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1.
Res Sq ; 2024 Apr 12.
Article in English | MEDLINE | ID: mdl-38659849

ABSTRACT

Carbon monoxide (CO) is an endogenous produced molecule and has shown efficacy in animal models of inflammation, organ injury, colitis and cancer metastasis. Because of its gaseous nature, there is a need for developing efficient CO delivery approaches, especially those capable of targeted delivery. In this study, we aim to take advantage of a previously reported approach of enrichment-triggered prodrug activation to achieve targeted delivery by targeting the folate receptor. The general idea is to exploit folate receptor-mediated enrichment as a way to accelerate a biomolecular Diels-Alder reaction for prodrug activation. In doing so, we first need to find ways to tune the reaction kinetics in order to ensure minimal rection without enrichment and optimal activation upon enrichment. In this feasibility study, we synthesized two diene-dienophile pairs and studied their reaction kinetics and ability to target the folate receptor. We found that folate conjugation significantly affects the reaction kinetics of the original diene-dienophile pairs. Such information will be very useful in future designs of similar targeted approaches of CO delivery.

2.
Angew Chem Int Ed Engl ; 63(26): e202403880, 2024 Jun 21.
Article in English | MEDLINE | ID: mdl-38630918

ABSTRACT

Reactive oxygen species (ROS) are critical for cellular signaling. Various pathophysiological conditions are also associated with elevated levels of ROS. Hence, ROS-sensitive triggers have been extensively used for selective payload delivery. Such applications are predicated on two key functions: (1) a sufficient magnitude of concentration difference for the interested ROS between normal tissue/cells and intended sites and (2) appropriate reaction kinetics to ensure a sufficient level of selectivity for payload release. Further, ROS refers to a group of species with varying reactivity, which should not be viewed as a uniform group. In this review, we critically analyze data on the concentrations of different ROS species under various pathophysiological conditions and examine how reaction kinetics affect the success of ROS-sensitive linker chemistry. Further, we discuss different ROS linker chemistry in the context of their applications in drug delivery and imaging. This review brings new insights into research in ROS-triggered delivery, highlights factors to consider in maximizing the chance for success and discusses pitfalls to avoid.


Subject(s)
Reactive Oxygen Species , Reactive Oxygen Species/metabolism , Humans , Drug Delivery Systems , Feasibility Studies , Animals , Kinetics
3.
Acta Pharm Sin B ; 13(5): 1990-2016, 2023 May.
Article in English | MEDLINE | ID: mdl-37250163

ABSTRACT

Click chemistry has been proven to be very useful in drug delivery. Due to the availability of a large number of click reactions with a various characteristics, selection of appropriate chemistry for a given application is often not a trivial task. This review is written for pharmaceutical researchers who are interested in click chemistry applications and yet may not be click chemistry experts. For this, the review gives an overview of available click reactions organized by application types. Further, the general understanding of click reactions being fast and high yielding sometimes overshadows the need to analyze reaction kinetics in assessing suitability of a given reaction for certain applications. For this, we highlight the need to analyze the relationship among reaction kinetics, concentration effects, and reaction time scales, knowing that lack of such analysis could easily lead to failures. Further, possible issues such as chemical stability with various click reagents are also discussed to aid experimental designs. Recent examples and extensive references are also provided to aid in-depth understanding of technical details. We hope this review will help those interested in using click chemistry in drug delivery to select the appropriate reactions/reagents and minimize the number of pitfalls.

4.
Pediatr Nephrol ; 38(5): 1687-1692, 2023 05.
Article in English | MEDLINE | ID: mdl-36352270

ABSTRACT

BACKGROUND: Peritonitis is an important complication and cause of morbidity in patients undergoing peritoneal dialysis (PD). Corynebacterium species, often considered skin and mucosal contaminants, are a rare cause of PD-associated peritonitis and have been acknowledged in published guidelines for the diagnosis and treatment of PD peritonitis only over the last decade. CASE-DIAGNOSIS/TREATMENT: We present two children with difficult-to-treat episodes of PD peritonitis due to Corynebacterium amycolatum. Episodes were associated with fever, abdominal pain and cloudy dialysate, high dialysate polymorphonuclear leukocyte counts, and elevated serum C-reactive protein and procalcitonin concentrations. Symptoms persisted beyond 5 days in 4 of 5 peritonitis episodes, and peritonitis relapsed despite in vitro sensitivity of the bacterial isolates to guideline-recommended antibiotics. C. amycolatum was cultured from the PD catheter tip despite 4 weeks of intraperitoneal glycopeptide therapy and clinical peritonitis resolution suggestive of efficient biofilm formation. Our systematic literature search identified three previous (adult) case descriptions of C. amycolatum peritonitis, all with repeat episodes by the same organism. The incidence of C. amycolatum as a cause of PD peritonitis has not yet been established but is likely underreported due to challenges in species differentiation. CONCLUSIONS: C. amycolatum is a rarely identified cause of refractory and/or relapsing PD peritonitis. Species differentiation of non-diphtheriae Corynebacterium isolates is critical, and prolonged antibiotic treatment, preferably with a glycopeptide antibiotic, is recommended, with a low threshold for PD catheter change or removal in case of repeat peritonitis.


Subject(s)
Peritoneal Dialysis , Peritonitis , Adult , Child , Humans , Peritoneal Dialysis/adverse effects , Corynebacterium , Peritonitis/diagnosis , Peritonitis/drug therapy , Peritonitis/etiology , Anti-Bacterial Agents/therapeutic use , Dialysis Solutions/therapeutic use , Glycopeptides/therapeutic use
5.
Acta Pharmaceutica Sinica B ; (6): 1990-2016, 2023.
Article in English | WPRIM (Western Pacific) | ID: wpr-982840

ABSTRACT

Click chemistry has been proven to be very useful in drug delivery. Due to the availability of a large number of click reactions with a various characteristics, selection of appropriate chemistry for a given application is often not a trivial task. This review is written for pharmaceutical researchers who are interested in click chemistry applications and yet may not be click chemistry experts. For this, the review gives an overview of available click reactions organized by application types. Further, the general understanding of click reactions being fast and high yielding sometimes overshadows the need to analyze reaction kinetics in assessing suitability of a given reaction for certain applications. For this, we highlight the need to analyze the relationship among reaction kinetics, concentration effects, and reaction time scales, knowing that lack of such analysis could easily lead to failures. Further, possible issues such as chemical stability with various click reagents are also discussed to aid experimental designs. Recent examples and extensive references are also provided to aid in-depth understanding of technical details. We hope this review will help those interested in using click chemistry in drug delivery to select the appropriate reactions/reagents and minimize the number of pitfalls.

6.
Front Pediatr ; 8: 580178, 2020.
Article in English | MEDLINE | ID: mdl-33330277

ABSTRACT

Background: Congenital nephrotic syndrome, historically defined by the onset of large proteinuria during the first 3 months of life, is a rare clinical disorder, generally with poor outcome. It is caused by pathogenic variants in genes associated with this syndrome or by fetal infections disrupting podocyte and/or glomerular basement membrane integrity. Here we describe an infant with congenital CMV infection and nephrotic syndrome that failed to respond to targeted antiviral therapy. Case and literature survey highlight the importance of the "tetrad" of clinical, virologic, histologic, and genetic workup to better understand the pathogenesis of CMV-associated congenital and infantile nephrotic syndromes. Case Presentation: A male infant was referred at 9 weeks of life with progressive abdominal distention, scrotal edema, and vomiting. Pregnancy was complicated by oligohydramnios and pre-maturity (34 weeks). He was found to have nephrotic syndrome and anemia, normal platelet and white blood cell count, no splenomegaly, and no syndromic features. Diagnostic workup revealed active CMV infection (positive CMV IgM/PCR in plasma) and decreased C3 and C4. Maternal anti-CMV IgG was positive, IgM negative. Kidney biopsy demonstrated focal mesangial proliferative and sclerosing glomerulonephritis with few fibrocellular crescents, interstitial T- and B-lymphocyte infiltrates, and fibrosis/tubular atrophy. Immunofluorescence was negative. Electron microscopy showed diffuse podocyte effacement, but no cytomegalic inclusions or endothelial tubuloreticular arrays. After 4 weeks of treatment with valganciclovir, plasma and urine CMV PCR were negative, without improvement of the proteinuria. Unfortunately, the patient succumbed to fulminant pneumococcal infection at 7 months of age. Whole exome sequencing and targeted gene analysis identified a novel homozygous, pathogenic variant (2071+1G>T) in NPHS1. Literature Review and Discussion: The role of CMV infection in isolated congenital nephrotic syndrome and the corresponding pathological changes are still debated. A search of the literature identified only three previous reports of infants with congenital nephrotic syndrome and evidence of CMV infection, who also underwent kidney biopsy and genetic studies. Conclusion: Complete workup of congenital infections associated with nephrotic syndrome is warranted for a better understanding of their pathogenesis ("diagnostic triad" of viral, biopsy, and genetic studies). Molecular testing is essential for acute and long-term prognosis and treatment plan.

7.
Oncotarget ; 8(38): 63187-63207, 2017 Sep 08.
Article in English | MEDLINE | ID: mdl-28968981

ABSTRACT

Aberrant enzymatic activities or expression profiles of epigenetic regulations are therapeutic targets for cancers. Among these, histone 3 lysine 9 methylation (H3K9Me2) and global de-acetylation on histone proteins are associated with multiple cancer phenotypes including leukemia, prostatic carcinoma, hepatocellular carcinoma and pulmonary carcinoma. Here, we report the discovery of the first small molecule capable of acting as a dual inhibitor targeting both G9a and HDAC. Our structure based design, synthesis, and screening for the dual activity of the small molecules led to the discovery of compound 14 which displays promising inhibition of both G9a and HDAC in low micro-molar range in cell based assays.

8.
Contemp Clin Dent ; 4(2): 170-5, 2013 Apr.
Article in English | MEDLINE | ID: mdl-24015004

ABSTRACT

BACKGROUND: Dental caries is essentially a process of diffusion and dissolution. If the aspect of dissolution can be curtailed some degree of prevention can be achieved. AIMS: The present study was carried out to evaluate and compare the effect of Er:YAG laser and Co2 laser irradiation combined with acidulated phosphate fluoride treatment on in vitro acid resistance of human enamel. DESIGN: An in vitro study was carried out on 30 human premolars to evaluate the enamel's acid resistance using an atomic emission spectrometry analysis. MATERIALS AND METHODS: A total of 60 enamel specimens were prepared from 30 human premolars and were randomly assigned to 6 groups: (1) Untreated (control); (2) 1.23% acidulated phosphate fluoride (APF) gel application alone for 4 min; (3) Er:YAG laser treatment alone; (4) Co2 laser treatment alone; (5) Er:YAG laser + APF gel application; (6) Co2 laser + APF gel application. The specimens were then individually immersed in 5 ml of acetate buffer solution (0.1 mol/L, pH 4.5) and incubated at 37°C for 24 h, and the acid resistance was evaluated by determining the calcium ion concentration using the atomic emission spectrometry. STATISTICAL ANALYSIS: An ANOVA model was constructed (P value of 0.05), followed by Tukey's test for multiple pair wise comparisons of mean values. RESULTS: Significant differences were found between the control group and the test groups (P < 0.001). CONCLUSIONS: Combining acidulated phosphate fluoride with either Er:YAG or Co2 laser had a synergistic effect in decreasing the enamel demineralization more than either fluoride treatment or laser treatment alone.

9.
Contemp Clin Dent ; 4(4): 467-71, 2013 Oct.
Article in English | MEDLINE | ID: mdl-24403790

ABSTRACT

AIM: To evaluate the prevalence of oral lesions status in human immunodeficiency virus (HIV) infected children of age 1 to 14 years in Anti Retro viral therapy (ART) centres in Tamil Nadu. MATERIALS AND METHODS: A of total 326 HIV infected children, age 1 to 14 years of which 174 male children and 152 female children were examined for Oral lesions in the Department of Pedodontics and Preventive Dentistry, Rajah Muthiah Dental College and Hospital, Annamalai University in association with the ART centers in Villupuram, Vellore and HIV Homes in Thiruvannamalai, Trichy and Salem in Tamil Nadu towns. STATISTICAL ANALYSIS: Statistical Package for Social Science for Windows (version 11 code: 3000135939012345). RESULT: Of the total 326 children, 201 (61.65%) had oral lesions. (68 [20.86%] with Oral Candidiasis [OC], 54 [16.56%] with Angular Cheilitis, 27 [8.28%] with Necrotizing Ulcerative Gingivitis [NUG], 25 [7.66%] with Necrotizing Ulcerative Periodontitis [NUP], 18 [5.53%] with Linear Gingival Erythema [LGE] and 9 [2.76%] with Apthous Ulcer.) Conclusion Among the oral lesions in HIV infected children, OC 20.86% was the predominant oral lesion followed by Angular Chelitis 16.56%, NUG 8.28%, NUP 7.66%, LGE5.53% and Apthous Ulcer 2.76%.

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