Chapter 20 - Molecular insights into anatomy and physiology
DNA; lipid; blubber; Bowhead whale; Balaena mysticetus; molecular evolution; longevity
Bowhead whales are some of the largest animals that occupy the Arctic Circle. Despite the challenges of living and giving birth in icy waters, having huge blubber stores, eating a fat-rich diet, and undergoing arduous migrations, bowheads achieved the longest known life span of mammals of 268 years. Their longevity is extended by fixed mutations that prevent DNA damage and cancer and through evolutionary modifications to their metabolism that compensate for an oxygen-poor environment. Recently, the bowhead genome and transcriptome libraries were made publicly available for study. Analyses suggest that their life span has been extended by evolutionary changes that result in the upregulation of DNA repair pathways. Molecular biologists are now undertaking laboratory experiments with whale samples that are informed by the bowhead genome and transcriptome to tackle questions that were inaccessible using classical model organisms such as rodents or fish. Biomedical researchers are also applying insights gained from research on bowheads into investigations of potential therapies for aging, senescence, and cancer. Moreover, researchers are using these results to inform our understanding of the evolutionary history of these traits. This chapter reviews the molecular basis for bowhead whale longevity and survival in their unique habitat and offers insights for further exploration into the molecular mechanisms that shape the extraordinary lives of these animals.
Cooper LN; Gorbunova V
The Bowhead Whale
2021
2021-01-01
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
journalArticle
<a href="http://doi.org/10.1016/B978-0-12-818969-6.00020-0" target="_blank" rel="noreferrer noopener"></a>
Preterm Birth Impacts the Timing and Excursion of Oropharyngeal Structures during Infant Feeding
Swallowing in mammals requires the precise coordination of multiple oropharyngeal structures, including the palatopharyngeal arch. During a typical swallow, the activity of the palatopharyngeus muscle produces pharyngeal shortening to assist in producing pressure required to swallow and may initiate epiglottal flipping to protect the airway. Most research on the role of the palatopharyngeal arch in swallowing has used pharyngeal manometry, which measures the relative pressures in the oropharynx, but does not quantify the movements of the structures involved in swallowing. In this study, we assessed palatopharyngeal arch and soft palate function by comparing their movements in a healthy population to a pathophysiological population longitudinally through infancy (term versus preterm pigs). In doing so, we test the impact of birth status, postnatal maturation, and their interaction on swallowing. We tracked the three-dimensional (3D) movements of radiopaque beads implanted into relevant anatomical structures and recorded feeding via biplanar high-speed videofluoroscopy. We then calculated the total 3D excursion of the arch and soft palate, the orientation of arch movement, and the timing of maximal arch constriction during each swallow. Soft palate excursion was greater in term infants at both 7 and 17 days postnatal, whereas arch excursion was largely unaffected by birth status. Maximal arch constriction occurred much earlier in preterm pigs relative to term pigs, a result that was consistent across age. There was no effect of postnatal age on arch or soft palate excursion. Preterm and term infants differed in their orientation of arch movement, which most likely reflects both differences in anatomy and differences in feeding posture. Our results suggest that the timing and coordination of oropharyngeal movements may be more important to feeding performance than the movements of isolated structures, and that differences in the neural control of swallowing and its maturation in preterm and term infants may explain preterm swallowing deficits.
Edmonds CE; Catchpole EA; Gould FDH; Bond LE; Stricklen BM; German RZ; Mayerl CJ
Integrative Organismal Biology
2020
1905-07
journalArticle
<a href="http://doi.org/10.1093/iob/obaa028" target="_blank" rel="noreferrer noopener">10.1093/iob/obaa028</a>
Chapter 21 - Age estimation
bowhead; stable isotopes; tympanic bulla; Age estimation; aspartic acid racemization; ovarian corpora counts; whaling artifacts
In the late 1980s, annual carbon isotope cycles in the baleen plates of bowhead whales formed the basis of the first effective means of estimating bowhead age. However, the baleen aging method could only be used for aging subadult whales less than about 20 years old, due to wearing of the plates. Since then, seven additional methods of estimating the age of bowheads have been developed. Each age estimation method has strengths and weaknesses depending on the life stage of the whale. No single method is fully applicable through the entire 200-year lifespan of a bowhead, although a combination of techniques can be quite effective and precise.
George JC; Lubetkin SC; Zeh JE; Thewissen JGM; Wetzel D; Givens GH
The Bowhead Whale
2021
2021-01-01
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
journalArticle
<a href="http://doi.org/10.1016/B978-0-12-818969-6.00021-2" target="_blank" rel="noreferrer noopener"></a>
Chapter 7 - Life history, growth, and form
life history; Bowhead whale; Balaena mysticetus; growth and form; longevity
Bering–Chukchi–Beaufort Sea bowhead whales are born at about 4.2m in length and 1000kg, in lead systems along the NW Alaskan coast. Bowheads in the other northern stocks are also born in ice-covered seas. Maximum body lengths (standard measure) can reach 19m. Regarding coloration: the skin is gray on neonates and young calves, and black on yearlings and adults. The size and shape of the chin patch is variable and does not change through life. After adulthood age, the specific areas of the skin lose pigment and turn white around the eye, the peduncle, genital groove, and base of the pectoral limb. Growth is rapid from birth to age 1, followed by a 3- to 4-year growth hiatus. Following the hiatus, the increase in body length is slow to sexual maturity at ~25years and ~13.5m in length. The Iñupiat recognize several growth forms associated with age; these include aġvaaq (neonate), ingutuq (yearling), qairaliq (postyearling), along with several names for large adults. Allometry of the head is marked and likely associated with extreme development of the baleen rack. The head is very large in relation to body—perhaps the largest in Mammalia. The blubber is among the thickest of any cetacean (to ~38cm). Body mass is similar to right whales of similar length; large bowheads can reach 100 metric tons or larger. Longevity can reach 200 or more years. The age of physical maturity is unclear, and adults may increase in length through life. Their ability to navigate ice-covered seas and break through ice to breathe is singular among baleen whales.
George JC; Thewissen JGM; Von Duyke A; Breed GA; Suydam RS; Sformo TL; Person BT; Brower Jr HK
The Bowhead Whale
2021
2021-01-01
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
journalArticle
<a href="http://doi.org/10.1016/B978-0-12-818969-6.00007-8" target="_blank" rel="noreferrer noopener"></a>
Chapter 9 - Anatomy of skull and mandible
bones; whale; Bowhead whale; skull; mandible; osteology; Balaena mysticetus;
The skull of the bowhead whale is composed of all the bones commonly found in mammals, although the shape of these bones is far from ordinary. Features related to feeding dominate the skull: there are no teeth, and the rostrum is long and curved, resembling a bow. The incisive and maxilla form a high arch that forms the origin of the baleen rack, and the mandibles are straight in lateral view, but deeply curved in the horizontal plane to make room for the tongue and baleen. The blowhole is located near the apex of the skull, and the boney portion of the nasal passage opens caudally into the nasopharynx ventral to the braincase. As in other baleen whales, the occipital projects rostrally, covering a portion of the parietals and frontals.
Hillmann DJ; Tarpley RJ; George JC; Nader PB; Thewissen JGM
The Bowhead Whale
2021
2021-01-01
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journalArticle
<a href="http://doi.org/10.1016/B978-0-12-818969-6.00009-1" target="_blank" rel="noreferrer noopener"></a>
Chapter 13 - Female and male reproduction
cetacean; pregnancy; Bowhead whale; testis; reproduction; Balaena mysticetus; uterus; vagina; ovary; penis; gestation; calving interval; conception; epididymis; mysticete; ovulation; sexual maturity; spermatozoa; uterine tube
An understanding of the functional morphology of the bowhead whale continues to have significance for population management. This chapter first examines the anatomical features of the bowhead whale reproductive system, with an emphasis on the female. This is followed by a consideration of the functional parameters of the female reproductive cycle, testicular function in the male, and the age at sexual maturity in both sexes.
Tarpley RJ; Hillmann DJ; George JC; Thewissen JGM
The Bowhead Whale
2021
2021-01-01
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journalArticle
<a href="http://doi.org/10.1016/B978-0-12-818969-6.00013-3" target="_blank" rel="noreferrer noopener"></a>
Chapter 33 - Commercial whaling
United States; Bowhead whale; Balaena mysticetus; Germany; Basques; Britain; the Netherlands; whaling; Yankee
The commercial hunt of the four stocks of bowhead whales by the nations of Europe and North America commenced in 1540 and came to an effective end at the start of World War I. At that time, all four stocks had been driven to near extinction. Whalers from many nations were involved, but the most important ones were those from Basque Country, the Netherlands, Germany, Great Britain, and the United States. The Spitsbergen stock was the first to be depleted, followed by the West Greenland–East Canada stock (including whaling efforts in Hudson Bay and Strait of Belle Isle) and, finally, the Okhotsk and Bering–Chukchi–Beaufort stocks. Competition with other products (e.g., gaslight and petroleum), political factors (e.g., US Civil War), and changes in demands (e.g., women’s fashion) caused a waxing and waning of the whaling industry, but the decrease in yield eventually stopped the hunt. Native peoples across the circumpolar Arctic suffered greatly even though commercial whalers sometimes had good relations with native people they encountered. Despite any possible good intentions, the end result was, on balance, negative and led to major changes in the indigenous cultures it affected.
Thewissen JGM; George JC
The Bowhead Whale
2021
2021-01-01
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journalArticle
<a href="http://doi.org/10.1016/B978-0-12-818969-6.00033-9" target="_blank" rel="noreferrer noopener"></a>
Chapter 39 - Past, present, and future
history; life history; Bowhead whale; bowhead whale; Balaena mysticetus; conservation; whaling; International Whaling Commission; Inupiat; prehistoric
We discuss the evolution, phylogenetic relations to right whales, and geographical distribution of bowhead whales. We summarize its relations to humans, including whaling by indigenous and European whalers, conservation efforts, and modern challenges with increased shipping, fishing, and climate change. We also discuss their adaptations that have usually been explained as related to living in the Arctic but might be better explained as related to frugal use of limited resources.
Thewissen JGM; George JC
The Bowhead Whale
2021
2021-01-01
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journalArticle
<a href="http://doi.org/10.1016/B978-0-12-818969-6.00039-X" target="_blank" rel="noreferrer noopener"></a>
Chapter 18 - Sensory systems
Bowhead whale; balance; olfaction; Balaena mysticetus; vision; audition; gustation; magnetosense; mechanosense
The sensory biology of bowhead whales reflects features both related to their origin from land mammals and adaptations to their current environment, polar seas. There is anatomical and genomic evidence that bowheads have a sense of smell. Their sense of taste may be limited to detecting salty flavorants and there is no vomeronasal organ. They lack binocular vision and color vision, and it is likely that they can perceive the magnetic field. Similar to other mysticetes, their organ of hearing is adjusted to low frequencies. Their organ of balance is much smaller than could be expected when compared to land mammals, and the functional reason for this is unclear. Sensory hairs on the face may detect water current, and, when exposed to air, wind direction.
Thewissen JGM; George JC; Suydam RS; Sformo TL
The Bowhead Whale
2021
2021-01-01
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journalArticle
<a href="http://doi.org/10.1016/B978-0-12-818969-6.00018-2" target="_blank" rel="noreferrer noopener"></a>
Chapter 8 - Prenatal development
Bowhead whale; fetus; Balaena mysticetus; embryo; gestation; heterochrony
The prenatal development of bowhead whales is poorly known, and no complete ontogenetic series exist. However, the available embryos and fetuses elucidate aspects of the development of the species, as well as that of all of mysticetes in general, and demonstrate the role of heterochrony in development. For instance, hair on the face of bowhead whale embryos develops at the same ontogenetic stage as it does in terrestrial mammals, even though body hair never develops. The absence of teeth characterizes all modern baleen whales, but bowhead whale fetuses initiate teeth around the same time as land mammals, to then resorb them in the fetal period. Baleen forms after that, late in the fetal period.
Thewissen JGM; Hillmann DJ; George JC; Stimmelmayr R; Tarpley RJ; Sheffield Gay; Suydam RS
The Bowhead Whale
2021
2021-01-01
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journalArticle
<a href="http://doi.org/10.1016/B978-0-12-818969-6.00008-X" target="_blank" rel="noreferrer noopener"></a>
Chapter 10 - Postcranial skeleton and musculature
forelimb; myology; Bowhead whale; muscles; skeleton; Balaena mysticetus; hindlimb;
The postcranial skeleton of bowhead whales was described in detail more than 100 years ago. The musculature of bowheads has not been studied in detail but matches that of other mysticetes in general features. In this chapter, we focus on some aspects of the skeleton that differs from that of other cetaceans. First, the skeleton of bowheads changes with ontogenetic age. Some of these changes are gross-morphologically, while others are biochemical and histological. Several are related to the life history of the species. Our discussion focuses on the changes in the morphology of the cervical vertebral column, the ontogenetic variation in carpals, and the variation in the hind limb. Individuals with external hind limbs occur infrequently, but there is a great variation in the size of ox coxae, femur, and tibia.
Thewissen JGM; Hillmann DJ; George JC; Tarpley RJ; Sheffield Gay; Stimmelmayr R; Suydam RS
The Bowhead Whale
2021
2021-01-01
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journalArticle
<a href="http://doi.org/10.1016/B978-0-12-818969-6.00010-8" target="_blank" rel="noreferrer noopener"></a>
The formation and position of middle ear ossicles during development in cetacea
The order Cetacea (dolphins, whales, and porpoises) evolved from terrestrial artiodactyls (even‐toed ungulates) around 50 million years ago. This transition from land to water occurred over an evolutionarily short period of less than 10 million years and is considered one of the best examples of macroevolutionary change among vertebrates. Among the sensory systems, the ear has developed a number of unique adaptations to adapt to water borne sounds. We hypothesize that a record of these evolutionary changes is preserved in the prenatal ontogeny. In particular, previous studies on fossils have identified a rotation of the middle ear ossicles with regard to the median plane, as well as a deflection of the axis of the cochlea. It is not clear whether these two movements are related to each other. The purpose of this study is to investigate middle ear development within odontocetes (toothed whales) using two species of dolphin (Stenella attenuata and stenella longirostris). Using Amira and Avizo 3‐D software we investigate the malleus, incus, and stapes over a range of embryological stages and their relationship to inner ear structures, such as the cochlea and semicircular canals. These data are then compared to what is known for adult Stenella. Data is collected on histological sections and CTs of heads of embryologic and fetal specimens. These specimens have either been stained using phosphotungstic acid and microCT scanned (stored in 70% ethanol) or sliced at 7μm and stained using hematoxylin and eosin. We photograph histologic specimens (every other slice) in the region containing the middle and inner ear structures. Avizo and Amira software version 2019.1 are used to reconstruct the middle ear ossicles, cochlea, and semicircular canals of Stenella from micro CT scans and histological specimens. After reconstruction we use the 3‐D images to evaluate changes in the formation and position of the middle ear ossicles through development. The outline of middle ear and cochlear development in these dolphins is similar to that of land mammals. For example, the otic capsule shows the formation of the cochlea, and ossicle formation passes through mesenchymal and cartilaginous stages. The malleus is attached to Meckel’s cartilage and the stapes is associated with the otic capsule. Additionally, there are general similarities in ossicular shape in the later fetal stages, however in earlier embryonic stages the manubrium of the malleus and the crura of the incus are not as apparent as they are in land mammals, possibly foreshadowing the specific adaptations of cetaceans. Changes within the position of the ossicles in relation to one another as well as the cochlea and semicircular canals occur in order for the middle ear to develop into its adult state. In adult odontocetes, the malleus is fused to the tympanic plate through its anterior process, the process gracilius, creating a folded tympanic membrane. These findings support our hypothesis that many of the middle ear adaptations for odontocetes can be visualized in utero. Preliminary evidence suggests that changes in ossicular position replicate cetacean evolution. This research continues to shed light on how and when these unique changes occur to allow cetacean specialization to underwater hearing.
Abano J;Schmidt C;Thewissen J;Sensor J
Faseb Journal
2020
2020-04
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journalArticle
<a href="http://doi.org/10.1096/fasebj.2020.34.s1.04412" target="_blank" rel="noreferrer noopener">10.1096/fasebj.2020.34.s1.04412</a>
Role of inflammation in the aging bones.
*Models; Aging; Aging/*physiology; Animals; Biological; Bone adaptation; Bone and Bones/cytology/immunology/*physiopathology; Bone Marrow Cells/physiology; Bone resorption; Cell Differentiation/*physiology; Cumulative Trauma Disorders/physiopathology; Humans; Inflammation; Inflammation/*physiopathology; Macrophages; Macrophages/*physiology; Osteoblasts; Osteoblasts/*physiology; Osteoclasts; Osteoclasts/*physiology
Chronic inflammation in aging is characterized by increased inflammatory cytokines, bone loss, decreased adaptation, and defective tissue repair in response to injury. Aging leads to inherent changes in mesenchymal stem cell (MSC) differentiation, resulting in impaired osteoblastogenesis. Also, the pro-inflammatory cytokines increase with aging, leading to enhanced myelopoiesis and osteoclastogenesis. Bone marrow macrophages (BMMs) play pivotal roles in osteoblast differentiation, the maintenance of hematopoietic stem cells (HSCs), and subsequent bone repair. However, during aging, little is known about the role of macrophages in the differentiation and function of MSC and HSC. Aged mammals have higher circulating pro-inflammatory cytokines than young adults, supporting the hypothesis of increased inflammation with aging. This review will aid in the understanding of the potential role(s) of pro-inflammatory (M1) and anti-inflammatory (M2) macrophages in differentiation and function of osteoblasts and osteoclasts in relation to aging.
Abdelmagid Samir M; Barbe Mary F; Safadi Fayez F
Life sciences
2015
2015-02
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/j.lfs.2014.11.011" target="_blank" rel="noreferrer noopener">10.1016/j.lfs.2014.11.011</a>
Mutation in osteoactivin decreases bone formation in vivo and osteoblast differentiation in vitro.
*Signal Transduction; Alkaline Phosphatase/metabolism; Animals; Apoptosis; Bone and Bones/metabolism/pathology; Cell Differentiation/genetics; Eye Proteins/*genetics; Inbred DBA; Male; Membrane Glycoproteins/*genetics; Mice; Mutation; Newborn; Osteoblasts/cytology/*physiology; Osteocalcin/*genetics; Osteogenesis/*genetics; Phenotype; Receptors; Transforming Growth Factor beta/metabolism
We have previously identified osteoactivin (OA), encoded by Gpnmb, as an osteogenic factor that stimulates osteoblast differentiation in vitro. To elucidate the importance of OA in osteogenesis, we characterized the skeletal phenotype of a mouse model, DBA/2J (D2J) with a loss-of-function mutation in Gpnmb. Microtomography of D2J mice showed decreased trabecular mass, compared to that in wild-type mice [DBA/2J-Gpnmb(+)/SjJ (D2J/Gpnmb(+))]. Serum analysis showed decreases in OA and the bone-formation markers alkaline phosphatase and osteocalcin in D2J mice. Although D2J mice showed decreased osteoid and mineralization surfaces, their osteoblasts were increased in number, compared to D2J/Gpnmb(+) mice. We then examined the ability of D2J osteoblasts to differentiate in culture, where their differentiation and function were decreased, as evidenced by low alkaline phosphatase activity and matrix mineralization. Quantitative RT-PCR analyses confirmed the decreased expression of differentiation markers in D2J osteoblasts. In vitro, D2J osteoblasts proliferated and survived significantly less, compared to D2J/Gpnmb(+) osteoblasts. Next, we investigated whether mutant OA protein induces endoplasmic reticulum stress in D2J osteoblasts. Neither endoplasmic reticulum stress markers nor endoplasmic reticulum ultrastructure were altered in D2J osteoblasts. Finally, we assessed underlying mechanisms that might alter proliferation of D2J osteoblasts. Interestingly, TGF-beta receptors and Smad-2/3 phosphorylation were up-regulated in D2J osteoblasts, suggesting that OA contributes to TGF-beta signaling. These data confirm the anabolic role of OA in postnatal bone formation.
Abdelmagid Samir M; Belcher Joyce Y; Moussa Fouad M; Lababidi Suzanne L; Sondag Gregory R; Novak Kimberly M; Sanyurah Afif S; Frara Nagat A; Razmpour Roshanak; Del Carpio-Cano Fabiola E; Safadi Fayez F
The American journal of pathology
2014
2014-03
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/j.ajpath.2013.11.031" target="_blank" rel="noreferrer noopener">10.1016/j.ajpath.2013.11.031</a>
Mutation in Osteoactivin Promotes Receptor Activator of NFkappaB Ligand (RANKL)-mediated Osteoclast Differentiation and Survival but Inhibits Osteoclast Function.
*Mutation; Akt; Animals; bone; bone marrow; Bone Remodeling; Cell Differentiation/*physiology; Cell Survival/*physiology; Eye Proteins/*genetics; Inbred DBA; MAP kinases (MAPKs); Membrane Glycoproteins/*genetics; Mice; osteoactivin; osteoclast; Osteoclasts/*cytology; osteopetrosis; RANK Ligand/metabolism/*physiology; Signal Transduction; X-Ray Microtomography
We previously reported on the importance of osteoactivin (OA/Gpnmb) in osteogenesis. In this study, we examined the role of OA in osteoclastogenesis, using mice with a nonsense mutation in the Gpnmb gene (D2J) and wild-type controls (D2J/Gpnmb(+)). In these D2J mice, micro-computed tomography and histomorphometric analyses revealed increased cortical thickness, whereas total porosity and eroded surface were significantly reduced in D2J mice compared with wild-type controls, and these results were corroborated by lower serum levels of
Abdelmagid Samir M; Sondag Gregory R; Moussa Fouad M; Belcher Joyce Y; Yu Bing; Stinnett Hilary; Novak Kimberly; Mbimba Thomas; Khol Matthew; Hankenson Kurt D; Malcuit Christopher; Safadi Fayez F
The Journal of biological chemistry
2015
2015-08
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<a href="http://doi.org/10.1074/jbc.M114.624270" target="_blank" rel="noreferrer noopener">10.1074/jbc.M114.624270</a>
How do different feeding delivery parameters affect swallowing behavior in infant pigs?
Adjerid K; Mayerl CJ; Gould FDH; Edmonds CE; Steer KE; Bond LE; German RZ
Integrative And Comparative Biology
2021
2021-03
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
journalArticle
<a href="http://doi.org/" target="_blank" rel="noreferrer noopener"></a>
Does birth weight affect neonatal body weight, growth, and physiology in an animal model?
PREMATURE infants; BIRTH weight; BODY weight; DEGLUTITION; PHYSIOLOGY; UMBILICAL cord clamping; WEIGHT gain; WEIGHT in infancy
Infant birth weight affects neuromotor and biomechanical swallowing performance in infant pig models. Preterm infants are generally born low birth weight and suffer from delayed development and neuromotor deficits. These deficits include critical life skills such as swallowing and breathing. It is unclear whether these neuromotor and biomechanical deficits are a result of low birth weight or preterm birth. In this study we ask: are preterm infants simply low birth weight infants or do preterm infants differ from term infants in weight gain and swallowing behaviors independent of birth weight? We use a validated infant pig model to show that preterm and term infants gain weight differently and that birth weight is not a strong predictor of functional deficits in preterm infant swallowing. We found that preterm infants gained weight at a faster rate than term infants and with nearly three times the variation. Additionally, we found that the number of sucks per swallow, swallow duration, and the delay of the swallows relative to the suck cycles were not impacted by birth weight. These results suggest that any correlation of developmental or swallowing deficits with reduced birth weight are likely linked to underlying physiological immaturity of the preterm infant.
Adjerid K; Mayerl CJ; Gould FDH; Edmonds CE; Stricklen BM; Bond LE; German RZ
PLOS One
2021
1905-07
journalArticle
<a href="http://doi.org/10.1371/journal.pone.0246954" target="_blank" rel="noreferrer noopener">10.1371/journal.pone.0246954</a>
IMPERATORIN, A PLANT DERIVED SMALL MOLECULE, INHIBITS OXIDATIVE STRESS AND PREVENTS MITOCHONDRIAL DAMAGE IN HUMAN OA CHONDROCYTES
Rheumatology; Orthopedics
Ahmad N; Ansari M; Haqqi T
Osteoarthritis and Cartilage
2019
2019-04
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<a href="http://doi.org/10.1016/j.joca.2019.02.790" target="_blank" rel="noreferrer noopener">10.1016/j.joca.2019.02.790</a>
Imperatorin suppresses IL-1beta-induced iNOS expression via inhibiting
Imperatorin; inflammation; iNOS; Osteoarthritis; Oxidative-stress; Plant-derived-polyphenol
Joint inflammation is a key player in the pathogenesis of osteoarthritis (OA). Imperatorin, a plant-derived small molecule has been reported to have anti-inflammatory properties; however, its effect on chondrocytes is not known. Here, we investigated the effects of Imperatorin on interleukin-1beta (IL-1beta) induced expression of inducible nitric oxide synthase (iNOS) and nitric oxide production in primary human OA chondrocytes and cartilage explants culture under pathological conditions and explored the associated signaling pathways. We pretreated chondrocytes or explants with Imperatorin (50 muM) followed by
Ahmad Nashrah; Ansari Mohammad Y; Bano Shabana; Haqqi Tariq M
International immunopharmacology
2020
2020-05-22
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journalArticle
<a href="http://doi.org/10.1016/j.intimp.2020.106612" target="_blank" rel="noreferrer noopener">10.1016/j.intimp.2020.106612</a>
Role of iNOS in osteoarthritis: Pathological and therapeutic aspects.
chondrocytes; osteoarthritis; iNOS; oxidative stress; inflammation; nitric oxide; iNOS inhibitor
Accumulating evidence suggests that inflammation has a key role in the pathogenesis of osteoarthritis (OA). Nitric oxide (NO) has been established as one of the major inflammatory mediators in OA and drives many pathological changes during the development and progression of OA. Excessive production of NO in chondrocytes promotes cartilage destruction and cellular injury. The synthesis of NO in chondrocytes is catalyzed by inducible NO synthase (iNOS), which is thereby an attractive therapeutic target for the treatment of OA. A number of direct and indirect iNOS inhibitors, bioactive compounds, and plant-derived small molecules have been shown to exhibit chondroprotective effects by suppressing the expression of iNOS. Many of these iNOS inhibitors hold promise for the development of new, disease-modifying therapies for OA; however, attempts to demonstrate their success in clinical trials are not yet successful. Many plant extracts and plant-derived small molecules have also shown promise in animal models of OA, though further studies are needed in human clinical trials to confirm their therapeutic potential. In this review, we discuss the role of iNOS in OA pathology and the effects of various iNOS inhibitors in OA.
Ahmad Nashrah; Ansari Mohammad Y; Haqqi Tariq M
Journal of cellular physiology
2020
2020-02
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Journal Article
<a href="http://doi.org/10.1002/jcp.29607" target="_blank" rel="noreferrer noopener">10.1002/jcp.29607</a>
Inhibition of cartilage degradation and suppression of PGE2 and MMPs expression by pomegranate fruit extract in a model of posttraumatic osteoarthritis.
*Phytotherapy; *Punicaceae; ACLT; Animal; Animals; Anterior Cruciate Ligament/drug effects/metabolism/pathology; Apoptosis; Cartilage/cytology/*drug effects/metabolism/pathology; Chondrocytes/drug effects/metabolism/pathology; Collagen Type II/genetics/metabolism; Dinoprostone/*metabolism; Disease Models; Disease Progression; Female; Fruit; Interleukins/metabolism; Joints/cytology/*drug effects/metabolism/pathology; Male; Messenger/metabolism; Metalloproteases/genetics/*metabolism; Mitogen-Activated Protein Kinases/metabolism; MMPs; NF-kappa B/metabolism; Osteoarthritis; Osteoarthritis/*drug therapy/etiology/metabolism/pathology; PGE(2); Plant Extracts/pharmacology/therapeutic use; Pomegranate; Rabbit; Rabbits; RNA; Synovial Fluid/metabolism
OBJECTIVE: Osteoarthritis (OA) is characterized by cartilage degradation in the affected joints. Pomegranate fruit extract (PFE) inhibits cartilage degradation in vitro. The aim of this study was to determine whether oral consumption of PFE inhibits disease progression in rabbits with surgically induced OA. METHODS: OA was surgically induced in the tibiofemoral joints of adult New Zealand White rabbits. In one group, animals were fed PFE in water for 8 wk postsurgery. In the second group, animals were fed PFE for 2 wk before surgery and for 8 wk postsurgery. Histologic assessment and scoring of the cartilage was per Osteoarthritis Research Society International guidelines. Gene expression and matrix metalloproteinases (MMP) activity were determined using quantitative reverse transcriptase polymerase chain reaction and fluorometric assay, respectively. Interleukin (IL)-1 beta, MMP-13, IL-6, prostaglandin (PG)E2, and type II collagen (COL2A1) levels in synovial fluid/plasma/culture media were quantified using enzyme-linked immunosorbent assay. Expression of active caspase-3 and poly (ADP-ribose) polymerase p85 was determined by immunohistochemistry. Effect of PFE and inhibitors of MMP-13, mitogen-activated protein kinase (MAPK) and nuclear factor (NF)-kappaB was studied in IL-1 beta-stimulated rabbit articular chondrocytes. RESULTS: Safranin-O-staining and chondrocyte cluster formation was significantly reduced in the anterior cruciate ligament transaction plus PFE fed groups. Expression of MMP-3, MMP-9, and MMP-13 mRNA was higher in the cartilage of rabbits given water alone but was significantly lower in the animals fed PFE. PFE-fed rabbits had lower IL-6,
Akhtar Nahid; Khan Nazir M; Ashruf Omer S; Haqqi Tariq M
Nutrition (Burbank, Los Angeles County, Calif.)
2017
2017-01
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/j.nut.2016.08.004" target="_blank" rel="noreferrer noopener">10.1016/j.nut.2016.08.004</a>
MicroRNA-602 and microRNA-608 regulate sonic hedgehog expression via target sites in the coding region in human chondrocytes.
Academic Medical Centers; Aged; Analysis of Variance; Animal; Animals; Anterior Cruciate Ligament/surgery; Blotting; Cells; Chondrocytes – Physiology; Chondrocytes/drug effects/*metabolism/pathology; Cultured; Disease Models; Female; Funding Source; Gene Expression Regulation/genetics/*physiology; Hedgehog Proteins/genetics/*metabolism; HEK293 Cells; Human; Humans; Immunohistochemistry; In Vitro Techniques; Interleukin-1beta/pharmacology; Knee/etiology/*metabolism/pathology; Male; Matrix Metalloproteinase 13/metabolism; MicroRNAs/genetics/*metabolism; Middle Age; Middle Aged; Ohio; Open Reading Frames/genetics/*physiology; Osteoarthritis; Osteoarthritis – Epidemiology; Osteoarthritis – Physiopathology; Polymerase Chain Reaction; Rabbits; Signal Transduction/genetics/physiology; T-Tests; Transfection; Up-Regulation/drug effects/genetics/physiology; Western
OBJECTIVE: Hedgehog (HH) signaling has recently been associated with cartilage degradation in osteoarthritis (OA). Because interleukin-1beta (IL-1beta) has been implicated as a principal instigator of OA, we sought to determine whether
Akhtar Nahid; Makki Mohammad S; Haqqi Tariq M
Arthritis & rheumatology (Hoboken, N.J.)
2015
2015-02
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1002/art.38952" target="_blank" rel="noreferrer noopener">10.1002/art.38952</a>
Intraskeletal Consistency in Patterns of Vascularity within Bat Limb Bones.
Bone; Chiroptera; Cortical porosity; Micro-CT; Synchrotron
Bats are the only mammals to have achieved powered flight. A key innovation allowing for bats to conquer the skies was a forelimb modified into a flexible wing. The wing bones of bats are exceptionally long and dynamically bend with wingbeats. Bone microarchitectural features supporting these novel performance attributes are still largely unknown. The humeri and femora of bats are typically avascular, with the exception of large-bodied taxa (e.g., pteropodid flying foxes). No thorough investigation of vascular canal regionalization and morphology has been undertaken as historically it has been difficult to reconstruct the 3D architecture of these canals. This study augments our understanding of the vascular networks supporting the bone matrix of a sample of bats (n=24) of variable body mass, representing three families (Pteropodidae (large-bodied, Species=6), Phyllostomidae (medium-bodied, Species=2), and Molossidae (medium-bodied, Species=1)). We employed Synchrotron Radiation-based micro-Computed Tomography (SRμCT) to allow for a detailed comparison of canal morphology within humeri and femora. Results indicated that across selected bats, canal number per unit volume is similar independent of body size. Differences in canal morphometry based on body size and bone type appear primarily related to a broader distribution of the canal network as cortical volume increases. Heavier bats display a relatively rich vascular network of mostly longitudinally-oriented canals that are localized mainly to the mid-cortical and endosteal bone envelopes. Taken together, our results suggest that relative vascularity of the limb bones of heavier bats forms support for nutrient exchange in a regional pattern. This article is protected by copyright. All rights reserved.
Andronowski JM; Cole Mary E; Hieronymous TL; Davis RA; Usher Logan R; Cooper LN
Anatomical Record
2021
2021-06-08
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
journalArticle
<a href="http://doi.org/10.1002/ar.24694" target="_blank" rel="noreferrer noopener">10.1002/ar.24694</a>
MITOCHONDRIAL DYSFUNCTION IN OSTEOARTHRITIS AND AGED CARTILAGE TRIGGERS INFLAMMATORY RESPONSE AND MATRIX DEGRADATION VIA ROS MEDIATED ACTIVATION OF JNK-MAPK/CFOS-AP1 AXIS IN CHONDROCYTES
Ansari M Y; Ahmad N; Voleti S; Wase S; Malik M; Novak K; Haqqi Tariq M
Osteoarthritis and Cartilage
2020
2020-04
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
journalArticle
n/a
INHIBITION OF LYSOSOMAL FUNCTION ENHANCES INFLAMMATORY GENE EXPRESSION, INDUCE OXIDATIVE STRESS AND APOPTOSIS IN HUMAN CHONDROCYTES
Rheumatology; Orthopedics
Ansari M Y; Ball H C; Wase S; Novak K; Haqqi T M
Osteoarthritis and Cartilage
2019
2019-04
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/j.joca.2019.02.233" target="_blank" rel="noreferrer noopener">10.1016/j.joca.2019.02.233</a>
Indian medicinal plant butea monosperma flower extract and its bioactive constituent butein activates autophagy in human oa chondrocytes under pathological conditions.
Ansari M Y; Haynie S; Haqqi; TM
Osteoarthritis & Cartilage
2016
2016-04-02
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/j.joca.2016.01.631" target="_blank" rel="noreferrer noopener">10.1016/j.joca.2016.01.631</a>
IL-1β induces low levels of autophagy which clears dysfunctional mitochondria and inhibits ROS, MMP-13 and ADAMTS5 expression in OA chondrocytes.
Ansari M Y; Khan MN; Haqqi T M
Osteoarthritis & Cartilage
2016
2016-04-02
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/j.joca.2016.01.266" target="_blank" rel="noreferrer noopener">10.1016/j.joca.2016.01.266</a>
Parkin clearance of dysfunctional mitochondria regulates ROS levels and increases survival of human chondrocytes.
Chondrocytes; Mitochondrial dysfunction; Osteoarthritis; Parkin; ROS
OBJECTIVE: Mitochondrial dysfunction, oxidative stress and chondrocyte death are important contributors to the development and pathogenesis of osteoarthritis (OA). In this study, we determined the expression and role of Parkin in the clearance of damaged/dysfunctional mitochondria, regulation of reactive oxygen species (ROS) levels and chondrocyte survival under pathological conditions. METHODS: Human chondrocytes were from the unaffected area of knee OA cartilage (n = 12) and were stimulated with IL-1beta to mimic pathological conditions. Mitochondrial membrane depolarization and ROS levels were determined using specific dyes and flow cytometry. Autophagy was determined by Western blotting for ATG5, Beclin1, immunofluorescence staining and confocal microscopy. Gene expression was determined by RT-qPCR. siRNA, wild-type and mutant Parkin plasmids were transfected using Amaxa system. Apoptosis was determined by PI staining of chondrocytes and TUNEL assay. RESULTS: IL-1beta-stimulated OA chondrocytes showed high levels of ROS generation, mitochondrial membrane damage, accumulation of damaged mitochondria and higher incidence of apoptosis. IL-1beta stimulation of chondrocytes with depleted Parkin expression resulted in sustained high levels of ROS, accumulation of damaged/dysfunctional mitochondria and enhanced apoptosis. Parkin translocation to depolarized/damaged mitochondria and recruitment of p62/SQSTM1 was required for the elimination of damaged/dysfunctional mitochondria in IL-1beta-stimulated OA chondrocytes. Importantly we demonstrate that Parkin elimination of depolarized/damaged mitochondria required the Parkin ubiquitin ligase activity and resulted in reduced ROS levels and inhibition of apoptosis in OA chondrocytes under pathological conditions. CONCLUSIONS: Our data demonstrates that Parkin functions to eliminate depolarized/damaged mitochondria in chondrocytes which is necessary for mitochondrial quality control, regulation of ROS levels and chondrocyte survival under pathological conditions.
Ansari M Y; Khan N M; Ahmad I; Haqqi T M
Osteoarthritis and cartilage
2018
2018-08
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/j.joca.2017.07.020" target="_blank" rel="noreferrer noopener">10.1016/j.joca.2017.07.020</a>
Elimination of dysfunctional mitochondria by parkin suppresses oxidative stress and expression of osteoarthritis related genes in human chondrocytes.
Ansari M Y; Khan N M; Ahmad I; Haqqi T M
Osteoarthritis & Cartilage
2017
2017-04-02
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/j.joca.2017.02.086" target="_blank" rel="noreferrer noopener">10.1016/j.joca.2017.02.086</a>
PARKIN DEFICIENCY IMPAIRS THE CLEARANCE OF DYSFUNCTIONAL MITOCHONDRIA AND AUGMENTS IL-1B INDUCED INFLAMMATION IN HUMAN ARTICULAR CHONDROCYTES
Rheumatology; Orthopedics
Ansari M Y; Novak K; Haqqi T M
Osteoarthritis and Cartilage
2019
2019-04
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/j.joca.2019.02.232" target="_blank" rel="noreferrer noopener">10.1016/j.joca.2019.02.232</a>
Mitochondrial dysfunction triggers catabolic response in chondrocytes via ROS mediated activation of JNK/AP1 pathway.
Inflammation; Osteoarthritis; Chondrocytes; Redox; cFos-AP1; JNK
Mitochondrial function is impaired in osteoarthritis (OA) but its impact on cartilage catabolism is not fully understood. Here, we investigated the molecular mechanism of mitochondrial dysfunction-induced activation of catabolic response in chondrocytes. Using cartilage slices from normal and OA cartilage, we show that mitochondrial membrane potential was lower in OA cartilage which was associated with increased production of mitochondrial superoxide and catabolic genes (IL-6, COX-2, MMP-3,-9,-13 and ADAMTS5). Pharmacological induction of mitochondrial dysfunction in chondrocytes and cartilage explants using CCCP increased the mitochondrial superoxide production and the expression of IL-6, COX-2, MMP-3,-9-13 and ADAMTS5 and cartilage matrix degradation. Mitochondrial dysfunction induced expression of catabolic genes was dependent on JNK/AP1 pathway but not the NFκB pathway. Scavenging of mitochondrial superoxide with MitoTEMPO or pharmacological inhibition of JNK or cFos/cJun blocked the mitochondrial dysfunction-induced expression of the catabolic genes in chondrocytes. We demonstrate here that mitochondrial dysfunction contributes to OA pathogenesis via JNK/AP1 mediated expression of catabolic genes. Our data shows that AP1 could be used as a therapeutic target for OA management.
Ansari M Y;Ahmad N;Voleti S;Wase SJ;Novak K;Haqqi TM
Journal of Cell Science
2020
2020-10-23
journalArticle
<a href="http://doi.org/10.1242/jcs.247353" target="_blank" rel="noreferrer noopener">10.1242/jcs.247353</a>
Lysosomal dysfunction in osteoarthritis and aged cartilage triggers apoptosis in chondrocytes through BAX mediated release of cytochrome c.
Osteoarthritis; Mitochondrial dysfunction; Apoptosis; Ageing; BAX; Lysosomal dysfunction
OBJECTIVE: Lysosomes are the major catabolic organelle of the cell and regulate the macromolecular and organelle turnover and programmed cell death. Here, we investigated the lysosome dysfunction in cartilage and its role in chondrocytes apoptosis and the associated mechanism. DESIGN: Lysosomal acidification in OA and aged cartilage was determined by LysoSensor staining. Lysosomal function in chondrocytes was blocked by siRNA mediated depletion of LAMP2 or with lysosome inhibitors. Chondrocyte apoptosis was determined by LDH release, Caspase-3/7 activation, TUNEL and PI uptake assays. Loss of mitochondrial membrane potential (MMP/ΔΨM) and mitochondrial superoxide level was determined by JC-1 and MitoSOX staining, respectively. Colocalization of mitochondria with BAX and Cytochrome c was determined by immunostaining. DMM was performed to induce OA in mice. RESULTS: Lysosomal acidification was found to be significantly decreased in aged mouse and human and mouse OA cartilage which also showed increased chondrocyte apoptosis. Inhibition of lysosomal function resulted in increased oxidative stress, accumulation of dysfunctional mitochondria and apoptosis in chondrocytes in monolayer and in cartilage explant cultures. Depletion of LAMP2 expression or treatment of chondrocytes with lysosomal function inhibitors increased the expression and mitochondrial translocation of BAX leading to Cytochrome c release. Lysosomal dysfunction-induced apoptosis in chondrocytes was not blocked by antioxidants MitoTempo or DPI but was abrogated by inhibiting BAX. CONCLUSION: Lysosomal dysfunction induce apoptosis in chondrocytes through BAX-mediated mitochondrial damage and release of Cytochrome c. Our data points to lysosomal function restoration and/or BAX inhibition in chondrocytes as a therapeutic approach for OA.
Ansari M Y;Ball HC;Wase SJ;Novak K;Haqqi TM
Osteoarthritis and Cartilage
2020
2020-11-05
journalArticle
<a href="http://doi.org/10.1016/j.joca.2020.08.014" target="_blank" rel="noreferrer noopener">10.1016/j.joca.2020.08.014</a>
Butein Activates Autophagy Through AMPK/TSC2/ULK1/mTOR Pathway to Inhibit IL-6 Expression in IL-1beta Stimulated Human Chondrocytes.
AMP-Activated Protein Kinases/metabolism; AMPK; Articular/cytology/pathology; Autophagy; Autophagy-Related Protein 5/antagonists & inhibitors/genetics/metabolism; Autophagy-Related Protein-1 Homolog/metabolism; Autophagy/*drug effects; Butein; Cartilage; Cell Survival/drug effects; Cells; Chalcones/*pharmacology; Chondrocytes/cytology/drug effects/metabolism; Cultured; Humans; Inflammation; Interleukin-1beta/*pharmacology; Interleukin-6/genetics/*metabolism; Intracellular Signaling Peptides and Proteins/metabolism; mTOR; Osteoarthritis; Osteoarthritis/metabolism/pathology; Phosphorylation/drug effects; Reactive Oxygen Species/metabolism; RNA; RNA Interference; Signal Transduction/*drug effects; Small Interfering/metabolism; TOR Serine-Threonine Kinases/metabolism; TSC2; Tuberous Sclerosis Complex 2 Protein; Tumor Suppressor Proteins/metabolism; ULK1
BACKGROUND/AIMS: Butein (2',3,4,4'-Tetrahydroxychalcone), a polyphenol produced by several plants including Butea monoserpma, has been reported to exert potent anti-inflammatory activity but the mechanism remains unknown. In the present work we investigated the mechanism of Butein-mediated suppression of IL-6 expression in normal and human osteoarthritis (OA) chondrocytes under pathological conditions. METHODS: Expression level of interleukin-6 (IL-6) protein in OA cartilage was analyzed by immunohistochemistry using a validated antibody. Chondrocytes derived from normal or OA cartilage by enzymatic digestion were pretreated with Butein followed by stimulation with interleukin-1beta (IL-1beta) and the levels of IL-6 mRNA were quantified by TaqMan assay and the protein levels were measured by Western immunoblotting. Autophagy activation was determined by Western blotting and confocal microscopy. Autophagy was inhibited by siRNA mediated knockdown of ATG5. RESULTS: Expression of IL-6 protein was high in the OA cartilage compared to smooth cartilage from the same patient. OA chondrocytes and cartilage explants stimulated with IL-1beta showed high level expression of IL-6 mRNA and protein. Butein increased the phosphorylation of AMPKalphaThr-172, TSC2Ser-1387 and ULK1Ser-317 and inhibited the phosphorylation of mTORSer-2448 and its downstream target p70S6K and increased autophagy flux that correlated with the suppression of the IL-1beta mediated expression of IL-6 in normal and OA chondrocytes. In OA chondrocytes with siRNA-mediated knockdown of ATG5 expression, treatment with Butein failed to activate autophagy and abrogated the suppression of IL-1beta induced IL-6 expression. CONCLUSION: Our findings demonstrate for the first time that Butein activate autophagy in OA chondrocytes via AMPK/TSC2/ULK1/mTOR pathway. Additionally, activation of autophagy was essential to block the IL-1beta-induced expression of IL-6 in OA chondrocytes. These data support further studies to evaluate the use of Butein or compounds derived from it for the management of OA.
Ansari Mohammad Y; Ahmad Nashrah; Haqqi Tariq M
Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology
2018
2018
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1159/000493225" target="_blank" rel="noreferrer noopener">10.1159/000493225</a>
Interleukin-1beta induced Stress Granules Sequester COX-2 mRNA and Regulates its Stability and Translation in Human OA Chondrocytes.
*Protein Biosynthesis; Cells; Chondrocytes/drug effects/metabolism/pathology; Cultured; Cyclooxygenase 2/*genetics; Dinoprostone/genetics; Fluorescence; Gene Expression Regulation; Humans; Immunoprecipitation; In Situ Hybridization; Interleukin-1beta/administration & dosage/*genetics; Messenger/genetics; Nitric Oxide/metabolism; Osteoarthritis/drug therapy/*genetics/pathology; RNA
Enhanced and immediate expression of cyclooxygenase-2 (COX-2) mRNA is observed in
Ansari Mohammad Y; Haqqi Tariq M
Scientific reports
2016
2016-06
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1038/srep27611" target="_blank" rel="noreferrer noopener">10.1038/srep27611</a>
Genetic inactivation of ZCCHC6 suppresses IL-6 expression and reduces the severity of experimental osteoarthritis in mice.
OBJECTIVE: Cytokine expression is tightly regulated post-transcriptionally but high levels of IL-6 in osteoarthritis (OA) indicate disruption of regulatory mechanisms. ZCCHC6 enzyme is implicated in post-transcriptional regulation of inflammatory cytokine expression but its role in OA pathogenesis is unknown. Here we studied whether ZCCHC6 directs the expression of IL-6 and influence OA pathogenesis in vivo. METHODS: Human and mouse chondrocytes were stimulated with recombinant IL-1beta. We knocked down the expression of ZCCHC6 in human chondrocytes by siRNAs. IL-6 transcript stability was determined by Actinomycin-D chase and 3'-uridylation of miRNAs was determined by deep sequencing. Zcchc6-/- mice were produced by gene targeting. OA was surgically induced in the knee joints of mice and the disease severity was scored using a semi-quantitative scoring system. RESULTS: ZCCHC6 was markedly upregulated in the damaged cartilage from human OA patients and from wild type mice with surgically-induced OA. Overexpression of ZCCHC6 induced the expression of IL-6 and its knockdown reduced the IL-6 transcript stability and IL-1beta-induced expression in chondrocytes. Reintroduction of Zcchc6 in Zcchc6-/- chondrocytes rescued the IL-1beta-induced
Ansari Mohammad Y; Khan Nazir M; Ahmad Nashrah; Green Jonathan; Novak Kimberly; Haqqi Tariq M
Arthritis & rheumatology (Hoboken, N.J.)
2018
2018-10
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1002/art.40751" target="_blank" rel="noreferrer noopener">10.1002/art.40751</a>
Genetic Inactivation of ZCCHC6 Suppresses Interleukin‐6 Expression and Reduces the Severity of Experimental Osteoarthritis in Mice.
ANIMAL experimentation; CARTILAGE; CARTILAGE cells; DACTINOMYCIN; DNA-binding proteins; GENE expression; GENETIC aspects; IN vivo studies; INTERLEUKINS; MICE; MICRORNA; OSTEOARTHRITIS; PREVENTION; SEQUENCE analysis; SEVERITY of illness index; SYNOVITIS; TRANSCRIPTION factors
Objective: Cytokine expression is tightly regulated posttranscriptionally, but high levels of interleukin‐6 (IL‐6) in patients with osteoarthritis (OA) indicate that regulatory mechanisms are disrupted in this disorder. The enzyme ZCCHC6 (zinc‐finger CCHC domain–containing protein 6; TUT‐7) has been implicated in posttranscriptional regulation of inflammatory cytokine expression, but its role in OA pathogenesis is unknown. The present study was undertaken to investigate whether ZCCHC6 directs the expression of IL‐6 and influences OA pathogenesis in vivo. Methods: Human and mouse chondrocytes were stimulated with recombinant IL‐1β. Expression of ZCCHC6 in human chondrocytes was knocked down using small interfering RNAs. IL‐6 transcript stability was determined by actinomycin D chase, and 3′‐uridylation of microRNAs was determined by deep sequencing. Zcchc6−/− mice were produced by gene targeting. OA was surgically induced in the knee joints of mice, and disease severity was scored using a semiquantitative grading system. Results: ZCCHC6 was markedly up‐regulated in damaged cartilage from human OA patients and from wild‐type mice with surgically induced OA. Overexpression of ZCCHC6 induced the expression of IL‐6, and its knockdown reduced IL‐6 transcript stability and IL‐1β–induced IL‐6 expression in chondrocytes. Reintroduction of Zcchc6 in Zcchc6−/− mouse chondrocytes rescued the IL‐1β–induced IL‐6 expression. Knockdown of ZCCHC6 reduced the population of micro‐RNA 26b (miR‐26b) with 3′‐uridylation by 60%. Zcchc6−/− mice with surgically induced OA produced low levels of IL‐6 and exhibited reduced cartilage damage and synovitis in the joints. Conclusion: These findings indicate that ZCCHC6 enhances IL‐6 expression in chondrocytes through transcript stabilization and by uridylating miR‐26b, which abrogates repression of IL‐6. Inhibition of IL‐6 expression and significantly reduced OA severity in Zcchc6−/− mice identify ZCCHC6 as a novel therapeutic target to inhibit disease pathogenesis. [ABSTRACT FROM AUTHOR]
Ansari Mohammad Y; Khan Nazir M; Ahmad Nashrah; Green Jonathan; Novak Kimberly; Haqqi Tariq M
Arthritis & Rheumatology
2019
2019-04
<a href="http://doi.org/10.1002/art.40751" target="_blank" rel="noreferrer noopener">10.1002/art.40751</a>
A standardized extract of Butea monosperma (Lam.) flowers suppresses the
*Butea; Aged; Autophagy; Autophagy/drug effects/physiology; Butea monosperma (Lam.); Chondrocytes/drug effects/*metabolism; Dose-Response Relationship; Drug; Flowers; Gene Expression; Humans; Interleukin-1beta/*pharmacology; Interleukin-6/*biosynthesis/genetics; Matrix Metalloproteinase 13/biosynthesis/genetics; Matrix Metalloproteinase 3/biosynthesis/genetics; Matrix Metalloproteinase 9/biosynthesis/genetics; Matrix Metalloproteinases/*biosynthesis/genetics; Middle Aged; mTOR; Nutraceuticals; Osteoarthritis; Osteoarthritis/*metabolism; Plant Extracts/isolation & purification/pharmacology
BACKGROUND/OBJECTIVE: Osteoarthritis (OA) is a leading cause of joint dysfunction, disability and poor quality of life in the affected population. The underlying mechanism of joint dysfunction involves increased oxidative stress, inflammation, high levels of cartilage extracellular matrix degrading proteases and decline in autophagy-a mechanism of cellular defense. There is no disease modifying therapies currently available for OA. Different parts of the Butea monosperma (Lam.) plant have widely been used in the traditional Indian Ayurvedic medicine system for the treatment of various human diseases including inflammatory conditions. Here we studied the chondroprotective effect of hydromethanolic extract of Butea monosperma (Lam.) flowers (BME) standardized to the concentration of Butein on human OA chondrocytes stimulated with IL-1beta. METHODS: The hydromethanolic extract of Butea monosperma (Lam.) (BME) was prepared with 70% methanol-water mixer using Soxhlet. Chondrocytes viability after BME treatment was measured by MTT assay. Gene expression levels were determined by quantitative polymerase chain reaction (qPCR) using TaqMan assays and immunoblotting with specific antibodies. Autophagy activation was determined by measuring the levels of microtubule associated protein 1 light chain 3-II (LC3-II) by immunoblotting and visualization of autophagosomes by transmission electron and confocal microscopy. RESULTS: BME was non-toxic to the OA chondrocytes at the doses employed and suppressed the IL-1beta induced expression of inerleukin-6 (IL-6) and matrix metalloprotease-3 (MMP-3), MMP-9 and MMP-13. BME enhanced autophagy in chondrocytes as determined by measuring the levels of
Ansari Mohammad Y; Khan Nazir M; Haqqi Tariq M
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie
2017
2017-12
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/j.biopha.2017.09.140" target="_blank" rel="noreferrer noopener">10.1016/j.biopha.2017.09.140</a>
The large protein 'L' of Peste-des-petits-ruminants virus exhibits RNA triphosphatase activity, the first enzyme in mRNA capping pathway.
Acid Anhydride Hydrolases/*metabolism; Animals; Baculoviridae/genetics; Cercopithecus aethiops; Cloning; Conventional mRNA capping; Enzyme Activation; Gene Expression; Genetic Vectors/genetics; Messenger/*genetics/*metabolism; Molecular; Morbillivirus; mRNA capping; Peste-des-petits-ruminants virus L protein; Peste-des-petits-ruminants virus/*physiology; Peste-des-Petits-Ruminants/*virology; PPRV; RNA; RNA Caps/*metabolism; RNA triphosphatase; Vero Cells; Viral Proteins/*metabolism
Peste-des-petits-ruminants is a highly contagious and fatal disease of goats and sheep caused by non-segmented, negative strand RNA virus belonging to the Morbillivirus genus-Peste-des-petits-ruminants virus (PPRV) which is evolutionarily closely related to Rinderpest virus (RPV). The large protein 'L' of the members of this genus is a multifunctional catalytic protein, which transcribes and replicates the viral genomic RNA as well as possesses mRNA capping, methylation and polyadenylation activities; however, the detailed mechanism of mRNA capping by PPRV L protein has not been studied. We have found earlier that the L protein of RPV has RNA triphosphatase (RTPase), guanylyltransferase (GTase) and methyltransferase activities, and unlike vesicular stomatitis virus (VSV), follows the conventional pathway of mRNA capping. In the present work, using a 5'-end labelled viral RNA as substrate, we demonstrate that PPRV L protein has RTPase activity when present in the ribonucleoprotein complex of purified virus as well as recombinant L-P complex expressed in insect cells. Further, a minimal domain in the C-terminal region (aa1640-1840) of the L protein has been expressed in E. coli and shown to exhibit RTPase activity. The RTPase activity of PPRV L protein is metal-dependent and functions with a divalent cation, either magnesium or manganese. In addition, RTPase associated nucleotide triphosphatase activity (NTPase) of PPRV L protein is also demonstrated. This work provides the first detailed study of RTPase activity and identifies the RTPase domain of PPRV L protein.
Ansari Mohammad Yunus; Singh Piyush Kumar; Rajagopalan Deepa; Shanmugam Purnima; Bellur Asutosh; Shaila Melkote Subbarao
Virus Genes
2019
2019-02
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1007/s11262-018-1617-5" target="_blank" rel="noreferrer noopener">10.1007/s11262-018-1617-5</a>
First person - Mohammad Yunus Ansari
Ansari MY
Journal of Cell Science
2020
2020-11
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
journalArticle
<a href="http://doi.org/10.1242/jcs.256644" target="_blank" rel="noreferrer noopener">10.1242/jcs.256644</a>
Oxidative stress and inflammation in osteoarthritis pathogenesis: Role of polyphenols.
Chondrocytes; Osteoarthritis; Inflammation; Polyphenols; Nrf2; Redox
Osteoarthritis (OA) is the most prevalent joint degenerative disease leading to irreversible structural and functional changes in the joint and is a major cause of disability and reduced life expectancy in ageing population. Despite the high prevalence of OA, there is no disease modifying drug available for the management of OA. Oxidative stress, a result of an imbalance between the production of reactive oxygen species (ROS) and their clearance by antioxidant defense system, is high in OA cartilage and is a major cause of chronic inflammation. Inflammatory mediators, such as interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) are highly upregulated in OA joints and induce ROS production and expression of matrix degrading proteases leading to cartilage extracellular matrix degradation and joint dysfunction. ROS and inflammation are interdependent, each being the target of other and represent ideal target/s for the treatment of OA. Plant polyphenols possess potent antioxidant and anti-inflammatory properties and can inhibit ROS production and inflammation in chondrocytes, cartilage explants and in animal models of OA. The aim of this review is to discuss the chondroprotective effects of polyphenols and modulation of different molecular pathways associated with OA pathogenesis and limitations and future prospects of polyphenols in OA treatment.
Ansari MY; Ahmad N; Haqqi TM
Biomedicine & Pharmacotherapy
2020
2020-07-03
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<a href="http://doi.org/10.1016/j.biopha.2020.110452" target="_blank" rel="noreferrer noopener">10.1016/j.biopha.2020.110452</a>