Jeenu Mittal

Intricate functions of matrix metalloproteinases in physiological and pathological conditions

Matrix metalloproteinases (MMPs) are a diverse group of proteolytic enzymes and play an important role in the degradation and remodeling of the extracellular matrix (ECM). In normal physiological conditions, MMPs are usually minimally expressed. Despite their low expression, MMPs have been implicated in many cellular processes ranging from embryological development to apoptosis. The activity of MMPs is controlled at three different stages: (1) transcription; (2) zymogen activation; and (3) inhibition of active forms by tissue inhibitor metalloproteinases (TIMPs). They can collectively degrade any component of ECM and basement membrane, and their excessive activity has been linked to numerous pathologies mainly including, but not limited to, tumor invasion and metastasis. The lack of information about several MMPs and the steady stream of new discoveries suggest that there is much more to be studied in this field. In particular, there is a need for controlling their expression in disease states. Various studies over the past 30 years have found that each MMP has a specific mode of activation, action, and inhibition. Drugs specifically targeting individual MMPs could revolutionize the treatment of a great number of health conditions and tremendously reduce their burden. In this review article, we have summarized the recent advances in understanding the role of MMPs in physiological and pathological conditions. J. Cell. Physiol. 231: 2599–2621, 2016.

Current concepts in the pathogenesis and treatment of chronic suppurative otitis media.

Otitis media (OM) is an inflammation of the middle ear associated with infection. Despite appropriate therapy, acute OM (AOM) can progress to chronic suppurative OM (CSOM) associated with ear drum perforation and purulent discharge. The effusion prevents the middle ear ossicles from properly relaying sound vibrations from the ear drum to the oval window of the inner ear, causing conductive hearing loss. In addition, the inflammatory mediators generated during CSOM can penetrate into the inner ear through the round window. This can cause the loss of hair cells in the cochlea, leading to sensorineural hearing loss. Pseudomonas aeruginosa and Staphylococcus aureus are the most predominant pathogens that cause CSOM. Although the pathogenesis of AOM is well studied, very limited research is available in relation to CSOM. With the emergence of antibiotic resistance as well as the ototoxicity of antibiotics and the potential risks of surgery, there is an urgent need to develop effective therapeutic strategies against CSOM. This warrants understanding the role of host immunity in CSOM and how the bacteria evade these potent immune responses. Understanding the molecular mechanisms leading to CSOM will help in designing novel treatment modalities against the disease and hence preventing the hearing loss.

Neurotransmitters: The Critical Modulators Regulating Gut–Brain Axis

Neurotransmitters, including catecholamines and serotonin, play a crucial role in maintaining homeostasis in the human body. Studies on these neurotransmitters mainly revolved around their role in the “fight or flight” response, transmitting signals across a chemical synapse and modulating blood flow throughout the body. However, recent research has demonstrated that neurotransmitters can play a significant role in the gastrointestinal (GI) physiology. Norepinephrine (NE), epinephrine (E), dopamine (DA), and serotonin have recently been a topic of interest because of their roles in the gut physiology and their potential roles in GI and central nervous system pathophysiology. These neurotransmitters are able to regulate and control not only blood flow, but also affect gut motility, nutrient absorption, GI innate immune system, and the microbiome. Furthermore, in pathological states, such as inflammatory bowel disease (IBD) and Parkinsons disease, the levels of these neurotransmitters are dysregulated, therefore causing a variety of GI symptoms. Research in this field has shown that exogenous manipulation of catecholamine serum concentrations can help in decreasing symptomology and/or disease progression. In this review article, we discuss the current state‐of‐the‐art research and literature regarding the role of neurotransmitters in regulation of normal GI physiology, their impact on several disease processes, and novel work focused on the use of exogenous hormones and/or psychotropic medications to improve disease symptomology. J. Cell. Physiol. 232: 2359–2372, 2017.

Mechanisms of programmed cell death signaling in hair cells and support cells post-electrode insertion trauma.

Abstract Conclusion: Programmed cell death (PCD) initially starts in the support cells (SCs) after electrode insertion trauma (EIT), followed by PCD in hair cells (HCs). Activation of caspase-3 was observed only in SCs. Protecting both SCs and HCs with selective otoprotective drugs at an early stage post implantation may help to preserve residual hearing. Objectives: Cochlear implant EIT can initiate sensory cell losses via necrosis and PCD within the organ of Corti, which can lead to a loss of residual hearing. PCD appears to be a major factor in HC loss post-EIT. The current study aimed to: (1) determine the onset of PCD in both SCs and HCs within the traumatized organ of Corti; and (2) identify the molecular mechanisms active within the HCs and SCs that are undergoing PCD. Methods: Adult guinea pigs were assigned to one of two groups: (1) EIT and (2) unoperated contralateral ears as controls. Immunostaining of dissected organ of Corti surface preparations for phosphorylated-Jun, cleaved caspase-3, and 4-hydroxy-2,3-nonenal (HNE) were performed at 6, 12, and 24 h post-EIT and for contralateral control ears. Results: At 6 h post-EIT the SCs immunolabeled for the presence of phosphorylated-Jun and activated caspase-3. Phosphorylated p-Jun labeling was observed at 12 h in both the HCs and SCs of middle and basal cochlear turns. Cleaved caspase-3 was not observed in HCs of any cochlear turn at up to 24 h post-EIT. Lipid peroxidation (HNE immunostaining) was first observed at 12 h post-EIT in both the HCs and SCs of the basal turn, and reached the apical turn by 24 h post-EIT.

Association of PRPS1 Mutations with Disease Phenotypes

Phosphoribosylpyrophosphate synthetase 1 (PRPS1) codes for PRS-I enzyme that catalyzes the first step of nucleotide synthesis. PRPS1 gene mutations have been implicated in a number of human diseases. Recently, new mutations in PRPS1 have been identified that have been associated with novel phenotypes like diabetes insipidus expanding the spectrum of PRPS1-related diseases. The purpose of this review is to evaluate current literature on PRPS1-related syndromes and summarize potential therapies. The overexpression of PRPS1 results in PRS-I superactivity resulting in purine overproduction. Patients with PRS-I superactivity demonstrate uric acid overproduction, hypotonia, ataxia, neurodevelopment abnormalities, and postlingual hearing impairment. On the other hand, decreased activity leads to X-linked nonsyndromic sensorineural deafness (DFNX-2), Charcot-Marie-Tooth disease-5 (CMTX5), and Arts syndrome depending on the residual activity of PRS-I. Mild PRS-I deficiency (DFNX-2) results in non-syndromic progressive hearing loss whereas moderate PRS-I deficiency (CMTX5) and severe PRS-I deficiency (Arts syndrome) present with peripheral or optic neuropathy, prelingual progressive sensorineural hearing loss, and central nervous system impairment. Currently, purine replacement via S-adenosylmethionine (SAM) supplementation in patients with Arts syndrome appears to improve their condition. This suggests that SAM supplementation can alleviate symptoms of PRPS1 deficient patients and open new avenues of therapeutic intervention.

Indispensable Role of Ion Channels and Transporters in the Auditory System

Ear is a complex system where appropriate ionic composition is essential for maintaining the tissue homeostasis and hearing function. Ion transporters and channels present in the auditory system plays a crucial role in maintaining proper ionic composition in the ear. The extracellular fluid, called endolymph, found in the cochlea of the mammalian inner ear is particularly unique due to its electrochemical properties. At an endocochlear potential of about +80 mV, signaling initiated by acoustic stimuli at the level of the hair cells is dependent on the unusually high potassium (K+) concentration of endolymph. There are ion channels and transporters that exists in the ear to ensure that K+ is continually being cycled into the stria media endolymph. This review is focused on the discussion of the molecular and genetic basis of previously and newly recognized ion channels and transporters that support sensory hair cell excitation based on recent knock‐in and knock‐out studies of these channels. This article also addresses the molecular and genetic defects and the pathophysiology behind Menieres disease as well as how the dysregulation of these ion transporters can result in severe defects in hearing or even deafness. Understanding the role of ion channels and transporters in the auditory system will facilitate in designing effective treatment modalities against ear disorders including Menieres disease and hearing loss. J. Cell. Physiol. 232: 743–758, 2017.

A novel combination of drug therapy to protect residual hearing post cochlear implant surgery

Abstract Conclusions A cocktail combining NAC, Mannitol, and Dexamethasone may be used to prevent loss of residual hearing post-implantation. There is a window of opportunity to treat the cochlea before the onset of cell death in HCs. Objective Inner ear trauma caused by cochlear implant electrode insertion trauma (EIT) initiates multiple molecular mechanisms in hair cells (HCs) or support cells (SCs), resulting in initiation of programmed cell death within the damaged tissues of the cochlea, which leads to loss of residual hearing. In earlier studies L-N-acetylcysteine (L-NAC), Mannitol, and dexamethasone have been shown independently to protect the HCs loss against different types of inner ear trauma. These three molecules have different otoprotective effects. The goal of this preliminary study is to test the efficacy of a combination of these molecules to enhance the otoprotection of HCs against EIT. Methods OC explants were dissected from P-3 rats and placed in serum-free media. Explants were divided into control and experimental groups. Control group: (1) untreated controls; (2) EIT. Experimental group: (1) EIT + L-NAC (5, 2, or 1 mM); (2) EIT + Mannitol (100, 50, or 10 mM); (3) EIT + Dex (20, 10, or 5 μg/mL); (4) EIT + L-NAC + Mannitol + Dex. After EIT was caused in an in-vitro model of CI, explants were cultured in media containing L-NAC alone, Mannitol alone, or Dex alone at decreasing concentrations. Concentrations of L-NAC, Mannitol, and Dex that showed 50% protection of hair cell loss individually were used as a combination in experimental group 4. Results There was an increase of total hair cell (THC) loss in the EIT OC explants when compared with control group HC counts or the tri-therapy cochlea. This study defined the dosage of L-NAC, Mannitol, and Dex for the survival of 50% protection of hair cells in vitro. Their combination provided close to 96% protection, demonstrating an additive effect.

Recent advancements in the regeneration of auditory hair cells and hearing restoration

Neurosensory responses of hearing and balance are mediated by receptors in specialized neuroepithelial sensory cells. Any disruption of the biochemical and molecular pathways that facilitate these responses can result in severe deficits, including hearing loss and vestibular dysfunction. Hearing is affected by both environmental and genetic factors, with impairment of auditory function being the most common neurosensory disorder affecting 1 in 500 newborns, as well as having an impact on the majority of elderly population. Damage to auditory sensory cells is not reversible, and if sufficient damage and cell death have taken place, the resultant deficit may lead to permanent deafness. Cochlear implants are considered to be one of the most successful and consistent treatments for deaf patients, but only offer limited recovery at the expense of loss of residual hearing. Recently there has been an increased interest in the auditory research community to explore the regeneration of mammalian auditory hair cells and restoration of their function. In this review article, we examine a variety of recent therapies, including genetic, stem cell and molecular therapies as well as discussing progress being made in genome editing strategies as applied to the restoration of hearing function.

Zika virus: An emerging global health threat

Zika virus (ZIKV) is an emerging healthcare threat. The presence of the mosquito Aedes species across South and Central America in combination with complementary climates have incited an epidemic of locally transmitted cases of ZIKV infection in Brazil. As one of the most significant current public health concerns in the Americas, ZIKV epidemic has been a cause of alarm due to its known and unknown complications. At this point, there has been a clear association between ZIKV infection and severe clinical manifestations in both adults and neonates, including but not limited to neurological deficits such as Guillain-Barré syndrome (GBS) and microcephaly, respectively. The gravity of the fetal anomalies linked to ZIKV vertical transmission from the mother has prompted a discussion on whether to include ZIKV as a formal member of the TORCH [Toxoplasma gondii, other, rubella virus, cytomegalovirus (CMV), and herpes] family of pathogens known to breach placental barriers and cause congenital disease in the fetus. The mechanisms of these complex phenotypes have yet to be fully described. As such, diagnostic tools are limited and no effective modalities are available to treat ZIKV. This article will review the recent advancements in understanding the pathogenesis of ZIKV infection as well as diagnostic tests available to detect the infection. Due to the increase in incidence of ZIKV infections, there is an immediate need to develop new diagnostic tools and novel preventive as well as therapeutic modalities based on understanding the molecular mechanisms underlying the disease.

Molecular Structure and Regulation of P2X Receptors With a Special Emphasis on the Role of P2X2 in the Auditory System

The P2X purinergic receptors are cation‐selective channels gated by extracellular adenosine 5′‐triphosphate (ATP). These purinergic receptors are found in virtually all mammalian cell types and facilitate a number of important physiological processes. Within the past few years, the characterization of crystal structures of the zebrafish P2X4 receptor in its closed and open states has provided critical insights into the mechanisms of ligand binding and channel activation. Understanding of this gating mechanism has facilitated to design and interpret new modeling and structure–function experiments to better elucidate how different agonists and antagonists can affect the receptor with differing levels of potency. This review summarizes the current knowledge on the structure, activation, allosteric modulators, function, and location of the different P2X receptors. Moreover, an emphasis on the P2X2 receptors has been placed in respect to its role in the auditory system. In particular, the discovery of three missense mutations in P2X2 receptors could become important areas of study in the field of gene therapy to treat progressive and noise‐induced hearing loss. J. Cell. Physiol. 231: 1656–1670, 2016.