On-demand release of a selective MMP-13 blocker from an enzyme-responsive injectable hydrogel protects cartilage from degenerative progression in osteoarthritis.

In osteoarthritis (OA), the degradation of cartilage is primarily driven by matrix metalloprotease-13 (MMP-13). Hence, the inhibition of MMP-13 has emerged as an attractive target for OA treatment. Among the various approaches that are being explored for MMP-13 regulation, blocking of the enzyme with specific binding molecules appears to be a more promising strategy for preventing cartilage degeneration. To enhance effectiveness and ensure patient compliance, it is preferable for the binding molecule to exhibit sustained activity when administered directly into the joint. Herein, we present an enzyme-responsive hydrogel that was designed to exhibit on-demand, the sustained release of BI-4394, a potent and highly selective MMP-13 blocker. The stable and compatible hydrogel was prepared using triglycerol monostearate. The efficacy of the hydrogel to prevent cartilage damage was assessed in a rat model of OA induced by anterior cruciate ligament transection (ACLT). The results revealed that in comparison to the rats administrated weekly with intra-articular BI-4394, the hydrogel implanted rats had reduced levels of inflammation and bone erosion. In comparison to untreated control, the cartilage in animals administered with BI-4394/hydrogel exhibited significant levels of collagen-2 and aggrecan along with reduced MMP-13. Overall, this study confirmed the potential of BI-4394 delivery using an enzyme-responsive hydrogel as a promising treatment option to treat the early stages of OA by preventing further cartilage degradation.

Estimation of Heritability under Correlated Errors Using the Full-Sib Model.

In plant and animal breeding, sometimes observations are not independently distributed. There may exist a correlated relationship between the observations. In the presence of highly correlated observations, the classical premise of independence between observations is violated. Plant and animal breeders are particularly interested to study the genetic components for different important traits. In general, for estimating heritability, a random component in the model must adhere to specific assumptions, such as random components, including errors, having a normal distribution, and being identically independently distributed. However, in many real-world situations, all of the assumptions are not fulfilled. In this study, correlated error structures are considered errors that are associated to estimate heritability for the full-sib model. The number of immediately preceding observations in an autoregressive series that are used to predict the value at the current observation is defined as the order of the autoregressive models. First-order and second-order autoregressive models i.e., AR(1) and AR(2) error structures, have been considered. In the case of the full-sib model, theoretical derivation of Expected Mean sum square (EMS) considering AR(1) structure has been obtained. A numerical explanation is provided for the derived EMS considering AR(1) structure. The predicted mean squares error (MSE) is obtained after including the AR(1) error structures in the model, and heritability is estimated using the resulting equations. It is noticed that correlated errors have a major influence on heritability estimation. Different correlation patterns, such as AR(1) and AR(2), can be inferred to change heritability estimates and MSE values. To attain better results, several combinations are offered for various scenarios.

Molecular docking and molecular dynamics to identify collagenase inhibitors as lead compounds to address osteoarthritis.

Osteoarthritis (OA) is a degenerative disease which affects a large number of individuals. Collagenases, which belong to a class of metalloproteases (MMPs), are responsible for the degradation of cartilage manifested in OA. Inhibition of the catalytic domains of these MMPs is one of the important therapeutic strategies proposed for the prevention of OA. The main objective of this work is to evaluate the binding of curcumin and its metabolites with the active sites of collagenases in comparison to standard inhibitors on the basis of our hypothesis that curcumin/metabolites could exhibit an inhibitory effect on MMPs. Here, we report the molecular docking analysis of curcumin and its metabolites with collagenases (MMP-1, MMP-8, MMP-13). Among the molecules tested, curcumin monoglucuronide (CMG) demonstrated the best binding affinity with MMP-13, which is specifically implicated in OA. The CMG-MMP-complexes were further subjected to molecular dynamic simulations to explore the stability of the complexes and to estimate the free binding energies. The results indicated that CMG preferentially bind to MMP-13 in comparison to that of MMP-1 and MMP-8 with binding free energies (ΔGbind) of (-60.55), (-27.02) and (-46.91) kcal/mol, respectively. This is the first study which suggests that curcumin monoglucuronide can be considered as an effective lead compound to prevent the progression of OA.Communicated by Ramaswamy H. Sarma.

SARS-CoV-2 and tissue damage: current insights and biomaterial-based therapeutic strategies.

The effect of SARS-CoV-2 infection on humanity has gained worldwide attention and importance due to the rapid transmission, lack of treatment options and high mortality rate of the virus. While scientists across the world are searching for vaccines/drugs that can control the spread of the virus and/or reduce the risks associated with infection, patients infected with SARS-CoV-2 have been reported to have tissue/organ damage. With most tissues/organs having limited regenerative potential, interventions that prevent further damage or facilitate healing would be helpful. In the past few decades, biomaterials have gained prominence in the field of tissue engineering, in view of their major role in the regenerative process. Here we describe the effect of SARS-CoV-2 on multiple tissues/organs, and provide evidence for the positive role of biomaterials in aiding tissue repair. These findings are further extrapolated to explore their prospects as a therapeutic platform to address the tissue/organ damage that is frequently observed during this viral outbreak. This study suggests that the biomaterial-based approach could be an effective strategy for regenerating tissues/organs damaged by SARS-CoV-2.

Recent advances in nanotherapeutic strategies that target nitric oxide pathway for preventing cartilage degeneration.

Nitric oxide (NO) is an important inflammatory mediator involved in the development and progression of osteoarthritis (OA). Increased production of NO in the affected joints promote cartilage damage. As NO synthesis is catalysed by the inducible NO synthase (iNOS) enzyme, iNOS inhibition serves as an attractive therapeutic target to prevent NO release. Despite a number of direct and indirect iNOS inhibitor molecules demonstrating chondro-protective effect, none have reached the clinic. Its limited bioavailability and adverse side effects served as a deterrent for pursuing clinical trials in OA patients. With the advent of nanotechnology, interest in targeting NO for preventing cartilage degeneration has revived. In this article, we discuss the limitations of the existing molecules and provide an insight on recent nanotechnology-based strategies that have been explored for the diagnosis and inhibition of NO in OA. These approaches hold promise in reviving the hitherto under explored potential of targeting NO to address OA.

Actin-binding carbon dots selectively target glioblastoma cells while sparing normal cells.

Curcumin, a pleiotropic signalling molecule from Curcuma longa, is reported to be effective against multiple cancers. Despite its promising effect, curcumin had failed in clinical trials due to its low aqueous solubility, stability and poor bioavailability. While several approaches are being attempted to overcome the limitations, the improved solubility observed with curcumin-derived carbon dots appeared to be a strategy worth exploring. To assess if the carbon dots possess bio-activity similar to curcumin, we synthesized carbon dots (CurCD) from curcumin and ethylenediamine. Unlike curcumin, the as-synthesized curcumin carbon dots exhibited excellent solubility, excitation-dependent emission and photostability. The anti-cancer activity evaluated with glioblastoma cells using the well-established in vitro models indicated its comparable/enhanced activity over curcumin. Besides, the selective affinity of CurCD to the actin filament, indicated it's prospective to serve as a marker of actin filaments. In addition, the non-toxic effects observed in normal cells and fish embryos indicated CurCD was more biocompatible than curcumin. While this work reveals the superior properties of CurCD over curcumin, it provides a new approach to explore other plant derived molecules with similar limitations like curcumin.