IU Indianapolis ScholarWorks :: Browsing by Author "Wu, Di"

Browsing by Author "Wu, Di"

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The baroreflex afferent pathway plays a critical role in H2S-mediated autonomic control of blood pressure regulation under physiological and hypertensive conditions
(Springer Nature, 2021) Li, Ying; Feng, Yan; Liu, Li; Li, Xue; Li, Xin-yu; Sun, Xun; Li, Ke-xin; Zha, Rong-rong; Wang, Hong-dan; Zhang, Meng-di; Fan, Xiong-xiong; Wu, Di; Fan, Yao; Zhang, Hao-cheng; Qiao, Guo-fen; Li, Bai-yan; Biomedical Engineering, School of Engineering and Technology
Hydrogen sulfide (H2S), which is closely related to various cardiovascular disorders, lowers blood pressure (BP), but whether this action is mediated via the modification of baroreflex afferent function has not been elucidated. Therefore, the current study aimed to investigate the role of the baroreflex afferent pathway in H2S-mediated autonomic control of BP regulation. The results showed that baroreflex sensitivity (BRS) was increased by acute intravenous NaHS (a H2S donor) administration to renovascular hypertensive (RVH) and control rats. Molecular expression data also showed that the expression levels of critical enzymes related to H2S were aberrantly downregulated in the nodose ganglion (NG) and nucleus tractus solitarius (NTS) in RVH rats. A clear reduction in BP by the microinjection of NaHS or L-cysteine into the NG was confirmed in both RVH and control rats, and a less dramatic effect was observed in model rats. Furthermore, the beneficial effects of NaHS administered by chronic intraperitoneal infusion on dysregulated systolic blood pressure (SBP), cardiac parameters, and BRS were verified in RVH rats. Moreover, the increase in BRS was attributed to activation and upregulation of the ATP-sensitive potassium (KATP) channels Kir6.2 and SUR1, which are functionally expressed in the NG and NTS. In summary, H2S plays a crucial role in the autonomic control of BP regulation by improving baroreflex afferent function due at least in part to increased KATP channel expression in the baroreflex afferent pathway under physiological and hypertensive conditions.
A Biomarker Characterizing Neurodevelopment with applications in Autism
(Nature Publishing Group, 2018-01-12) Wu, Di; José, Jorge V.; Nurnberger, John I., Jr.; Torres, Elizabeth B.; Medicine, School of Medicine
Despite great advances in neuroscience and genetic studies, our understanding of neurodevelopmental disorders is still quite limited. An important reason is not having objective psychiatric clinical tests. Here we propose a quantitative neurodevelopment assessment by studying natural movement outputs. Movement is central to behaviors: It involves complex coordination, temporal alterations, and precise dynamic controls. We carefully analyzed the continuous movement output data, collected with high definition electromagnetic sensors at millisecond time scales. We unraveled new metrics containing striking physiological information that was unseen neither by using traditional motion assessments nor by naked eye observations. Our putative biomarker leads to precise individualized classifications. It illustrates clear differences between Autism Spectrum Disorder (ASD) subjects from mature typical developing (TD) individuals. It provides an ASD complementary quantitative classification, which closely agrees with the clinicaly assessed functioning levels in the spectrum. It also illustrates TD potential age-related neurodevelopmental trajectories. Applying our movement biomarker to the parents of the ASD individuals studied in the cohort also shows a novel potential familial signature ASD tie. This paper proposes a putative behavioral biomarker to characterize the level of neurodevelopment with high predicting power, as illustrated in ASD subjects as an example.
Clonal hematopoiesis driven by mutated DNMT3A promotes inflammatory bone loss
(Elsevier, 2024) Wang, Hui; Divaris, Kimon; Pan, Bohu; Li, Xiaofei; Lim, Jong-Hyung; Saha, Gundappa; Barovic, Marko; Giannakou, Danai; Korostoff, Jonathan M.; Bing, Yu; Sen, Souvik; Moss, Kevin; Wu, Di; Beck, James D.; Ballantyne, Christie M.; Natarajan, Pradeep; North, Kari E.; Netea, Mihai G.; Chavakis, Triantafyllos; Hajishengallis, George; Biostatistics and Health Data Science, Richard M. Fairbanks School of Public Health
Clonal hematopoiesis of indeterminate potential (CHIP) arises from aging-associated acquired mutations in hematopoietic progenitors, which display clonal expansion and produce phenotypically altered leukocytes. We associated CHIP-DNMT3A mutations with a higher prevalence of periodontitis and gingival inflammation among 4,946 community-dwelling adults. To model DNMT3A-driven CHIP, we used mice with the heterozygous loss-of-function mutation R878H, equivalent to the human hotspot mutation R882H. Partial transplantation with Dnmt3aR878H/+ bone marrow (BM) cells resulted in clonal expansion of mutant cells into both myeloid and lymphoid lineages and an elevated abundance of osteoclast precursors in the BM and osteoclastogenic macrophages in the periphery. DNMT3A-driven clonal hematopoiesis in recipient mice promoted naturally occurring periodontitis and aggravated experimentally induced periodontitis and arthritis, associated with enhanced osteoclastogenesis, IL-17-dependent inflammation and neutrophil responses, and impaired regulatory T cell immunosuppressive activity. DNMT3A-driven clonal hematopoiesis and, subsequently, periodontitis were suppressed by rapamycin treatment. DNMT3A-driven CHIP represents a treatable state of maladaptive hematopoiesis promoting inflammatory bone loss.
CXCR5+ follicular cytotoxic T cells control viral infection in B cell follicles
(Nature, 2016) Leong, Yew Ann; Chen, Yaping; Ong, Hong Sheng; Wu, Di; Man, Kevin; Deleage, Claire; Minnich, Martina; Meckiff, Benjamin J.; Wei, Yunbo; Hou, Zhaohua; Zotos, Dimitra; Fenix, Kevin A.; Atnerkar, Anurag; Preston, Simon; Chipman, Jeffrey G.; Beilman, Greg J.; Allison, Cody C.; Sun, Lei; Wang, Peng; Xu, Jiawei; Toe, Jesse G.; Lu, Hao K.; Tao, Yong; Palendira, Umaimainthan; Dent, Alexander L.; Landay, Alan L.; Pellegrini, Marc; Comerford, Iain; McColl, Shaun R.; Schacker, Timothy W.; Long, Heather M.; Estes, Jacob D.; Busslinger, Meinrad; Belz, Gabrielle T.; Lewin, Sharon R.; Kallies, Axel; Yu, Di; Department of Microbiology and Immunology, IU School of Medicine
During unresolved infections, some viruses escape immunological control and establish a persistant reservoir in certain cell types, such as human immunodeficiency virus (HIV), which persists in follicular helper T cells (TFH cells), and Epstein-Barr virus (EBV), which persists in B cells. Here we identified a specialized group of cytotoxic T cells (TC cells) that expressed the chemokine receptor CXCR5, selectively entered B cell follicles and eradicated infected TFH cells and B cells. The differentiation of these cells, which we have called 'follicular cytotoxic T cells' (TFC cells), required the transcription factors Bcl6, E2A and TCF-1 but was inhibited by the transcriptional regulators Blimp1, Id2 and Id3. Blimp1 and E2A directly regulated Cxcr5 expression and, together with Bcl6 and TCF-1, formed a transcriptional circuit that guided TFC cell development. The identification of TFC cells has far-reaching implications for the development of strategies to control infections that target B cells and TFH cells and to treat B cell–derived malignancies.
Inhibition of the Growth of Breast Cancer-Associated Brain Tumors by the Osteocyte-Derived Conditioned Medium
(MDPI, 2021-03-03) Sano, Tomohiko; Sun, Xun; Feng, Yan; Liu, Shengzhi; Hase, Misato; Fan, Yao; Zha, Rongrong; Wu, Di; Aryal, Uma K.; Li, Bai-Yan; Sudo, Akihiro; Yokota, Hiroki; Biomedical Engineering, School of Engineering and Technology
The brain is a common site of metastasis from advanced breast cancer but few effective treatments are available. We examined a therapeutic option with a conditioned medium (CM), focusing on the role of Lrp5 and β-catenin in Wnt signaling, and IL1ra in osteocytes. Osteocytes presented the innate anti-tumor effect and the overexpression of the above genes strengthened their action. In a mouse model, the injection of their CM inhibited mammary tumors and tumor-driven osteolysis. Importantly, Lrp5- and/or IL1ra-overexpressing osteocytes or the local administration of β-catenin-overexpressing CM markedly inhibited brain tumors. In the transport analysis, tumor-suppressing factors in CM were shown to diffuse through the skull. Mechanistically, the CM with overexpression of the above genes downregulated oncogenic genes such as MMP9, Runx2, TGFβ, and Snail in breast cancer cells. Also, the CM with β-catenin overexpression downregulated CXCL1 and CXCL5 and upregulated tumor suppressors such as LIMA1, DSP, p53, and TRAIL in breast cancer cells. Notably, whole-genome proteomics revealed that histone H4 was enriched in CM and acted as an atypical tumor suppressor. Lrp5-overexpressing MSCs were also shown to act as anti-tumor agents. Collectively, this study demonstrated the therapeutic role of engineered CM in brain tumors and the tumor-suppressing action of extracellular histone H4. The result sheds light on the potential CM-based therapy for breast cancer-associated brain metastases in a minimally invasive manner.
Loading-induced antitumor capability of murine and human urine
(Wiley, 2020-06) Wu, Di; Fan, Yao; Liu, Shengzhi; Woollam, Mark D.; Sun, Xun; Murao, Eiji; Zha, Rongrong; Prakash, Rahul; Park, Charles; Siegel, Amanda P.; Liu, Jing; Agarwal, Mangilal; Li, Bai-Yan; Yokota, Hiroki; Biomedical Engineering, School of Engineering and Technology
While urine has been considered as a useful bio-fluid for health monitoring, its dynamic changes to physical activity are not well understood. We examined urine's possible antitumor capability in response to medium-level, loading-driven physical activity. Urine was collected from mice subjected to 5-minute skeletal loading and human individuals before and after 30-minute step aerobics. Six cancer cell lines (breast, prostate, and pancreas) and a mouse model of the mammary tumor were employed to evaluate the effect of urine. Compared to urine collected prior to loading, urine collected post-activity decreased the cellular viability, proliferation, migration, and invasion of tumor cells, as well as tumor weight in the mammary fat pad. Detection of urinary volatile organic compounds and ELISA assays showed that the loading-conditioned urine reduced cholesterol and elevated dopamine and melatonin. Immunohistochemical fluorescent images presented upregulation of the rate-limiting enzymes for the production of dopamine and melatonin in the brain. Molecular analysis revealed that the antitumor effect was linked to the reduction in molecular vinculin-linked molecular force as well as the downregulation of the Lrp5-CSF1-CD105 regulatory axis. Notably, the survival rate for the high expression levels of Lrp5, CSF1, and CD105 in tumor tissues was significantly lowered in the Cancer Genome Atlas database. Collectively, this study revealed that 5- or 10-minute loading-driven physical activity was sufficient to induce the striking antitumor effect by activating the neuronal signaling and repressing cholesterol synthesis. The result supported the dual role of loading-conditioned urine as a potential tumor suppressor and a source of diagnostic biomarkers.
Mechanical stimulations can inhibit local and remote tumor progression by downregulating WISP1
(Wiley, 2020-09) Liu, Shengzhi; Wu, Di; Sun, Xun; Fan, Yao; Zha, Rongrong; Jalali, Aydin; Teli, Meghana; Sano, Tomonori; Siegel, Amanda; Sudo, Akihiro; Agarwal, Mangilal; Robling, Alexander; Li, Bai-Yan; Yokota, Hiroki; Biomedical Engineering, School of Engineering and Technology
Mechanical stimulations can prevent bone loss, but their effects on the tumor-invaded bone or solid tumors are elusive. Here, we evaluated the effect of knee loading, dynamic loads applied to the knee, on metastasized bone and mammary tumors. In a mouse model, tumor cells were inoculated to the mammary fat pad or the proximal tibia. Daily knee loading was then applied and metabolic changes were monitored mainly through urine. Urine samples were also collected from human subjects before and after step aerobics. The result showed that knee loading inhibited tumor progression in the loaded tibia. Notably, it also reduced remotely the growth of mammary tumors. In the urine, an altered level of cholesterol was observed with an increase in calcitriol, which is synthesized from a cholesterol derivative. In urinary proteins, knee loading in mice and step aerobics in humans markedly reduced WNT1-inducible signaling pathway protein 1, WISP1, which leads to poor survival among patients with breast cancer. In the ex vivo breast cancer tissue assay, WISP1 promoted the growth of cancer fragments and upregulated tumor-promoting genes, such as Runx2, MMP9, and Snail. Collectively, the present preclinical and human study demonstrated that mechanical stimulations, such as knee loading and step aerobics, altered urinary metabolism and downregulated WISP1. The study supports the benefit of mechanical stimulations for locally and remotely suppressing tumor progression. It also indicated the role of WISP1 downregulation as a potential mechanism of loading-driven tumor suppression.
Mechanical tibial loading remotely suppresses brain tumors by dopamine-mediated downregulation of CCN4
(Springer Nature, 2021-05-24) Fan, Yao; Zha, Rongrong; Sano, Tomohiko; Zhao, Xinyu; Liu, Shengzhi; Woollam, Mark D.; Wu, Di; Sun, Xun; Li, Kexin; Egi, Motoki; Li, Fangjia; Minami, Kazumasa; Siegel, Amanda P.; Horiuchi, Takashi; Liu, Jing; Agarwal, Mangilal; Sudo, Akihiro; Nakshatri, Harikrishna; Li, Bai-Yan; Yokota, Hiroki; Biomedical Engineering, School of Engineering and Technology
Mechanical loading to the bone is known to be beneficial for bone homeostasis and for suppressing tumor-induced osteolysis in the loaded bone. However, whether loading to a weight-bearing hind limb can inhibit distant tumor growth in the brain is unknown. We examined the possibility of bone-to-brain mechanotransduction using a mouse model of a brain tumor by focusing on the response to Lrp5-mediated Wnt signaling and dopamine in tumor cells. The results revealed that loading the tibia with elevated levels of tyrosine hydroxylase, a rate-limiting enzyme in dopamine synthesis, markedly reduced the progression of the brain tumors. The simultaneous application of fluphenazine (FP), an antipsychotic dopamine modulator, enhanced tumor suppression. Dopamine and FP exerted antitumor effects through the dopamine receptors DRD1 and DRD2, respectively. Notably, dopamine downregulated Lrp5 via DRD1 in tumor cells. A cytokine array analysis revealed that the reduction in CCN4 was critical for loading-driven, dopamine-mediated tumor suppression. The silencing of Lrp5 reduced CCN4, and the administration of CCN4 elevated oncogenic genes such as MMP9, Runx2, and Snail. In summary, this study demonstrates that mechanical loading regulates dopaminergic signaling and remotely suppresses brain tumors by inhibiting the Lrp5-CCN4 axis via DRD1, indicating the possibility of developing an adjuvant bone-mediated loading therapy.
Neuropeptide Y-mediated sex- and afferent-specific neurotransmissions contribute to sexual dimorphism of baroreflex afferent function
(Impact Journals, 2016-10-04) Liu, Yang; Wu, Di; Qu, Mei-Yu; He, Jian-Li; Yuan, Mei; Zhao, Miao; Wang, Jian-Xin; He, Jian; Wang, Lu-Qi; Guo, Xin-Jing; Zuo, Meng; Zhao, Shu-Yang; Ma, Mei-Na; Li, Jun-Nan; Shou, Weinian; Qiao, Guo-Fen; Li, Bai-Yan; Department of Pediatrics, IU School of Medicine
BACKGROUND: Molecular and cellular mechanisms of neuropeptide-Y (NPY)-mediated gender-difference in blood pressure (BP) regulation are largely unknown. METHODS: Baroreceptor sensitivity (BRS) was evaluated by measuring the response of BP to phenylephrine/nitroprusside. Serum NPY concentration was determined using ELISA. The mRNA and protein expression of NPY receptors were assessed in tissue and single-cell by RT-PCR, immunoblot, and immunohistochemistry. NPY was injected into the nodose while arterial pressure was monitored. Electrophysiological recordings were performed on nodose neurons from rats by patch-clamp technique. RESULTS: The BRS was higher in female than male and ovariectomized rats, while serum NPY concentration was similar among groups. The sex-difference was detected in Y1R, not Y2R protein expression, however, both were upregulated upon ovariectomy and canceled by estrogen replacement. Immunostaining confirmed Y1R and Y2R expression in myelinated and unmyelinated afferents. Single-cell PCR demonstrated that Y1R expression/distribution was identical between A- and C-types, whereas, expressed level of Y2R was ~15 and ~7 folds higher in Ah- and C-types than A-types despite similar distribution. Activation of Y1R in nodose elevated BP, while activation of Y2R did the opposite. Activation of Y1R did not alter action potential duration (APD) of A-types, but activation of Y2R- and Y1R/Y2R in Ah- and C-types frequency-dependently prolonged APD. N-type ICa was reduced in A-, Ah- and C-types when either Y1R, Y2R, or both were activated. The sex-difference in Y1R expression was also observed in NTS. CONCLUSIONS: Sex- and afferent-specific expression of Neuropeptide-Y receptors in baroreflex afferent pathway may contribute to sexual-dimorphic neurocontrol of BP regulation.
Overexpression of Lrp5 enhanced the anti-breast cancer effects of osteocytes in bone
(Springer Nature, 2021-07-06) Liu, Shengzhi; Wu, Di; Sun, Xun; Fan, Yao; Zha, Rongrong; Jalali, Aydin; Feng, Yan; Li, Kexin; Sano, Tomohiko; Vike, Nicole; Li, Fangjia; Rispoli, Joseph; Sudo, Akihiro; Liu, Jing; Robling, Alexander; Nakshatri, Harikrishna; Li, Bai-Yan; Yokota, Hiroki; Biomedical Engineering, School of Engineering and Technology
Osteocytes are the most abundant cells in bone, which is a frequent site of breast cancer metastasis. Here, we focused on Wnt signaling and evaluated tumor-osteocyte interactions. In animal experiments, mammary tumor cells were inoculated into the mammary fat pad and tibia. The role of Lrp5-mediated Wnt signaling was examined by overexpressing and silencing Lrp5 in osteocytes and establishing a conditional knockout mouse model. The results revealed that administration of osteocytes or their conditioned medium (CM) inhibited tumor progression and osteolysis. Osteocytes overexpressing Lrp5 or β-catenin displayed strikingly elevated tumor-suppressive activity, accompanied by downregulation of tumor-promoting chemokines and upregulation of apoptosis-inducing and tumor-suppressing proteins such as p53. The antitumor effect was also observed with osteocyte-derived CM that was pretreated with a Wnt-activating compound. Notably, silencing Lrp5 in tumors inhibited tumor progression, while silencing Lrp5 in osteocytes in conditional knockout mice promoted tumor progression. Osteocytes exhibited elevated Lrp5 expression in response to tumor cells, implying that osteocytes protect bone through canonical Wnt signaling. Thus, our results suggest that the Lrp5/β-catenin axis activates tumor-promoting signaling in tumor cells but tumor-suppressive signaling in osteocytes. We envision that osteocytes with Wnt activation potentially offer a novel cell-based therapy for breast cancer and osteolytic bone metastasis.

Browsing by Author "Wu, Di"

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