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Rheumatoid arthritis (RA) and associated inflammatory complications are the most prevalent illnesses and can turn into fatal conditions if left untreated. Allopathic medicine is not satisfactory for curing RA. Scientific literature reports reveal that several phyto-compounds viz. flavonoids, saponins, and terpenoids, can heal joints and organs from auto-inflammatory rheumatoid arthritis and pain. Gene ontology, gene network analysis, molecular clustering, and literature review were used to optimise RA-specific highly expressed genes. In-silico molecular docking was performed to short-out potential phytomolecules (Neohesperidin dihydrochalcone (NHDC)) from 1000 datasets-library against RA and validate using MD simulation running at 100 ns. In-vitro anti-inflammatory assays of NHDC inhibited egg-albumin denaturation, IC50 of 47.739 ± 0.51 µg/ml. The ex-vivo MTT assay with NHDC rendered 67.209% inhibition at 100 µM against fd-FLS-cells. NHDC downregulated pro-inflammatory cytokine IL-17A production by 61.11% and 50% at 300 and 200 µM, respectively. Thus, this Studies recommend that NHDC may be highlighted as a novel multi-target PADI4 and JAK3 inhibitor with better efficacy and minimal toxicity in RA warranted to In-Vivo and clinical investigation. The current findings have uncovered remarkable genes and signalling pathways linked to RA, which could enhance our existing comprehension of the molecular mechanisms that drive its development and progression.
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Drug delivery to the buccal mucosa is one of the most convenient ways to treat common mouth problems. Here, we propose a spray-dried re-dispersible mucoadhesive controlled release gargle formulation to improve the efficacy of chlorhexidine. The present investigation portrays an approach to get stable and free-flowing spray-dried porous aggregates of chlorhexidine-loaded sodium alginate nanoparticles. The ionic gelation technique aided with the chlorhexidine's positive surface charge-based crosslinking, followed by spray drying of the nanoparticle's dispersion in the presence of lactose- and leucine-yielded nano-aggregates with good flow properties and with a size range of about 120-350 nm. Provided with the high entrapment efficiency (87%), the particles showed sustained drug release behaviors over a duration of 10 h, where 87% of the released drug got permeated within 12 h. The antimicrobial activity of the prepared formulation was tested on S. aureus, provided with a higher zone of growth inhibition than the marketed formulation. Aided with an appropriate mucoadhesive strength, this product exhibited extended retention of nanoparticles in the throat region, as shown by in vivo imaging results. In conclusion, the technology, provided with high drug retention and extended effect, could be a potential candidate for treating several types of throat infections.
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Clorexidina , Faringe , Staphylococcus aureus , Sistemas de Liberação de Medicamentos/métodos , Preparações de Ação Retardada , Antissépticos Bucais , Tamanho da PartículaRESUMO
MAIN CONCLUSION: The high affinity nitrate transport system is a potential target for improving nitrogen use efficiency of bread wheat growing either under optimal or limiting nitrate concentration. Nitrate uptake is one of the most important traits to take into account to improve nitrogen use efficiency in wheat (Triticum aestivum L.). In this study, we aimed to gain an insight into the regulation of NO3- -uptake and translocation systems in two contrasting wheat genotypes [K9107(K9) vs. Choti Lerma (CL)]. Different conditions, such as NO3--uptake rates, soil-types, N-free solid external media, and external NO3- levels at the seedling stage, were considered. We also studied the contribution of homeolog expression of five genes encoding two nitrate transporters in the root tissue, along with their overall transcript expression levels relative to specific external nitrate availability. We observed that K9107 had a higher 15N influx than Choti Lerma under both limiting as well as optimum external N conditions in vermiculite-perlite (i.e., N-free solid) medium, with the improved translocation efficiency in Choti Lerma. However, in different soil types, different levels of 15N-enrichment in both the genotypes were found. Our results also demonstrated that the partitioning of dry matter in root and shoot was different under these growing conditions. Moreover, K9107 showed significantly higher relative expression of TaNRT2.1 at the lowest and TaNPF6.1 and TaNPF6.2 at the highest external nitrate concentrations. We also observed genotype-specific and nitrate starvation-dependent homeolog expression bias in all five nitrate transporter genes. Our data suggest that K9107 had a higher NO3- influx capacity, involving different nitrate transporters, than Choti Lerma at the seedling stage.
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Nitratos , Triticum , Pão , Genótipo , Transportadores de Nitrato , Nitratos/metabolismo , Nitrogênio/metabolismo , Raízes de Plantas/genética , Raízes de Plantas/metabolismo , Solo , Triticum/genética , Triticum/metabolismoRESUMO
Water deficit is a significant impediment to enhancing rice yield. Genetic engineering tools have enabled agriculture researchers to develop drought-tolerant cultivars of rice. A common strategy to achieve this involves expressing drought-tolerant genes driven by constitutive promoters such as CaMV35S. However, the use of constitutive promoters is often limited by the adverse effects it has on the growth and development of the plant. Additionally, it has been observed that monocot-derived promoters are more successful in driving gene expression in monocots than in dicots. Substitution of constitutive promoters with stress-inducible promoters is the currently used strategy to overcome this limitation. In the present study, a 1514 bp AP2/ERF promoter that drives the expression of a transcription factor was cloned and characterized from drought-tolerant Indian rice genotype N22. The AP2/ERF promoter was fused to the GUS gene (uidA) and transformed in Arabidopsis and rice plants. Histochemical GUS staining of transgenic Arabidopsis plants showed AP2/ERF promoter activity in roots, stems, and leaves. Water deficit stress and ABA upregulate promoter activity in transformed Arabidopsis and rice. Quantitative PCR for uidA expression confirmed induced GUS activity in Arabidopsis and rice. This study showed that water deficit inducible Os-AP2/ERF-N22 promoter can be used to overcome the limitations of constitutive promoters. Transformants overexpressing Os-AP2/ERF-N22 showed higher relative water content, membrane stability index, total chlorophyll content, chlorophyll stability index, wax content, osmotic potential, stomatal conductance, transpiration rate, photosynthetic rate and radical scavenging activity. Drought tolerant (N22) showed higher expression of Os-AP2/ERF-N22 than the susceptible (MTU1010) cultivar. Supplementary Information: The online version contains supplementary material available at 10.1007/s12298-022-01246-9.
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Osteoarthritis (OA), a disorder of joints, is prevalent in older age. The contemporary cure for OA is aimed to confer symptomatic relief, consisting of temporary pain and swelling relief. In this paper, we discuss various modalities responsible for the onset of OA and associated with its severity. Inhibition of chondrocytes receptors such as DDR2, SDF-1, Asporin, and CXCR4 by specific pharmacological inhibitors attenuates OA, a critical step for finding potential disease modifying drugs. We critically analyzed recent OA studies with an emphasis on intermediate target molecules for OA intervention. We also explored some novel and safe treatments for OA by considering disease prognosis crosstalk with cellular signaling pathways.
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Osteoartrite/tratamento farmacológico , Animais , Cartilagem Articular/metabolismo , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Articulações/metabolismo , Osteoartrite/epidemiologia , Osteoartrite/etiologia , Osteoartrite/metabolismo , PrognósticoRESUMO
Polycystin-1 (PC1) and -2 (PC2), products of the PKD1 and PKD2 genes, are mutated in autosomal dominant polycystic kidney disease (ADPKD). They localize to the primary cilia; however, their ciliary function is in dispute. Loss of either the primary cilia or PC1 or PC2 causes cyst formation. However, loss of both cilia and PC1 or PC2 inhibits cyst growth via an unknown pathway. To help define a pathway, we studied cilium length in human and mouse kidneys. We found cilia are elongated in kidneys from patients with ADPKD and from both Pkd1 and Pkd2 knockout mice. Cilia elongate following polycystin inactivation. The role of intraflagellar transport proteins in Pkd1-deficient mice is also unknown. We found that inactivation of Ift88 (a gene expressing a core component of intraflagellar transport) in Pkd1 knockout mice, as well as in a new Pkd2 knockout mouse, shortened the elongated cilia, impeded kidney and liver cystogenesis, and reduced cell proliferation. Multi-stage in vivo analysis of signaling pathways revealed ß-catenin activation as a prominent, early, and sustained event in disease onset and progression in Pkd2 single knockout but not in Pkd2.Ift88 double knockout mouse kidneys. Additionally, AMPK, mTOR and ERK pathways were altered in Pkd2 single knockout mice but only AMPK and mTOR pathway alteration were rescued in Pkd2.Ift88 double knockout mice. Thus, our findings advocate an essential role of polycystins in the structure and function of the primary cilia and implicate ß-catenin as a key inducer of cystogenesis downstream of the primary cilia. Our data suggest that modulating cilium length and/or its associated signaling events may offer novel therapeutic approaches for ADPKD.
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Cistos , Doenças Renais Policísticas , Rim Policístico Autossômico Dominante , Animais , Cílios , Cistos/genética , Humanos , Rim , Fígado , Camundongos , Camundongos Knockout , Rim Policístico Autossômico Dominante/genética , Canais de Cátion TRPP/genéticaRESUMO
Mucosa has now been recognized as a potential site for both local and systemic delivery of therapeutics. Mucoadhesive drug delivery systems with customizable release profiles have recently gained considerable interest among formulation scientists to improve clinical outcomes of drugs. This review summarizes the current development in the processing methods and polymers involved in mucoadhesive drug delivery systems. Mucoadhesive drug delivery systems are suitable for drugs that have a localized effect, undergo extensive pre-systemic metabolism, narrow absorption window, and narrow therapeutic index. Polymer characteristics like surface charge, hydrophilic surface groups, wettability, molecular weight, chain flexibility, molecular conformations, etc. are critical for assessing the extent of mucoadhesiveness and treatment response. The current review focuses on valuable principles, merits, drawbacks, and future outlooks of different mucoadhesive drug delivery systems.
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Composição de Medicamentos/métodos , Sistemas de Liberação de Medicamentos/métodos , Mucosa Bucal/metabolismo , Preparações Farmacêuticas/administração & dosagem , Adesividade , Animais , Vias de Administração de Medicamentos , Previsões , Humanos , Mucosa Bucal/efeitos dos fármacos , Preparações Farmacêuticas/metabolismoRESUMO
γ-Tocopherol methyltransferase (γ-TMT) (EC 2.1.1.95) is the last enzyme in the tocopherol biosynthetic pathway and it catalyzes the conversion of γ-tocopherol into α-tocopherol, the nutritionally significant and most bioactive form of vitamin E. Although the γ-TMT gene has been successfully overexpressed in many crops to enhance their α-tocopherol content but still only few attempts have been made to uncover its structural, functional and regulation aspects at protein level. In this study, we have cloned the complete 909bp coding sequence of Glycine max γ-TMT (Gm γ-TMT) gene that encodes the corresponding protein comprising of 302 amino acid residues. The deduced Gm γ-TMT protein showed 74-87% sequence identity with other characterized plant γ-TMTs. Gm γ-TMT belongs to Class I Methyl Transferases that have a Rossmann-like fold which consists of a seven-stranded ß sheet joined by α helices. Heterologous expression of Gm γ-TMT in pET29a expression vector under the control of bacteriophage T7 promoter produced a 37.9 kDa recombinant Gm γ-TMT protein with histidine hexamer tag at its C-terminus. The expression of recombinant Gm γ-TMT protein was confirmed by western blotting using anti-His antibody. The recombinant protein was purified by Ni2+-NTA column chromatography. The purified protein showed SAM dependent methyltransferase activity. The α-tocopherol produced in the in-vitro reaction catalyzed by the purified enzyme was detected using reverse phase HPLC. This study has laid the foundation to unveil the biochemical understanding of Gm γ-TMT enzyme which can be further explored by studying its kinetic behaviour, substrate specificity and its interaction with other biomolecules.
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Glycine max/enzimologia , Metiltransferases/genética , gama-Tocoferol/metabolismo , Clonagem Molecular , Regulação da Expressão Gênica de Plantas , Metiltransferases/biossíntese , Metiltransferases/química , Plantas Geneticamente Modificadas , Sementes/genéticaRESUMO
Eleven germplasms of faba bean seeds from four agroclimatic regions of Bihar, India, have been investigated to estimate their nutritional (soluble protein, free amino acids, starch, reducing and non reducing sugar, total soluble sugar) and antinutritional (total extractable phenol and condensed tannin/proanthocyanidin) parameters. These parameters were found in varying concentration in all genotypes studied. The highest concentration of total extractable phenol and proanthocyanidin (condensed tannin) (2.56 and 1.59 % leucocyanidin equivalents respectively on dry matter basis) were found in Samastipur while the lowest from Patna (0.95 and 0.426 % leucocyanidin equivalent on dry matter basis). The different nutritional parameters were also found to be in variable concentration among different germplasms viz. total soluble protein ≈ 20-32 %, free amino acids ≈ 188-348 mg/100 g, starch ≈ 27-33 %, reducing sugars ≈ 85-188 mg/100 g, non reducing sugars ≈ 0.7-1.7 % and total soluble sugars ≈ 0.8-1.9 %.
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BACKGROUND: The expanding clinical indications of cardiac rhythm management have led to an increased use of pacemaker implantation which is associated with increased incidence of pacemaker infections. Staphylococcus aureus and epidermidis account for the vast majority of pacemaker infections. Pacemaker infection due to Mycobacterium tuberculosis (M. tuberculosis) is very rare, only few cases having been reported till date. METHODS: We describe here a study of three patients of pacemaker pocket infection with M. tuberculosis. CONCLUSION: The possibility of mycobacterial pacemaker infection should always be kept in mind in patients with delayed pacemaker infection.
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BACKGROUND: Currently available live, oral rotavirus vaccines (LORVs) have significantly reduced severe rotavirus hospitalizations and deaths worldwide. However, LORVs are not as effective in low- and middle-income countries (LMIC) where rotavirus disease burden is highest. Next-generation rotavirus vaccine (NGRV) candidates in development may have a greater public health impact where they are needed most. The feasibility and acceptability of possible new rotavirus vaccines were explored as part of a larger public health value proposition for injectable NGRVs in LMICs. OBJECTIVE: To assess national stakeholder preferences for currently available LORVs and hypothetical NGRVs and understand rationales and drivers for stated preferences. METHODS: Interviews were conducted with 71 national stakeholders who influence vaccine policy and national programming. Stakeholders from Ghana, Kenya, Malawi, Peru, Senegal, and Sri Lanka were interviewed using a mixed-method guide. Vaccine preferences were elicited on seven vaccine comparisons involving LORVs and hypothetical NGRVs based on information presented comparing the vaccines' attributes. Reasons for vaccine preference were elicited in open-ended questions, and the qualitative data were analyzed on key preference drivers. RESULTS: Nearly half of the national stakeholders interviewed preferred a highly effective standalone, injectable NGRV over current LORVs. When presented as having similar efficacy to the LORV, however, very few stakeholders preferred the injectable NGRV, even at substantially lower cost. Similarly, a highly effective standalone injectable NGRV was generally not favored over an equally effective oral NGRV following a neonatal-infant schedule, despite higher cost of the neonatal option. An NGRV-DTP-containing combination vaccine was strongly preferred over all other options, whether delivered alone with efficacy similar to current LORVs or co-administered alongside an LORV (LORV + NGRV-DTP) to increase efficacy. CONCLUSION: Results from these national stakeholder interviews provide valuable insights to inform ongoing and future NGRV research and development.
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Infecções por Rotavirus , Vacinas contra Rotavirus , Rotavirus , Hospitalização , Humanos , Lactente , Recém-Nascido , Pobreza , Infecções por Rotavirus/prevenção & controleRESUMO
BACKGROUND: Live oral rotavirus vaccines (LORVs) have significantly reduced rotavirus hospitalizations and deaths worldwide. However, LORVs are less effective in low- and middle-income countries (LMICs). Next-generation rotavirus vaccines (NGRVs) may be more effective but require administration by injection or a neonatal oral dose, adding operational complexity. Healthcare providers (HPs) were interviewed to assess rotavirus vaccine preferences and identify delivery issues as part of an NGRV value proposition. OBJECTIVE: Determine HP vaccine preferences about delivering LORVs compared to injectable (iNGRV) and neonatal oral (oNGRV) NGRVs. METHODS: 64 HPs from Ghana, Kenya, Malawi, Peru, and Senegal were interviewed following a mixed-method guide centered on three vaccine comparisons: LORV vs. iNGRV; LORV vs. oNGRV; oNGRV vs. iNGRV. HPs reviewed attributes for each vaccine in the comparisons, then indicated and explained their preference. Additional questions elicited views about co-administering iNGRV+LORV for greater public health impact, a possible iNGRV-DTP-containing combination vaccine, and delivering neonatal doses. RESULTS: Almost all HPs preferred oral vaccine options over iNGRV, with many emphasizing an aversion to additional injections. Despite this strong preference, HPs described challenges delivering oral doses. Preferences for LORV vs. oNGRV were split, marked by disparate views on rotavirus disease epidemiology and the safety, need, and feasibility of delivering neonatal vaccines. Although overwhelmingly enthusiastic about an iNGRV-DTP-containing combination option, several HPs had concerns. HP views were divided on the feasibility of co-administering iNGRV+LORV, citing challenges around logistics and caregiver sensitization. CONCLUSION: Our findings provide valuable insights on delivering NGRVs in routine immunization. Despite opposition to injectables, openness to co-administering LORV+iNGRV to improve efficacy suggests future HP support of iNGRV if adequately informed of its advantages. Rationales for LORV vs. oNGRV underscore needs for training on rotavirus epidemiology and stronger service integration. Expressed challenges delivering existing LORVs merit further examination and indicate need for improved delivery.
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Infecções por Rotavirus , Vacinas contra Rotavirus , Rotavirus , Países em Desenvolvimento , Pessoal de Saúde , Humanos , Lactente , Recém-Nascido , Infecções por Rotavirus/epidemiologiaRESUMO
INTRODUCTION: Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has emerged as one of the biggest global health issues. Spike protein (S) and nucleoprotein (N), the major immunogenic components of SARS-CoV-2, have been shown to be involved in the attachment and replication of the virus inside the host cell. AREAS COVERED: Several investigations have shown that the SARS-CoV-2 nucleoprotein can elicit a cell-mediated immune response capable of regulating viral replication and lowering viral burden. However, the development of an effective vaccine that can stop the transmission of SARS-CoV-2 remains a matter of concern. Literature was retrieved using the keywords COVID-19 vaccine, role of nucleoprotein as vaccine candidate, spike protein, nucleoprotein immune responses against SARS-CoV-2, and chimera vaccine in PubMed, Google Scholar, and Google. EXPERT OPINION: We have focussed on the use of chimera protein, consisting of N and S-1 protein components of SARS-CoV-2, as a potential vaccine candidate. This may act as a polyvalent mixed recombinant protein vaccine to elicit a strong T and B cell immune response, which will be capable of neutralizing the wild and mutated variants of SARS-CoV-2, and also restricting its attachment, replication, and budding in the host cell.
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COVID-19 , Proteínas Virais de Fusão , Vacinas Virais , Anticorpos Neutralizantes , Anticorpos Antivirais , COVID-19/prevenção & controle , Vacinas contra COVID-19 , Humanos , Nucleoproteínas , SARS-CoV-2 , Glicoproteína da Espícula de Coronavírus/genéticaRESUMO
Novel coronavirus disease 2019 (COVID-19) is by far the worst pandemic disease in the current millennium. The first human-to-human transmission was observed in December 2019 in China and is caused by the highly contagious severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which has infected millions of people within months across the globe. SARS-CoV-2 is a spike protein enveloped virus with particle-like characteristics and a diameter of 60-140 nm. Real-time PCR, reverse transcriptase PCR, isothermal PCR, immunological-based detection technique and nano-based diagnostic system have been explained for the identification and differentiation of different types of virus including SARS-COV-2. Synthetic nanoparticles can closely mimic the virus and interact strongly with its virulent proteins due to their morphological similarities. Some of the antiviral nanomaterials are also discussed, for example zinc oxide nanoparticle is an antiviral agent with a tetrapod morphology that mimics the cell surface by interacting with the viral capsid. It suppressed the viral proteins upon UV radiation due to reaction caused by photocatalysis. Hence, nanoparticle-based strategies for tackling viruses have immense potential. The second part of the review points to the latest in vitro and in vivo procedures for screening viral particles and the usage of nanoparticles in diagnostic and therapeutics. This would be beneficial for early detection and assists for the safe and effective therapeutic management of COVID-19.
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With the advancement of isothermal nucleic acid amplification techniques, detection of the pathogenic DNA in clinical samples at point-of-need is no longer a dream. The newly developed recombinase polymerase amplification (RPA) assay incorporated in a suitcase laboratory has shown promising diagnostic efficacy over real-time PCR in detection of leishmania DNA from clinical samples. For broader application of this point-of-need system, we undertook a current multi-country diagnostic evaluation study towards establishing this technique in different endemic settings which would be beneficial for the ongoing elimination programs for leishmaniasis. For this study purpose, clinical samples from confirmed visceral leishmaniasis (VL) and post-kala-azar dermal leishmaniasis (PKDL) patients were subjected to both real-time PCR and RPA assay in Bangladesh, India, and Nepal. Further skin samples from confirmed cutaneous leishmaniasis (CL) patients were also included from Sri Lanka. A total of 450 clinical samples from VL patients, 429 from PKDL patients, 47 from CL patients, and 322 from endemic healthy/healthy controls were under investigation to determine the diagnostic efficacy of RPA assay in comparison to real-time PCR. A comparative sensitivity of both methods was found where real-time PCR and RPA assay showed 96.86% (95% CI: 94.45-98.42) and 88.85% (95% CI: 85.08-91.96) sensitivity respectively in the diagnosis of VL cases. This new isothermal method also exhibited promising diagnostic sensitivity (93.50%) for PKDL cases, when a skin sample was used. Due to variation in the sequence of target amplicons, RPA assay showed comparatively lower sensitivity (55.32%) than that of real-time PCR in Sri Lanka for the diagnosis of CL cases. Except for India, the assay presented absolute specificity in the rest of the sites. Excellent concordance between the two molecular methods towards detection of leishmania DNA in clinical samples substantiates the application of RPA assay incorporated in a suitcase laboratory for point-of-need diagnosis of VL and PKDL in low resource endemic settings. However, further improvisation of the method is necessary for diagnosis of CL.
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The 5th Post-Kala-Azar Dermal Leishmaniasis (PKDL) Consortium meeting brought together PKDL experts from all endemic areas to review and discuss existing and new data on PKDL. This report summarizes the presentations and discussions and provides the overall conclusions and recommendations.
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Leishmaniose Visceral/diagnóstico , Leishmaniose Visceral/epidemiologia , Animais , Humanos , Cinética , Vacinas contra Leishmaniose , Leishmaniose Cutânea , Leishmaniose Visceral/imunologia , Leishmaniose Visceral/terapia , Sri Lanka/epidemiologia , XenodiagnósticoRESUMO
In order to identify the genetic variations in root system architecture traits and their probable association with high- and low-affinity nitrate transport system, we performed several experiments on a genetically diverse set of wheat genotypes grown under two external nitrogen levels (optimum and limited nitrate conditions) at two growth points of the seedling stage. Further, we also examined the nitrate uptake and its transport under different combinations of nitrate availability in the external media using 15N-labelled N-source (15NO3-), and gene expression pattern of different high- and low-affinity nitrate transporters. We observed that nitrate starvation invariably increases the total root size in all genotypes. However, the variation of component traits of total root size under nitrate starvation is genotype-specific at both stages. Further, we also observed genotypic variation in both nitrate uptake and translocation depending on the growth stage, external nitrate concentration and growing conditions. The expression of the TaNRT2.1 gene was invariably up-regulated under low external nitrate concentration; however, it gets reduced after a longer period (21 days) of starvation than the early stage (14 days). Among the four NRT1.1 orthologs, TaNPF6.3 and TaNPF6.4 consistently showed higher expression than TaNPF6.1 and TaNPF6.2 at higher nitrate concentration at both the growth stages. TaNPF6.3 and TaNPF6.4 apparently showed a feature of typical low-affinity nitrate transporter gene at higher external nitrate concentration at 14 and 21 days growth stages, respectively. The present study reveals the complex root system of wheat that has genotype-specific N-foraging along with highly coordinated high- and low-affinity nitrate transport systems for nitrate uptake and transport.
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Nitratos , Raízes de Plantas , Triticum , Genótipo , Nitratos/metabolismo , Nitratos/farmacologia , Nitrogênio/farmacologia , Raízes de Plantas/efeitos dos fármacos , Triticum/efeitos dos fármacos , Triticum/genéticaRESUMO
Discoidin domain receptor2 (DDR2), a cell membrane tyrosine kinase on chondrocytes surface plays main role in cell-ECM interaction during the progressive degeneration of articular cartilage in osteoarthritis. The degraded component of ECM, type II collagen upon DDR2 binding provokes synthesis of matrix metalloproteinases (MMPs), responsible for severe destruction of joint tissues. DDR2 knockout has been investigated to decline the expression of MMP-1 and 13. Previously, various molecules were effective in preclinical level against different targets in OA, but found to be collapsed in clinical trial due to insufficient target specificity and clinical toxicity. Review emphasizes the role of DDR2 in the degeneration of cartilage in osteoarthritis (OA) and its blocking by DDR2 antagonist attenuates the disease severity. DDR2 in chondrocytes contributes paramount role in degradation of cartilage at early stage of osteoarthritis via collagen 2 binding through the felicitation of TGF-ß signaling molecule and other triggering factors. DDR2 involvement in regulation of matrix metalloproteinase (MMP), cross talking interaction in maintenance of ECM-chondrocytes, bone developments, interference RNA and designing the DDR2 antagonists have been critically investigated. The exploration may conclude that the DDR2 could be the novel pharmacological target to prevent the progression of osteoarthritis at early stage because of over expression of DDR2 and MMP which further promotes severe cartilage degeneration. Owing to pharmacological specificity of DDR2 in OA as drug target, it is to be hypothesized that development of safe molecules as DDR2 antagonist could be the good option in the treatment of OA with promising landmark.
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Receptor com Domínio Discoidina 2/metabolismo , Osteoartrite/metabolismo , Animais , Cartilagem Articular/metabolismo , Progressão da Doença , Humanos , Metaloendopeptidases/metabolismo , Estudos ProspectivosRESUMO
BACKGROUND: We investigated the relationship of treatment regimens for visceral leishmaniasis (VL) with post-kala-azar dermal leishmaniasis (PKDL) and visceral leishmaniasis relapse (VLR) development. METHODS: Study subjects included cohorts of patients cured of VL since treatment with monotherapy by sodium stibogluconate (SSG), miltefosine (MF), paromomycin intramuscular injection (PMIM), liposomal amphotericin B [AmBisome (AMB)] in a single dose (SDAMB) and in multidose (MDAMB), and combination therapies by AMB+PMIM, AMB+MF, and PMIM+MF. Follow up period was 4 years after treatment. Cohorts were prospective except SSG (retrospective) and MF (partially retrospective). We compared incidence proportion and rate in 100-person-4year of PKDL and VLR by treatment regimens using univariate and multivariate analysis. FINDINGS: 974 of 984 enrolled participants completed the study. Overall incidence proportion for PKDL and VLR was 12.3% (95% CI, 10.4%-14.5%) and 7.0% (95% CI, 5.6%-8.8%) respectively. The incidence rate (95% CI) of PKDL and VLR was 14.0 (8.6-22.7) and 7.6 (4.1-14.7) accordingly. SSG cohort had the lowest incidence rate of PKDL at 3.0 (1.3-7.3) and VLR at 1.8 (0.6-5.6), followed by MDAMB at 8.2 (4.3-15.7) for PKDL and at 2.7 (0.9-8.4) for VLR. INTERPRETATION: Development of PKDL and VLR is related with treatment regimens for VL. SSG and MDAMB resulted in less incidence of PKDL and VLR compared to other treatment regimens. MDAMB should be considered for VL as a first step for prevention of PKDL and VLR since SSG is highly toxic and not recommended for VL.