Potential Growth Regulators Research Articles

PDCD4 Is an Androgen-Repressed Tumor Suppressor that Regulates Prostate Cancer Growth and Castration Resistance.

Androgen receptor (AR) transcriptional activity contributes to prostate cancer development and castration resistance. The growth and survival pathways driven by AR remain incompletely defined. Here, we found PDCD4 to be a new target of AR signaling and a potent regulator of prostate cancer cell growth, survival, and castration resistance. The 3' untranslated region of PDCD4 is directly targeted by the androgen-induced miRNA, miR-21. Androgen treatment suppressed PDCD4 expression in a dose responsive and miR-21-dependent manner. Correspondingly, AR inhibition dose-responsively induced PDCD4 expression. Using data from prostate cancer tissue samples in The Cancer Genome Atlas (TCGA), we found a significant and inverse correlation between miR-21 and PDCD4 mRNA and protein levels. Higher Gleason grade tumors exhibited significantly higher levels of miR-21 and significantly lower levels of PDCD4 mRNA and protein. PDCD4 knockdown enhanced androgen-dependent cell proliferation and cell-cycle progression, inhibited apoptosis, and was sufficient to drive androgen-independent growth. On the other hand, PDCD4 overexpression inhibited miR-21-mediated growth and androgen independence. The stable knockdown of PDCD4 in androgen-dependent prostate cancer cells enhanced subcutaneous tumor take rate in vivo, accelerated tumor growth, and was sufficient for castration-resistant tumor growth. IMPLICATIONS: This study provides the first evidence that PDCD4 is an androgen-suppressed protein capable of regulating prostate cancer cell proliferation, apoptosis, and castration resistance. These results uncover miR-21 and PDCD4-regulated pathways as potential new targets for castration-resistant prostate cancer.

Systemic Blockade of ACVR2B Ligands Protects Myocardium from Acute Ischemia-Reperfusion Injury.

Activin A and myostatin, members of the transforming growth factor (TGF)-β superfamily of secreted factors, are potent negative regulators of muscle growth, but their contribution to myocardial ischemia-reperfusion (IR) injury is not known. The aim of this study was to investigate if activin 2B (ACVR2B) receptor ligands contribute to myocardial IR injury. Mice were treated with soluble ACVR2B decoy receptor (ACVR2B-Fc) and subjected to myocardial ischemia followed by reperfusion for 6 or 24 h. Systemic blockade of ACVR2B ligands by ACVR2B-Fc was protective against cardiac IR injury, as evidenced by reduced infarcted area, apoptosis, and autophagy and better preserved LV systolic function following IR. ACVR2B-Fc modified cardiac metabolism, LV mitochondrial respiration, as well as cardiac phenotype toward physiological hypertrophy. Similar to its protective role in IR injury in vivo, ACVR2B-Fc antagonized SMAD2 signaling and cell death in cardiomyocytes that were subjected to hypoxic stress. ACVR2B ligand myostatin was found to exacerbate hypoxic stress. In addition to acute cardioprotection in ischemia, ACVR2B-Fc provided beneficial effects on cardiac function in prolonged cardiac stress in cardiotoxicity model. By blocking myostatin, ACVR2B-Fc potentially reduces cardiomyocyte death and modifies cardiomyocyte metabolism for hypoxic conditions to protect the heart from IR injury.

Galectins-1 and-3 Increase in Equine Post-traumatic Osteoarthritis.

Galectins are potent regulators of cell adhesion, growth and apoptosis in diverse cell types, including chondrocytes and synovial fibroblasts. Elevations in synovial fluid galectin-3 have been observed in rheumatoid arthritis, juvenile idiopathic arthritis and experimental inflammatory arthritis in animal models, whereas galectin-1 is thought to be protective. Less is known about galectins-1 and-3 in osteoarthritis (OA). Therefore, the purpose of this study was: (1) to determine whether galectin-1 and-3 synovial fluid concentrations and synovial membrane and cartilage histochemical staining were altered following osteochondral injury in an experimental equine osteoarthritis (OA) model and (2) to measure galectin-1 and-3 mRNA expression and synovial fluid concentrations in naturally occurring equine carpal OA. Synovial fluid galectin-1 and-3 concentrations were quantified using custom ELISAs in two research horse cohorts undergoing experimental OA induction (n = 5 and 4) and in a cohort of horses with naturally occurring carpal OA (n = 57). Galectin mRNA expression in synovial membrane and cartilage tissue obtained from carpal joints of horses with naturally occurring OA was measured using RT-qPCR, and galectin immunostaining was assessed in synovial membrane and osteochondral tissues in the experimental model (n = 5). Synovial fluid galectin-1 and-3 concentrations increased following experimental carpal osteochondral fragmentation. Cartilage galectin-1 mRNA expression increased with OA severity in naturally occurring disease. The superficial zone of healthy articular cartilage stained intensely for galectin-3 in sham-operated joints, whereas galectin-1 staining was nearly absent. Chondrocyte galectin-1 and-3 immunoreactivity increased following cartilage injury, particularly in galectin-1 positive chondrones. Galectins-1 and-3 are present in healthy equine synovial fluid and increase following post-traumatic OA. Healthy superficial zone chondrocytes express galectin-3, whereas galectin-1 chondrocyte staining is limited predominantly to chondrones and injured cartilage. Further work is needed to clarify the functions of galectins-1 and-3 in healthy and OA joints.

INTERSECTION BETWEEN GENES CONTROLLING VASCULARIZATION AND ANGIOGENESIS IN RENAL CELL CARCINOMAS

To show that application of the systemic analysis may significantly improve comparison of different datasets. Different genes and proteins may converge on the same functional outputs. A comparison of 2datasets by only identification names of affected molecules may miss that, leading to a conclusion that there is nothing in common for these datasets. Systemic analysis may overcome this limitation, by focusing on functions represented by the identification names. Datasets were retrieved from open sources. Systemic analysis of vascularization features and angiogenesis signature was performed by using Cytoscape and its plugs-in. In contrary to the initial statement of the lack of overlap between the vascularization features and the angiogenesis genes-signature in renal carcinomas, we observed an intersection on the functional level. Analysis of the networks built with identification names of vascularization and angiogenesis datasets showed an intersection, which included potent regulators of vessel formation and growth. Analysis of networks may expose functional links, which may be missed by a direct identification names comparison.

Myostatin Deletion Prevents Kidney Specific Increases in NOX4 in Obesity and Protects Against Renal Injury and Hypertension

Obesity is well characterized for its ability to compromise cardiometabolic function; being highly associated with hypertension and chronic kidney disease. Myostatin is a myokine, a cytokine–like factor that regulates muscle function and growth, which is a potent negative regulator of skeletal muscle growth and has been shown to be upregulated in obesity. NADPH oxidase 4 (NOX4) is known to play a key role in kidney function in diabetic nephropathy. However, while myostatin deletion has been shown to improve endothelial dysfunction in obesity, research has not been translated into a functional outcome (ie. blood pressure, kidney function, role of renal NOX4). The purpose of this study was to examine the effect of myostatin deletion on blood pressure regulation and kidney function in obesity.The model used was the db/db mouse, a well characterized mimic of the human condition of obesity, in combination with constitutive myostatin deletion. Kidney function was assessed using metabolic cages and urine analyzed for electrolyte concentration and micro‐albumin excretion. Blood pressure was quantified using in vivo radiotelemetry.The current study found that myostatin deletion improves renal injury and prevents hypertension in the db/db mouse. Microalbumin excretion, a measure of renal injury, was significantly elevated in obesity compared to lean mice (892.5 ± 180.1 vs. 230.9 ± 63.7 ug/day, p < 0.05) and significantly improved with myostatin deletion (200.2 ± 49.1 ug/day). Blood pressure was elevated with obesity compared to lean control (117.5 ± 1.2 vs. 107.8 ± 1.5 mmHg, p < 0.05) and significantly improved with myostatin deletion (108.4 ± 1.8 mmHg). Further, the significant polydipsia (excessive thirst) and polyuria (excess urination) that accompanies obesity is improved with deletion of myostatin. The improved renal dynamics observed with myostatin deletion were accompanied with an ability of the kidney to concentrate sodium compared to the obese control (105.1 ± 11.2 vs. 53.2 ± 8.0 mM, p < 0.05), resulting in a more efficient kidney. Important confounding variables were identified and found to be unchanged in obesity (weight, fat profiles, activity, heart rate, and aldosterone) thus the improved cardiovascular outcomes occur despite full presentation of the classic db/db phenotype. Renal NOX4 mRNA was found to be significantly upregulated in obesity when normalized to lean mice (> 300 %) and rescued with myostatin deletion (~ 40 %). To conclude, myostatin deletion ameliorates kidney injury (and data suggests a novel role for NOX4), results in a more efficient kidney and rescues blood pressure in obesity. These experimental observations suggest that myostatin inhibition could serve as an effective target for prevention/reversal of obesity‐derived changes to renal and cardiovascular function.Support or Funding InformationResearch Support: Stepp and Fulton NHLBI R01 HL124773 and Butcher AHA 17POST33410322This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Cucurbitacin B acts a potential insect growth regulator by antagonizing 20-hydroxyecdysone activity.

20-Hydroxyecdysone (20E), a crucial insect steroid hormone, can bind to its cognate nuclear receptor composed of ecdysone receptor (EcR) and ultraspiracle (USP) to activate expression of 20E-response genes, enabling subsequent metamorphosis. In this study, we tried to find out which steroid-like compounds can block insect metamorphosis effectively and provide useful information for biopesticide study. For this purpose, we screened 126 steroid-like compounds for possible 20E antagonists using a dual-luciferase reporter assay with Drosophila melanogaster Kc and Bombyx mori Bm12 cells. Among 126 steroid-like compounds, three cucurbitacins (CucB, D and E) were identified as 20E antagonists in both Kc and Bm12 cells. Notably, CucB caused significant molting defects and mortality in both B. mori and D. melanogaster larvae, and dramatically hindered larval growth of Helicoverpa armigera by its anti-feeding activity. In vivo and in vitro experiments demonstrate that CucB acts as a potential insect growth regulator by antagonizing 20E activity and thus blocking molting and metamorphosis induced by 20E signaling. © 2017 Society of Chemical Industry.

Withania somnifera acts as a potential insect growth regulator in the polyphagous pest, Pericallia ricini

Abstract Both seed and root extracts of the medicinal plant, Ashwagandha, Withania somnifera exhibit insect growth regulatory activity against the polyphagous pest, Pericallia ricini. Topical administration of W. somnifera seed and root extracts to last instar larvae of P. ricini disrupted moulting and metamorphosis, leading to a number of developmental abnormalities such as delay in larval-pupal and pupal-adult ecdysis, formation of larval-pupal, pupal-adult and larval-pupal-adult mosaics/chimeras, ecdysial failure, suppression of pupation and adult emergence and formation of abnormal pupae and adultoids. The treatment with seed extracts was more severe than that of root extracts as it completely suppressed the pupation and adult emergence. The results clearly suggest that the medicinal plant, W. somnifera acts as a potential insect growth regulatory (IGR) disrupting the moulting and metamorphosis as a consequence of interference with the endocrine system.

Chromosomal Micro-aberration in a Saudi Family with Juvenile Myoclonic Epilepsy.

Epilepsy is etiologically and genetically complex neurological disorder affecting millions of people worldwide. Juvenile myoclonic epilepsy (JME) is the most common epilepsy syndrome that starts in the teen age group commonly between ages 12, 18, and lasts till adulthood. One out of fourteen people with epilepsy suffers with JME. Myoclonic seizures and muscle twitching or uncontrolled jerking are the most common type of seizures in the people suffering with JME. To observe the novel CNVs involved in JME, we investigated a Saudi family with nine siblings including one male and one female affected members. In this study we used high density whole genome Agilent sure print G3 Hmn CGH 2x 400K array-CGH chips. Our results showed CNVs including the amplifications and deletions in different chromosomal regions in the patients as compared to the normal members of the family. Amplifications were observed in the chromosome 22 cytoband 22q11.23 with LDL receptor related protein 5 like (LRP5L), Immunoglobulin Lambda-Like Polypeptide 3 (IGLL3) and crystallin beta B2 pseudogene (CRYBB2P) genes respectively whereas the deletions were observed in the chromosomal regions 4q22.2 with Glutamate receptor, ionotropic, delta 2 (GRID2) as potential gene cytoband 1p31.1 with potential Neuronal Growth Regulator 1 gene (NEGR1) gene in this region and NME/NM23 family member (NME7) gene cytoband 1q24. Moreover, the array CGH resulting in deletions and duplication were also validated by using primer for simple PCR or also by using quantitative real time PCR analysis. We found deletions and duplication in JME patients in our study for the first time in Saudi population. The findings in this study suggest that the array-CGH may be considered as a first line of genetic testing for diagnosis of epilepsy unless strong evidence is presented for a monogenic syndrome. The use of high throughput technique in this study will help to identify novel mechanisms underlying epileptic disorder in order to lower the burden of epilepsy in Saudi Arabia.

Correction to: Effect of paclobutrazol, a potential growth regulator on stalk mechanical strength, lignin accumulation and its relation with lodging resistance of maize

In the original publication of the article, the Table 3 was wrongly published. The correct Table 3 is provided here.

Homeodomain-interacting protein kinase promotes tumorigenesis and metastatic cell behavior.

ABSTRACTAberrations in signaling pathways that regulate tissue growth often lead to tumorigenesis. Homeodomain-interacting protein kinase (Hipk) family members are reported to have distinct and contradictory effects on cell proliferation and tissue growth. From these studies, it is clear that much remains to be learned about the roles of Hipk family protein kinases in proliferation and cell behavior. Previous work has shown that Drosophila Hipk is a potent growth regulator, thus we predicted that it could have a role in tumorigenesis. In our study of Hipk-induced phenotypes, we observed the formation of tumor-like structures in multiple cell types in larvae and adults. Furthermore, elevated Hipk in epithelial cells induces cell spreading, invasion and epithelial-to-mesenchymal transition (EMT) in the imaginal disc. Further evidence comes from cell culture studies, in which we expressed Drosophila Hipk in human breast cancer cells and showed that it enhances proliferation and migration. Past studies have shown that Hipk can promote the action of conserved pathways implicated in cancer and EMT, such as Wnt/Wingless, Hippo, Notch and JNK. We show that Hipk phenotypes are not likely to arise from activation of a single target, but rather through a cumulative effect on numerous target pathways. Most Drosophila tumor models involve mutations in multiple genes, such as the well-known RasV12 model, in which EMT and invasiveness occur after the additional loss of the tumor suppressor gene scribble. Our study reveals that elevated levels of Hipk on their own can promote both hyperproliferation and invasive cell behavior, suggesting that Hipk family members could be potent oncogenes and drivers of EMT.

Effect of paclobutrazol, a potential growth regulator on stalk mechanical strength, lignin accumulation and its relation with lodging resistance of maize

Effect of paclobutrazol, a potential growth regulator on stalk mechanical strength, lignin accumulation and its relation with lodging resistance of maize

Foliar Applications of Urea and a Potent Growth Regulator Ameliorate Calyx-end Cracking in Persimmon

Foliar Applications of Urea and a Potent Growth Regulator Ameliorate Calyx-end Cracking in Persimmon

Design and evaluation of novel natriuretic peptide derivatives with improved pharmacokinetic and pharmacodynamic properties

C-type natriuretic peptide (CNP) and its receptor, natriuretic peptide receptor B (NPR-B), are potent positive regulators of endochondral bone growth, making the CNP pathway one of the most promising therapeutic targets for the treatment of growth failure. However, the administration of exogenous CNP is not fully effective, due to its rapid clearance in vivo. Modification of CNP to potentially druggable derivatives may result in increased resistance to proteolytic degradation, longer plasma half-life (T1/2), and better distribution to target tissues. In the present study, we designed and evaluated CNP/ghrelin chimeric peptides as novel CNP derivatives. We have previously reported that the ghrelin C-terminus increases peptide metabolic stability. Therefore, we combined the 17-membered, internal disulfide ring portion of CNP with the C-terminal portion of ghrelin. The resultant peptide displayed improved biokinetics compared to CNP, with increased metabolic stability and longer plasma T1/2. Repeated subcutaneous administration of the chimeric peptide to mice resulted in a significant acceleration in longitudinal growth, whereas CNP(1–22) did not. These results suggest that the ghrelin C-terminus improves the stability of CNP, and the chimeric peptide may be useful as a novel therapeutic agent for growth failure and short stature.

Salicylic Acid Induced Alterations of Some Physiological Parameters in Wheat Grown Under Salinity

It has been proposed that salicylic acid (SA) acts as an endogenous signal molecule responsible for inducing abiotic stress tolerance in plants. The effect of salicylic acid (SA) supply in varied concentrations (0, 50, 75 and 100 mM/L) on growth, total polyphenolic content and antioxidant activity NaCl-stressed (0, 50, 100, 150 mM/kg) was investigated. Exogenously applied SA increased plant growth significantly both in saline and non-saline conditions. As a consequence of salinity stress studied parameters decreased while increasing levels of SA increased growth, total polyphenolic content and antioxidant activity. These results suggest that SA could be used as a potential growth regulator to improve plant salinity stress resistance.

24-Epibrassinolide alleviates organic pollutants-retarded root elongation by promoting redox homeostasis and secondary metabolism in Cucumis sativus L

Environmental pollution by organic pollutants (OPs) has become a global concern due to its detrimental effects on the environment and human health. As plants are used to remediate contaminated sites, understanding the responses of plants to various OPs and fortification of plant tolerance are of great significance. In this work, we studied the biochemical and molecular responses of cucumber plants to three well-known OPs, 2,4,6-trichlorophenol, chlorpyrifos and oxytetracycline in the absence or presence of 24-epibrassinolide (EBR), a potent regulator of plant growth and stress tolerance. The results showed that the selected three OPs retarded root elongation; however, the phytotoxic effects of OPs were attenuated by exogenous EBR. OPs induced accumulations of both hydrogen peroxide (H2O2) and nitric oxide (NO) in root tips and resulted in an increased malondialdehyde (MDA) content, an indicator of membrane lipid peroxidation. Exogenous EBR reduced accumulations of H2O2, NO and MDA in the roots by increasing the expression of antioxidant and detoxification genes and the activities of the corresponding enzymes. Intriguingly, EBR not only promoted the activities of glutathione S-transferase and glutathione reductase, but also increased the content of reduced glutathione without altering the content of oxidized glutathione, which resulted in a reduced redox state under OPs stress. Furthermore, EBR increased the free radical scavenging capacity, flavonoid content and the activity and transcription of secondary metabolism related enzymes. Our results suggest that EBR treatment may fortify secondary metabolism to enhance antioxidant capacity in response to OPs treatment, which might have potential implication in phytoremediation of OPs.

Spermidine induces physiological and biochemical changes in southern highbush blueberry under drought stress

Drought stress is one of the main environmental stresses that have effect on plant growth and development. Spermidine (SPD) plays an important role in the defense responses to drought stress in plants. In this study, we investigated the effects of exogenous SPD on plant growth, net photosynthetic rate (Pn), antioxidant enzyme activities, chlorophyll, malondialdehyde (MDA) and phytohormone contents in leaves of blueberry (Vaccinium corymbosum ‘Misty’) seedlings under drought stress. Drought stress severely reduced the relative water content (RWC), chlorophyll, Pn, specific leaf weight (SLW), indole-3-acetic acid, gibberellic acid and polyamine contents, while increased relative electrolyte conductivity (REC), MDA, total soluble sugar and abscisic acid (ABA) contents, the activities of SOD and POD. Compared with seedlings without SPD treatment, SPD increased the RWC, chlorophyll content, Pn, SLW, SOD and POD activities and decreased REC, MDA, total soluble sugar and ABA contents in seedlings. These results signified the role of SPD in alleviating the negative effects of drought stress on plants and suggested that SPD could be used as a potential growth regulator for improving plant growth under drought stress.

Improvement of drought tolerance of soybean plants by using methyl jasmonate.

Methyl jasmonate (MeJA) is a naturally occurring plant growth regulator and play vital roles in plant defense and many developmental processes such as root growth and seed germination. This study was undertaken to study the possible role of using methyl jasmonate to alleviate the adverse effect of water stress on soybean genotypes (Giza 22 and 35). The results showed that water stress reduced shoot length, fresh and dry weights of shoot and root, photosynthetic pigments, relative water content and oil content in the shoots of all soybean genotypes. On the other hand, there was a considerable increase in cell wall fractionation, saturated and unsaturated fatty acids, flavonoids, phenolic acid and sugar fraction content in the shoots of the soybean genotypes in response to thewater stress. Foliar spray with methyl jasmonate increased all the above parameters as compared to stressed plants. The results investigate the important role of MeJA in alleviation ofwater stress in soybean plants and suggest that MeJA could be used for improving plant growth under water stress as a potential growth regulator. The soybean genotypes Giza 22 was found to be more resistant to water stress than Giza 35.

Maltose binding protein-fusion enhances the bioactivity of truncated forms of pig myostatin propeptide produced in E. coli.

Myostatin (MSTN) is a potent negative regulator of skeletal muscle growth. MSTN propeptide (MSTNpro) inhibits MSTN binding to its receptor through complex formation with MSTN, implying that MSTNpro can be a useful agent to improve skeletal muscle growth in meat-producing animals. Four different truncated forms of pig MSTNpro containing N-terminal maltose binding protein (MBP) as a fusion partner were expressed in E. coli, and purified by the combination of affinity chromatography and gel filtration. The MSTN-inhibitory capacities of these proteins were examined in an in vitro gene reporter assay. A MBP-fused, truncated MSTNpro containing residues 42–175 (MBP-Pro42-175) exhibited the same MSTN-inhibitory potency as the full sequence MSTNpro. Truncated MSTNpro proteins containing either residues 42–115 (MBP-Pro42-115) or 42–98 (MBP-Pro42-98) also exhibited MSTN-inhibitory capacity even though the potencies were significantly lower than that of full sequence MSTNpro. In pull-down assays, MBP-Pro42-175, MBP-Pro42-115, and MBP-Pro42-98 demonstrated their binding to MSTN. MBP was removed from the truncated MSTNpro proteins by incubation with factor Xa to examine the potential role of MBP on MSTN-inhibitory capacity of those proteins. Removal of MBP from MBP-Pro42-175 and MBP-Pro42-98 resulted in 20-fold decrease in MSTN-inhibitory capacity of Pro42-175 and abolition of MSTN-inhibitory capacity of Pro42-98, indicating that MBP as fusion partner enhanced the MSTN-inhibitory capacity of those truncated MSTNpro proteins. In summary, this study shows that MBP is a very useful fusion partner in enhancing MSTN-inhibitory potency of truncated forms of MSTNpro proteins, and MBP-fused pig MSTNpro consisting of amino acid residues 42–175 is sufficient to maintain the full MSTN-inhibitory capacity.

Recombinant myostatin reduces highly expressed microRNAs in differentiating C2C12 cells

Myostatin is small glycopeptide that is produced and secreted by skeletal muscle. It is a potent negative regulator of muscle growth that has been associated with conditions of frailty. In C2C12 cells, myostatin limits cell differentiation. Myostatin acts through activin receptor IIB, activin receptor-like kinase (ALK) and Smad transcription factors. microRNAs (miRNA) are short, 22 base pair nucleotides that bind to the 3′ UTR of target mRNA to repress translation or reduce mRNA stability. In the present study, expression in differentiating C2C12 cells of the myomiRs miR-1 and 133a were down-regulated following treatment with 1µg of recombinant myostatin at 1 d post-induction of differentiation while all myomiRs (miR-1, 133a/b and 206) were upregulated by SB431542, a potent ALK4/5/7 inhibitor which reduces Smad2 signaling, at 1 d and all, with the exception of miR-206, were upregulated by SB431542 at 3 d. The expression of the muscle-enriched miR-486 was greater following treatment with SB431542 but not altered by myostatin. Other highly expressed miRNAs in skeletal muscle, miR-23a/b and 145, were altered only at 1 d post-induction of differentiation. miR-27b responded differently to treatments at 1 d, where it was upregulated, as compared to 3 d, where it was downregulated. Neither myostatin nor SB431542 altered cell size or cell morphology. The data indicate that myostatin represses myomiR expression in differentiating C2C12 cells and that inhibition of Smad signaling with SB431542 can result in large changes in highly expressed miRNAs in differentiating myoblasts.

Mosquito-Disseminated Insecticide for Citywide Vector Control and Its Potential to Block Arbovirus Epidemics: Entomological Observations and Modeling Results from Amazonian Brazil.

BackgroundMosquito-borne viruses threaten public health worldwide. When the ratio of competent vectors to susceptible humans is low enough, the virus’s basic reproductive number (R0) falls below 1.0 (each case generating, on average, <1.0 additional case) and the infection fades out from the population. Conventional mosquito control tactics, however, seldom yield R0 < 1.0. A promising alternative uses mosquitoes to disseminate a potent growth-regulator larvicide, pyriproxyfen (PPF), to aquatic larval habitats; this kills most mosquito juveniles and substantially reduces adult mosquito emergence. We tested mosquito-disseminated PPF in Manacapuru, a 60,000-inhabitant city (~650 ha) in Amazonian Brazil.Methods and FindingsWe sampled juvenile mosquitoes monthly in 100 dwellings over four periods in February 2014–January 2016: 12 baseline months, 5 mo of citywide PPF dissemination, 3 mo of focal PPF dissemination around Aedes-infested dwellings, and 3 mo after dissemination ended. We caught 19,434 juvenile mosquitoes (66% Aedes albopictus, 28% Ae. aegypti) in 8,271 trap-months. Using generalized linear mixed models, we estimated intervention effects on juvenile catch and adult emergence while adjusting for dwelling-level clustering, unequal sampling effort, and weather-related confounders. Following PPF dissemination, Aedes juvenile catch decreased by 79%–92% and juvenile mortality increased from 2%–7% to 80%–90%. Mean adult Aedes emergence fell from 1,077 per month (range 653–1,635) at baseline to 50.4 per month during PPF dissemination (range 2–117). Female Aedes emergence dropped by 96%–98%, such that the number of females emerging per person decreased to 0.06 females per person-month (range 0.002–0.129). Deterministic models predict, under plausible biological-epidemiological scenarios, that the R0 of typical Aedes-borne viruses would fall from 3–45 at baseline to 0.004–0.06 during PPF dissemination. The main limitations of our study were that it was a before–after trial lacking truly independent replicates and that we did not measure mosquito-borne virus transmission empirically.ConclusionsMosquito-disseminated PPF has potential to block mosquito-borne virus transmission citywide, even under adverse scenarios. Our results signal new avenues for mosquito-borne disease prevention, likely including the effective control of Aedes-borne dengue, Zika, and chikungunya epidemics. Cluster-randomized controlled trials will help determine whether mosquito-disseminated PPF can, as our findings suggest, develop into a major tool for improving global public health.