore, we discovered that enhanced EZH2 activity mediates the increased stemness and metastasis capacity. The same findings also apply to single cell-derived populations, indicating mechanisms distinct from clonal selection. Taken together, our work revealed an unappreciated role of the bone microenvironment in metastasis evolution and elucidated an epigenomic reprogramming process driving terminal-stage, multi-organ metastases.
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•Experimental bone metastases (BoM) spread to other organs in mouse models•Evolving barcodes delineate further spread from BoM in spontaneous metastasis•BoM spurs metastatic seeds with increased stemness and reduced organotropism•EZH2 mediates secondary metastasis invigorated by the bone microenvironment
Delineation of cancer cell spreading from primary bone metastasis by an evolving barcode system highlights the impact of the bone microenvironment in shaping secondary metastasis through mechanisms distinct from clonal selection.
Molecular alterations in genes involved in DNA mismatch repair (MMR) promote cancer initiation and foster tumour progression. Cancers deficient in MMR frequently show favourable prognosis and ...indolent progression. The functional basis of the clinical outcome of patients with tumours that are deficient in MMR is not clear. Here we genetically inactivate MutL homologue 1 (MLH1) in colorectal, breast and pancreatic mouse cancer cells. The growth of MMR-deficient cells was comparable to their proficient counterparts in vitro and on transplantation in immunocompromised mice. By contrast, MMR-deficient cancer cells grew poorly when transplanted in syngeneic mice. The inactivation of MMR increased the mutational burden and led to dynamic mutational profiles, which resulted in the persistent renewal of neoantigens in vitro and in vivo, whereas MMR-proficient cells exhibited stable mutational load and neoantigen profiles over time. Immune surveillance improved when cancer cells, in which MLH1 had been inactivated, accumulated neoantigens for several generations. When restricted to a clonal population, the dynamic generation of neoantigens driven by MMR further increased immune surveillance. Inactivation of MMR, driven by acquired resistance to the clinical agent temozolomide, increased mutational load, promoted continuous renewal of neoantigens in human colorectal cancers and triggered immune surveillance in mouse models. These results suggest that targeting DNA repair processes can increase the burden of neoantigens in tumour cells; this has the potential to be exploited in therapeutic approaches.
Alzheimer's disease (AD) is the most prevalent form of age-related dementia, and its effect on society increases exponentially as the population ages. Accumulating evidence suggests that ...neuroinflammation, mediated by the brain's innate immune system, contributes to AD neuropathology and exacerbates the course of the disease. However, there is no experimental evidence for a causal link between systemic inflammation or neuroinflammation and the onset of the disease.
The viral mimic, polyriboinosinic-polyribocytidilic acid (PolyI:C) was used to stimulate the immune system of experimental animals. Wild-type (WT) and transgenic mice were exposed to this cytokine inducer prenatally (gestation day (GD)17) and/or in adulthood. Behavioral, immunological, immunohistochemical, and biochemical analyses of AD-associated neuropathologic changes were performed during aging.
We found that a systemic immune challenge during late gestation predisposes WT mice to develop AD-like neuropathology during the course of aging. They display chronic elevation of inflammatory cytokines, an increase in the levels of hippocampal amyloid precursor protein (APP) and its proteolytic fragments, altered Tau phosphorylation, and mis-sorting to somatodendritic compartments, and significant impairments in working memory in old age. If this prenatal infection is followed by a second immune challenge in adulthood, the phenotype is strongly exacerbated, and mimics AD-like neuropathologic changes. These include deposition of APP and its proteolytic fragments, along with Tau aggregation, microglia activation and reactive gliosis. Whereas Aβ peptides were not significantly enriched in extracellular deposits of double immune-challenged WT mice at 15 months, they dramatically increased in age-matched immune-challenged transgenic AD mice, precisely around the inflammation-induced accumulations of APP and its proteolytic fragments, in striking similarity to the post-mortem findings in human patients with AD.
Chronic inflammatory conditions induce age-associated development of an AD-like phenotype in WT mice, including the induction of APP accumulations, which represent a seed for deposition of aggregation-prone peptides. The PolyI:C mouse model therefore provides a unique tool to investigate the molecular mechanisms underlying the earliest pathophysiological changes preceding fibrillary Aβ plaque deposition and neurofibrillary tangle formations in a physiological context of aging. Based on the similarity between the changes in immune-challenged mice and the development of AD in humans, we suggest that systemic infections represent a major risk factor for the development of AD.
Ripretinib (DCC-2618) was designed to inhibit the full spectrum of mutant KIT and PDGFRA kinases found in cancers and myeloproliferative neoplasms, particularly in gastrointestinal stromal tumors ...(GISTs), in which the heterogeneity of drug-resistant KIT mutations is a major challenge. Ripretinib is a “switch-control” kinase inhibitor that forces the activation loop (or activation “switch”) into an inactive conformation. Ripretinib inhibits all tested KIT and PDGFRA mutants, and notably is a type II kinase inhibitor demonstrated to broadly inhibit activation loop mutations in KIT and PDGFRA, previously thought only achievable with type I inhibitors. Ripretinib shows efficacy in preclinical cancer models, and preliminary clinical data provide proof-of-concept that ripretinib inhibits a wide range of KIT mutants in patients with drug-resistant GISTs.
•Ripretinib broadly inhibits primary and drug-resistant KIT/PDGFRA mutants•KIT/PDGFRA inhibitor of all known activation loop mutations•In drug-resistant cancers, ripretinib blocks kinase signaling and tumor growth•Circulating tumor DNA data confirm broad inhibition of mutant KIT in GIST patients
To overcome the often multi-subclonal mutations in treatment-resistant GIST, Smith et al. design ripretinib, which targets a broad spectrum of KIT and PDGFRA mutants. Ripretinib shows efficacy in KIT and PDGFRA mutant cancer models and reduces circulating tumor DNA mutant allele frequency in two GIST patients.
The lysyl oxidase-like protein LOXL2 has been suggested to contribute to tumor progression and metastasis, but
evidence has been lacking. Here we provide functional evidence that LOXL2 is a key ...driver of breast cancer metastasis in two conditional transgenic mouse models of PyMT-induced breast cancer. LOXL2 ablation in mammary tumor cells dramatically decreased lung metastasis, whereas LOXL2 overexpression promoted metastatic tumor growth. LOXL2 depletion or overexpression in tumor cells does not affect extracellular matrix stiffness or organization in primary and metastatic tumors, implying a function for LOXL2 independent of its conventional role in extracellular matrix remodeling. In support of this likelihood, cellular and molecular analyses revealed an association of LOXL2 action with elevated levels of the EMT regulatory transcription factor Snail1 and expression of several cytokines that promote premetastatic niche formation. Taken together, our findings established a pathophysiologic role and new function for LOXL2 in breast cancer metastasis.
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Human group 1 ILCs consist of at least three phenotypically distinct subsets, including NK cells, CD127+ ILC1, and intraepithelial CD103+ ILC1. In inflamed intestinal tissues from Crohn’s disease ...patients, numbers of CD127+ ILC1 increased at the cost of ILC3. Here we found that differentiation of ILC3 to CD127+ ILC1 is reversible in vitro and in vivo. CD127+ ILC1 differentiated to ILC3 in the presence of interleukin-2 (IL-2), IL-23, and IL-1β dependent on the transcription factor RORγt, and this process was enhanced in the presence of retinoic acid. Furthermore, we observed in resection specimen from Crohn’s disease patients a higher proportion of CD14+ dendritic cells (DC), which in vitro promoted polarization from ILC3 to CD127+ ILC1. In contrast, CD14− DCs promoted differentiation from CD127+ ILC1 toward ILC3. These observations suggest that environmental cues determine the composition, function, and phenotype of CD127+ ILC1 and ILC3 in the gut.
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•CD127+ ILC1 can differentiate into ILC3•Differentiation of ILC1 to ILC3 is reversible•Differentiation of ILC1 to ILC3 is driven by IL-23 and accelerated by IL-1β and RA•Distinct dendritic cell subsets induce differentiation of ILC1 to ILC3 and vice versa
Group 3 innate lymphoid cells (ILC3) can give rise to ILC1 in inflamed intestinal tissue. Spits and colleagues report bidirectional plasticity between ILC1 and ILC3 in the intestinal lamina propria in response to distinct environmental changes, suggesting functional adaptation without the need to recruit new cells from the circulation.
The mechanism by which pharmacologic administration of the hormone FGF21 increases energy expenditure to cause weight loss in obese animals is unknown. Here we report that FGF21 acts centrally to ...exert its effects on energy expenditure and body weight in obese mice. Using tissue-specific knockout mice, we show that βKlotho, the obligate coreceptor for FGF21, is required in the nervous system for these effects. FGF21 stimulates sympathetic nerve activity to brown adipose tissue through a mechanism that depends on the neuropeptide corticotropin-releasing factor. Our findings provide an unexpected mechanistic explanation for the strong pharmacologic effects of FGF21 on energy expenditure and weight loss in obese animals.
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•FGF21 acts directly on the nervous system to stimulate sympathetic nerve activity•The effects of FGF21 on sympathetic outflow require corticotropin-releasing factor•The central actions of FGF21 are required for it to cause weight loss
FGF21 promotes weight loss and improves insulin sensitivity when administered to obese rodents, monkeys, and humans. Owen et al. find in obese mice that these therapeutic effects require FGF21 to act directly on the brain, where it stimulates sympathetic nerve activity via the neuropeptide CRF to activate brown fat.
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