Annals of Medicinal Chemistry and Research

Urea Transporter Inhibitors as Novel Diuretics

Review Article | Open Access

  • 1. Department of Pharmacology, Peking University, PR China
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Corresponding Authors
Baoxue Yang, Department of Pharmacology, School of Basic Medical Sciences, Peking University, 38 Xueyuan Lu, Haidian District, Beijing 100191,China, Tel: 86-10-8280-5622

Urea transporter (UT) proteins, including isoforms of UT-A in kidney tubule epithelia and UT-B in vasa recta endothelia and erythrocytes, play an important role in the urine concentration mechanism by mediated an intra renal urea recycling, suggesting that functional inhibition of these proteins could have therapeutic use as a novel class of diuretic. Recently several classes of UT inhibitors have been identified and found to functionally inhibit UTs. A class of thienoquinolins, which specifically inhibit both UT-A and UT-B, exhibit diuretic activity. It is predicated that UT inhibitors have potential clinical applications as sodium-sparing diuretics in edema from different etiologies, such as congestive heart failure and cirrhosis.


Yang B (2015) Urea Transporter Inhibitors as Novel Diuretics. Ann Med Chem Res 1(2): 1008.


•    Urea transporter
•    Urine concentrating mechanism
•    Kidney
•    Diuretic
•    Drug target 


Diuretics are used clinically to treat a variety of diseases, including edema, hypertension, and heart failure [1,2] and are often used for long-term therapy. However, long-term use of conventional diuretics, such as loop diuretics, thiazides, amiloride, acetazolamide can have several adverse effects, including hypokalaemia, hyperkalaemia, hyponatraemia, hyperuricemia, hyperlipidemia, and glucose tolerance decrease [3-5]. The adverse effects result from the mechanism by which these diuretics act on the specific targets to reduce sodium reabsorption. Increased water excretion follows the salt excretion. Therefore, it would be desirable to discover novel diuretic targets and develop diuretics that do not cause electrolyte disturbances.

Intrarenal urea recycling is involved in the urinary concentrating mechanism [6,7]. The phenotype analysis on mice with urea transporter (UT) gene knockout shows that UTs play important role in the intrarenal urea recycling (Figure 1) and the urinary concentrating mechanism [8-11]. A short and a long loop of Henle are depicted within the 4 kidney zones, along with an arterial (descending) and venous (ascending) vasa recta (DVR and AVR, respectively). The pathways allowing urea to recycle in kidney are indicated by black arrows. In normal condition, concentrated urea is delivered to the tip of the papilla by the terminal part of the collecting ducts expressing the vasopressinregulated urea transporters UT-A1/3. Urea is taken up by ascending blood in AVR, and a significant fraction of it is returned to the inner medulla by being reintroduced either in the DVR (expressing UT-B). A significant amount of urea is assumed to be secreted by an active transport in the pars recta and be transferred from descending limb of loops of Henle via UT-A2- mediated fluxes. The UT null mice have polyuria and low urine osmolality without electrolyte loss. In vivo effect of UT inhibitors causes significant diuresis with normal Na+ , K+ , Cl- excretion [12,13]. These data indicate that UT inhibitors may be developed as a novel class of diuretics. This review will summarize the information on the molecular characteristics of UTs, the renal phenotypes of UT null mice, the discovery of UT inhibitors and the diuretic effect of UT inhibitors.

Molecular characteristics, localization and function of UTs

Urea transporters are a family of proteins facilitates the passive transport of urea across the plasma membrane in certain cell types. Two urea transporter genes have been cloned, Slc14a1 encoding UT-B)[14-17] and Slc14a2 encoding several UT-A members (UT-A1-A6) via alternative splicing and alternative promoters [18-24].

UT-B is a glycosylated protein, which molecular weight is between 37∼ 65 kDa [25,26]. UT-B is localized in the nonfenestrated endothelial cells that are characteristic of descending vasa recta (Figure 1) [27-30]. UT-B has also been identified in bladder, colon, testis, brain, heart, aorta, cochlea, mesenteric artery, etc. [31-40]. UT-B also transports several chemical analogues of urea, including methyl urea, formamide, acetamide, acrylamide, methylformamide, ammonium carbamate, etc [41]. Previous studies show that rat and mouse UT-B can function as a water channel, in addition to its role as a urea transporter[26,42].

UT-A subfamily includes 6 members. UT-A1 is the largest protein (97~117 kD) of the members and is expressed in the apical plasma membrane and in cytoplasm of the inner medullary collecting ducts (IMCD) (Figure 1) [43-48]. UT-A2 and UT-A1 have the same C-terminal amino acid sequence [49, 50]. UT-A2, with a 55 kDa molecular weight, is expressed in the thin descending limb of the loop of Henle [51-54]. UT-A3 and UT-A1 have the same N-terminal amino acid sequence [55]. UTA3, having glycosylated protein bands at 44 and 67 kDa and a 40 kDa non-glycosylated UT-A3 protein band by Western blot, is expressed in inner medullary tip [56,57]. UT-A3 protein is most abundant in the inner medullary tip, weakly detected in the inner medullary base and outer medulla, and absent in cortex [56]. UT-A4 and UT-A1 have the same N- and C-terminal amino acid sequences, but UT-A4 is smaller and essentially consists of the N-terminal quarter of UT-A1 spliced into the C-terminal quarter of UT-A1. UT-A4 mRNA is detected in rat kidney medulla. UT-A5 is expressed in testis ( [58] and UT-A6 is expressed in colon but not in kidney.

Studies on UT knockout mouse models revealed and confirmed the physiological functions of UTs in urine concentration mechanism. The UT-B null mice were polyuric, consuming and excreting approximately 50% more fluid than litter-matched wild-type mice [59]. The urine osmolality in UT-B null mice was significantly lower than that in wild-type mice. Plasma urea concentration was significantly higher, and urinary urea concentration was significantly lower in the UT-B null mice. These opposing changes suggest that plasma urea increased because the kidney was less able to recycle urea and concentrate urea in the urine. The urine-to-plasma ratio of urea concentration reflects the capacity of the kidney to concentrate urea above its level in body fluids. This ratio was markedly decreased in UT-B null mice. UT-B deficiency also produced a 2-fold reduction in inner medullary urea concentration with little effect on inner medullary Na+ , K+ and Cl- concentrations. These observations suggest that UT-B functional defect caused urea selective diuresis.

Another transgenic mouse model with UT-A1/A3 deletion provided evidence that UT-A1 and UT-A3 play important role in urine concentrating mechanism, and the functional inhibition of UT-A1 and UT-A3 cause a urea-dependent osmotic diuresis [60]. In water-restricted UT-A1/A3 null mice there was a significantly reduced concentration of urea in the inner medullary interstitium compared to wild-type mice (Fenton et al. 2004) [60], but no reduction in the Na+ , Cl- or K+ concentrations. UT-A1/A3 null mice had a substantially attenuated corticomedullary osmolality gradient and no urea gradient, yet the corticomedullary sodium gradients were almost identical to wild-type mice. These data indicate that NaCl accumulation in the inner medulla is not reliant on either IMCD urea transport or the accumulation of urea in the IMCD interstitium. Taken together, these data suggest that the functional inhibition of urea transporters may cause diuresis without electrolyte loss. Urea transporter inhibitors may be developed as a novel class of diuretics.

Urea transporter inhibitors

A high throughput UT inhibitor screening assay, using human erythrocytes based on UT-B-facilitated acetamide transport, was set up in Verkman group [61]. From a small molecule library, several classes of chemical compounds phenylsulfoxyoxozole, benzenesulfonanilide, phthalazinamine, and aminobenzimidazole were identified as selective UT-B inhibitors [61]. Some active compounds have the potent inhibition activity on UT-B urea transport with IC50 ~10 nM, with ~100% inhibition at higher concentrations. Though the potency of the best compound was excellent, it was not further developed because of their relatively low potency for rodent UT-B, low UT-A inhibition activity, and low metabolic in hepatic microsomes, making them difficult to perform diuresis in vivo. In a follow-on [62-64] screen produced several other classes of UT-B inhibitors. In vitro studies showed that UTBinh-14 fully and reversibly inhibited urea transport with IC50 of ~10 nmol/l for human UT-B and ~25 nmol/l for mouse UT-B. UTBinh-14 was highly selective against UT-B vs. UT-A isoforms. Intraperitoneal administration of UTBinh-14 in mice to achieve therapeutic concentrations in kidney, urine osmolality following dDAVP in UTBinh-14-treated mice was significantly lower than in vehicle-treated mice. UTBinh-14 also increased urine output and reduced osmolality in mice given free access to water. Though these data provided proof-of-concept for the potential utility of UT-B inhibition to reduce urinary concentration in a high-vasopressin state, the reduction in urine osmolality was relatively modest.

UT-A isoform is the most important for urinary concentration as it is the rate-limiting step in apical membrane urea transport in the inner medullary collecting duct and hence required to establish the hyper molar renal medullary interstitium. Several classes of compounds with UT-A inhibition activity were found in Verkman group [65,66]. These compounds have a wide range of UT-A1 vs. UT-B selectivity. They found that intravenous administration of an indole thiazole or α-sultambenzosulfonamide increased urine output by 3~5-fold and reduced urine osmolality by 2-fold compared to vehicle control rats, even under conditions of maximum antidiuresis produced by 1-deamino-8-D-arginine vasopressin (DDAVP). The diuresis was reversible and showed urea > salt excretion [66].

By integrated cell based high throughput screening and in silico methods, a class of small-molecule drug-like compounds with thienoquinolins core structure was found to have inhibition activity on both UT-A and UT-B. The structure and activity relationship analysis showed a compound PU-48, named chemically as methyl 3-amino-6-methoxythieno [2,3- b] quinoline-2-carboxylate (Figure 2A), had the best UT-A and UT-B inhibition activity. IC50s of PU-48 on UT-B facilitated urea transport were micromole level in human, rat, and mouse, as determined by erythrocyte lysis assay [67]. PU-48 has stronger inhibition activity on rat UT-A (IC50 0.32 µmol/l) than rat UT-B (IC50 0.90 µmol/l) (Figure 2B).

To confirm the effect of PU-48 on UT-As expressed in inner medullary collecting ducts, the efficiency of urea transport in the rat terminal portion of collecting duct was measured using the tubule perfusion technique. PU-48 significantly reduced basal urea transport by 31.1% at 10 µmol/l and completely inhibited the vasopressin-stimulated component of urea transport at 1, 5, and 10 µmol/l (Figure 2C). PU-48 had no significant effect on the expression of UT-A1, UT-A2, UT-A3, UT-B, AQP1, AQP2, AQP3, AQP4, NCC, or NKCC2 in rat kidney as determined by Western blot analysis, indicating that PU-48 is a highly selective UT inhibitor. PU-48 did not affect the hERG, NaV1.5, or CaV1.2 channels and had no cytotoxicity at effective doses, suggesting that PU-48 is not hazardous.

Diuretic activity and characteristics of UT inhibitors

In vivo activity of PU-48 on urinary concentrating function was evaluated in wild-type and UT-B null mice fed ad libitum in metabolic cages. In the 2 h before administration of PU-48, urine output was higher and urinary osmolality was lower in UT-B null mice than in wild-type mice (Figure 3A,B). Urine output significantly increased and urinary osmolality significantly decreased after subcutaneous administration of PU-48 at 100 mg/kg in both UT-B null mice and wild-type mice [68]. These data suggest that PU-48 exert sits diuretic effect by strongly inhibiting the inner medullary collecting duct UT-As. PU-48 significantly increased urea excretion in both wild-type mice and UT-B-null mice (Figure 3C). Notably, the excretion of non-urea solutes did not change (Figure 3D) in both wild-type and UT-B null mice, indicating no significant loss of Na+ , K+ , or Cl- [13].

To confirm the diuretic activity of PU-48, rat model was assessed using metabolic cages. Urine output significantly increased in a dose-dependent manner in rats subcutaneously administered PU-48 at 3.125, 12.5, and 50 mg/kg (Figure 4A). Urinary osmolality was significantly decreased. The peak changes of urine output, urinary osmolality and urinary urea concentration occurred 2 h after PU-48 administration, with values returning to baseline by 10 h [13].

Diuretic characteristics of PU-48 for continuous use were evaluated in rats. PU-48 at 50 mg/kg was subcutaneously injected every 6 h for 6 days. As shown in Figure 4B, the 24 h urine output in PU-48 treated rats was significantly higher than that in vehicle control rats. Notably, blood urea, T-CHO, TGs, and LDL-C in PU-48-treated rats were similar with those in vehicle control rats, which are normal levels (Table 1). It was also found that total osmolalities were significantly less in inner medullary tissue of PU-48-treated rats than those in vehicle control rats, which was primarily because of a reduction in inner medulla urea concentration (Figure 4C). Na+ and Cl- concentration was similar with those in vehicle control rats, which indicates that the diuretic effect of PU-14 does not cause electrolyte imbalance and abnormal metabolism. These experimental results suggest that urea transporter inhibitors may be developed as a novel class of diuretics performing urea-selective diuresis without disturbing electrolyte excretion and metabolism [13].

Clinical significance of urea transporter inhibitors as diuretics

Urea transporter inhibitors used as diuretics have potential clinical significance. Urea transporter inhibitors have a different mechanism-of-action from conventional diuretics, which block salt transport across kidney tubule epithelial cells. Urea transporter inhibitors can be widely used to increase renal water excretion in conditions associated with total body fluid overload, including congestive heart failure, cirrhosis and nephrotic syndrome [69]. By disrupting countercurrent mechanisms and intrarenal urea recycling, urea transport inhibitors, alone or in combination with conventional diuretics, may induce a diuresis in states of refractory edema where conventional diuretics are ineffective [70]. However, many challenges remain in the clinical development of urea transporter, including demonstration of efficacy in clinically relevant models of refractory edema and SIADH (syndrome of inappropriate antidiuretic hormone), and in medical chemistry in the selection of inhibitors with appropriate pharmacological properties.

Table 1: Blood chemistry in control or PU-48 treated rats (adapted from Ren et al. 2014) [13].

  Control (n = 6) PU-48 (n = 6)
Serum osmolality, mOsm/kg H2 O 302±1.5 305±2.6
Serum Na, mM 150.1±10.1 145.2±6
Serum K, mM 4.4±0.8 4.2±0.8
Serum Cl, mM 107.3±9.9 104.6±4.7
Serum urea, mM 8.0±0.9 8.5±1.3
Serum TG, mM 1.0±0.8 0.8±0.5
Serum HDL-C, mM 0.6±0.2 0.7±0.2
Serum LDL-C, mM 0.2±0.1 0.3±0.1
Serum Glu, mM 9.3±0.9 8.7±1.7
Serum Chol, mM 1.4±0.3 1.7±0.4
Serum ALDO, pg/ml 75.1±12.1 78.7±5.8



Supported National Natural Science Foundation of China grants 30500171, 30870921, 31200869, 81261160507, and 81170632, Drug Discovery Program grant 2009ZX09301-010-30, the 111 project, International Science & Technology Cooperation Program of China 2012DFA11070.


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Received : 09 Mar 2015
Accepted : 01 Apr 2015
Published : 02 Apr 2015
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Journal of Human Nutrition and Food Science
ISSN : 2333-6706
Launched : 2013
JSM Regenerative Medicine and Bioengineering
ISSN : 2379-0490
Launched : 2013
JSM Spine
ISSN : 2578-3181
Launched : 2016
Archives of Palliative Care
ISSN : 2573-1165
Launched : 2016
JSM Nutritional Disorders
ISSN : 2578-3203
Launched : 2017
Annals of Neurodegenerative Disorders
ISSN : 2476-2032
Launched : 2016
Journal of Fever
ISSN : 2641-7782
Launched : 2017
JSM Bone Marrow Research
ISSN : 2578-3351
Launched : 2016
JSM Mathematics and Statistics
ISSN : 2578-3173
Launched : 2014
Journal of Autoimmunity and Research
ISSN : 2573-1173
Launched : 2014
JSM Arthritis
ISSN : 2475-9155
Launched : 2016
JSM Head and Neck Cancer-Cases and Reviews
ISSN : 2573-1610
Launched : 2016
JSM General Surgery Cases and Images
ISSN : 2573-1564
Launched : 2016
JSM Anatomy and Physiology
ISSN : 2573-1262
Launched : 2016
JSM Dental Surgery
ISSN : 2573-1548
Launched : 2016
Annals of Emergency Surgery
ISSN : 2573-1017
Launched : 2016
Annals of Mens Health and Wellness
ISSN : 2641-7707
Launched : 2017
Journal of Preventive Medicine and Health Care
ISSN : 2576-0084
Launched : 2018
Journal of Chronic Diseases and Management
ISSN : 2573-1300
Launched : 2016
Annals of Vaccines and Immunization
ISSN : 2378-9379
Launched : 2014
JSM Heart Surgery Cases and Images
ISSN : 2578-3157
Launched : 2016
Annals of Reproductive Medicine and Treatment
ISSN : 2573-1092
Launched : 2016
JSM Brain Science
ISSN : 2573-1289
Launched : 2016
JSM Biomarkers
ISSN : 2578-3815
Launched : 2014
JSM Biology
ISSN : 2475-9392
Launched : 2016
Archives of Stem Cell and Research
ISSN : 2578-3580
Launched : 2014
Annals of Clinical and Medical Microbiology
ISSN : 2578-3629
Launched : 2014
JSM Pediatric Surgery
ISSN : 2578-3149
Launched : 2017
Journal of Memory Disorder and Rehabilitation
ISSN : 2578-319X
Launched : 2016
JSM Tropical Medicine and Research
ISSN : 2578-3165
Launched : 2016
JSM Head and Face Medicine
ISSN : 2578-3793
Launched : 2016
JSM Cardiothoracic Surgery
ISSN : 2573-1297
Launched : 2016
JSM Bone and Joint Diseases
ISSN : 2578-3351
Launched : 2017
JSM Bioavailability and Bioequivalence
ISSN : 2641-7812
Launched : 2017
JSM Atherosclerosis
ISSN : 2573-1270
Launched : 2016
Journal of Genitourinary Disorders
ISSN : 2641-7790
Launched : 2017
Journal of Fractures and Sprains
ISSN : 2578-3831
Launched : 2016
Journal of Autism and Epilepsy
ISSN : 2641-7774
Launched : 2016
Annals of Marine Biology and Research
ISSN : 2573-105X
Launched : 2014
JSM Health Education & Primary Health Care
ISSN : 2578-3777
Launched : 2016
JSM Communication Disorders
ISSN : 2578-3807
Launched : 2016
Annals of Musculoskeletal Disorders
ISSN : 2578-3599
Launched : 2016
Annals of Virology and Research
ISSN : 2573-1122
Launched : 2014
JSM Renal Medicine
ISSN : 2573-1637
Launched : 2016
Journal of Muscle Health
ISSN : 2578-3823
Launched : 2016
JSM Genetics and Genomics
ISSN : 2334-1823
Launched : 2013
JSM Anxiety and Depression
ISSN : 2475-9139
Launched : 2016
Clinical Journal of Heart Diseases
ISSN : 2641-7766
Launched : 2016
JSM Pain and Management
ISSN : 2578-3378
Launched : 2016
JSM Women's Health
ISSN : 2578-3696
Launched : 2016
Clinical Research in HIV or AIDS
ISSN : 2374-0094
Launched : 2013
Journal of Endocrinology, Diabetes and Obesity
ISSN : 2333-6692
Launched : 2013
Journal of Substance Abuse and Alcoholism
ISSN : 2373-9363
Launched : 2013
JSM Neurosurgery and Spine
ISSN : 2373-9479
Launched : 2013
Journal of Liver and Clinical Research
ISSN : 2379-0830
Launched : 2014
Journal of Drug Design and Research
ISSN : 2379-089X
Launched : 2014
JSM Clinical Oncology and Research
ISSN : 2373-938X
Launched : 2013
JSM Bioinformatics, Genomics and Proteomics
ISSN : 2576-1102
Launched : 2014
JSM Chemistry
ISSN : 2334-1831
Launched : 2013
Journal of Trauma and Care
ISSN : 2573-1246
Launched : 2014
JSM Surgical Oncology and Research
ISSN : 2578-3688
Launched : 2016
Annals of Food Processing and Preservation
ISSN : 2573-1033
Launched : 2016
Journal of Radiology and Radiation Therapy
ISSN : 2333-7095
Launched : 2013
JSM Physical Medicine and Rehabilitation
ISSN : 2578-3572
Launched : 2016
Annals of Clinical Pathology
ISSN : 2373-9282
Launched : 2013
Annals of Cardiovascular Diseases
ISSN : 2641-7731
Launched : 2016
Journal of Behavior
ISSN : 2576-0076
Launched : 2016
Annals of Clinical and Experimental Metabolism
ISSN : 2572-2492
Launched : 2016
Clinical Research in Infectious Diseases
ISSN : 2379-0636
Launched : 2013
JSM Microbiology
ISSN : 2333-6455
Launched : 2013
Journal of Urology and Research
ISSN : 2379-951X
Launched : 2014
Journal of Family Medicine and Community Health
ISSN : 2379-0547
Launched : 2013
Annals of Pregnancy and Care
ISSN : 2578-336X
Launched : 2017
JSM Cell and Developmental Biology
ISSN : 2379-061X
Launched : 2013
Annals of Aquaculture and Research
ISSN : 2379-0881
Launched : 2014
Clinical Research in Pulmonology
ISSN : 2333-6625
Launched : 2013
Journal of Immunology and Clinical Research
ISSN : 2333-6714
Launched : 2013
Annals of Forensic Research and Analysis
ISSN : 2378-9476
Launched : 2014
JSM Biochemistry and Molecular Biology
ISSN : 2333-7109
Launched : 2013
Annals of Breast Cancer Research
ISSN : 2641-7685
Launched : 2016
Annals of Gerontology and Geriatric Research
ISSN : 2378-9409
Launched : 2014
Journal of Sleep Medicine and Disorders
ISSN : 2379-0822
Launched : 2014
JSM Burns and Trauma
ISSN : 2475-9406
Launched : 2016
Chemical Engineering and Process Techniques
ISSN : 2333-6633
Launched : 2013
Annals of Clinical Cytology and Pathology
ISSN : 2475-9430
Launched : 2014
JSM Allergy and Asthma
ISSN : 2573-1254
Launched : 2016
Journal of Neurological Disorders and Stroke
ISSN : 2334-2307
Launched : 2013
Annals of Sports Medicine and Research
ISSN : 2379-0571
Launched : 2014
JSM Sexual Medicine
ISSN : 2578-3718
Launched : 2016
Annals of Vascular Medicine and Research
ISSN : 2378-9344
Launched : 2014
JSM Biotechnology and Biomedical Engineering
ISSN : 2333-7117
Launched : 2013
Journal of Hematology and Transfusion
ISSN : 2333-6684
Launched : 2013
JSM Environmental Science and Ecology
ISSN : 2333-7141
Launched : 2013
Journal of Cardiology and Clinical Research
ISSN : 2333-6676
Launched : 2013
JSM Nanotechnology and Nanomedicine
ISSN : 2334-1815
Launched : 2013
Journal of Ear, Nose and Throat Disorders
ISSN : 2475-9473
Launched : 2016
JSM Ophthalmology
ISSN : 2333-6447
Launched : 2013
Journal of Pharmacology and Clinical Toxicology
ISSN : 2333-7079
Launched : 2013
Annals of Psychiatry and Mental Health
ISSN : 2374-0124
Launched : 2013
Medical Journal of Obstetrics and Gynecology
ISSN : 2333-6439
Launched : 2013
Annals of Pediatrics and Child Health
ISSN : 2373-9312
Launched : 2013
JSM Clinical Pharmaceutics
ISSN : 2379-9498
Launched : 2014
JSM Foot and Ankle
ISSN : 2475-9112
Launched : 2016
JSM Alzheimer's Disease and Related Dementia
ISSN : 2378-9565
Launched : 2014
Journal of Addiction Medicine and Therapy
ISSN : 2333-665X
Launched : 2013
Journal of Veterinary Medicine and Research
ISSN : 2378-931X
Launched : 2013
Annals of Public Health and Research
ISSN : 2378-9328
Launched : 2014
Annals of Orthopedics and Rheumatology
ISSN : 2373-9290
Launched : 2013
Journal of Clinical Nephrology and Research
ISSN : 2379-0652
Launched : 2014
Annals of Community Medicine and Practice
ISSN : 2475-9465
Launched : 2014
Annals of Biometrics and Biostatistics
ISSN : 2374-0116
Launched : 2013
JSM Clinical Case Reports
ISSN : 2373-9819
Launched : 2013
Journal of Cancer Biology and Research
ISSN : 2373-9436
Launched : 2013
Journal of Surgery and Transplantation Science
ISSN : 2379-0911
Launched : 2013
Journal of Dermatology and Clinical Research
ISSN : 2373-9371
Launched : 2013
JSM Gastroenterology and Hepatology
ISSN : 2373-9487
Launched : 2013
Annals of Nursing and Practice
ISSN : 2379-9501
Launched : 2014
JSM Dentistry
ISSN : 2333-7133
Launched : 2013
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