Natural Analogues Research Articles

Generalized color orderings: CEGM integrands and decoupling identities

In a recent paper, we defined generalized color orderings (GCO) and Feynman diagrams (GFD) to compute color-dressed generalized biadjoint amplitudes. In this work, we study the Cachazo-Early-Guevara-Mizera (CEGM) representation of generalized partial amplitudes and “decoupling” identities. This representation is a generalization of the Cachazo-He-Yuan (CHY) formulation as an integral over the configuration space X(k,n) of n points on CPk−1 in generic position.Unlike the k=2 case, Parke-Taylor-like integrands are not enough to compute all partial amplitudes for k>2. Here we give a set of constraints that integrands associated with GCOs must satisfy and use them to construct all (3,n<9) integrands, all (3,9) integrands up to four undetermined constants, and 95% of (4,8) integrands up to 24 undetermined constants.k=2 partial amplitudes are known to satisfy identities. Among them, the so-called U(1) decoupling identities are the simplest ones. These are characterized by a label i and a color ordering in X(2,|[n]∖{i}|). Here we introduce decoupling identities for k>2 determined combinatorially using GCOs. Moreover, we identify the natural analog of U(1) identities as those characterized by a pair of labels i≠j, and a pair of GCOs, one in X(k,|[n]∖{i}|) and the other in X(k−1,|[n]∖{j}|). We call them double extension identities.We also provide explicit connections among different ways of representing GCOs, such as configurations of lines, configurations of points, and reorientation classes of uniform oriented matroids (chirotopes).

Synthesis and Neuroprotective Evaluation of Substituted Indanone/Benzofuranone and Piperidine Hybrids.

Based on the neuroprotection of butylphthalide and donepezil, a series of indanone/benzofuranone and piperidine hybrids were designed and synthesized for assessment of their neuroprotective activities, aiming to enhance the bioavailability and therapeutic efficacy of natural phthalide analogues. Within this study, it was observed that most indanone derivatives bearing 1-methylpiperidine in the tail segment demonstrated superior neuroprotective effects on the oxygen glucose deprivation/reperfusion (OGD/R)-induced rat primary neuronal cell injury model in vitro compared to benzofuranone compounds. Among the synthesized compounds, 11 (4, 14, 15, 22, 26, 35, 36, 37, 48, 49, and 52) displayed robust cell viabilities in the OGD/R model, along with favorable blood-brain barrier permeability as confirmed by the parallel artificial membrane permeability assay. Notably, compound 4 showed significant neuronal cell viabilities within the concentration range of 3.125 to 100 μM, without inducing cytotoxicity. Further results from in vivo middle cerebral artery occlusion/R experiments revealed that 4 effectively ameliorated ischemia-reperfusion injury, reducing the infarct volume to 18.45% at a dose of 40 mg/kg. This outcome suggested a superior neuroprotective effect compared to edaravone at 20 mg/kg, further highlighting the potential therapeutic efficacy of compound 4 in addressing neurological disorders.

Structure-Activity Relationship Study of Biselyngbyolide B Reveals Mitochondrial Fission-Induced Cytotoxicity in Cancer.

A systematic structure-activity relationship study of the potent anticancer marine macrolide biselyngbyolide B has been accomplished. A total of 11 structural variants of the parent natural product, of which 2 are natural analogues, have been studied against a human colorectal carcinoma cell line. The requisite functional units of the parent molecule responsible for the cytotoxic activities have been disclosed. Biselyngbyolide C, one of the natural analogues of biselyngbyolide B, has been studied in depth to explore its molecular mechanism. Interestingly, the in vitro data demonstrated an induction of dynamin-related protein 1-mediated mitochondrial fission and reactive oxygen species production which led to activation of ASK1/P38/JNK-mediated apoptosis in colon cancer cells as an important pathway for biselyngbyolide B-mediated cytotoxicity. Notably, this study revealed that a macrolide participated in mitochondrial fission to promote apoptosis of cancer cells, providing new insight.

Deglacial Pulse of Neutralized Carbon From the Pacific Seafloor: A Natural Analog for Ocean Alkalinity Enhancement?

AbstractThe ocean carbon reservoir controls atmospheric carbon dioxide (CO2) on millennial timescales. Radiocarbon (14C) anomalies in eastern North Pacific sediments suggest a significant release of geologic 14C‐free carbon at the end of the last ice age but without evidence of ocean acidification. Using inverse carbon cycle modeling optimized with reconstructed atmospheric CO2 and 14C/C, we develop first‐order constraints on geologic carbon and alkalinity release over the last 17.5 thousand years. We construct scenarios allowing the release of 850–2,400 Pg C, with a maximum release rate of 1.3 Pg C yr−1, all of which require an approximate equimolar alkalinity release. These neutralized carbon addition scenarios have minimal impacts on the simulated marine carbon cycle and atmospheric CO2, thereby demonstrating safe and effective ocean carbon storage. This deglacial phenomenon could serve as a natural analog to the successful implementation of gigaton‐scale ocean alkalinity enhancement, a promising marine carbon dioxide removal method.

In-silico screening and identification of glycomimetic as potential human sodium-glucose co-transporter 2 inhibitor

Sodium-glucose co-transporter 2 (SGLT2) is one of the important targets against type II diabetes mellitus. A typical SGLT2 inhibitor acts by inhibiting glucose reabsorption, thus lowering the blood glucose level. Unlike SGLT1, SGLT2 is responsible for almost 90% glucose reabsorption from glomerular filtrate. The current SGLT2 inhibitors include gliflozins, often prescribed as second or third-line agents in diabetes mellitus. The SGLT2 inhibitors also benefit patients with heart and kidney disease. Due to instability issues with the natural O-aryl glycoside analogues C-glycoside analogues were developed and showed improved stability. Despite enhanced bioavailability and selectivity of newer derivatives, some serious side effects are associated with gliflozin analogues. At the present study, we applied in-silico approaches to find new glycomimetic compounds as potent SGLT2 inhibitors that could show improvement in side effects associated with current analogues. This work applied both ligand-based and structure-based drug approaches to find potential compounds. We developed a 3D-QSAR method to screen potential inhibitors from a library of ten thousand compounds and performed docking studies. The compounds were ranked based on predicted pIC50 and docking score. An initial screening of five thousand compounds was conducted, and the subsequently selected top 12 compounds were based on binding free energy calculations. These selected compounds were subjected to molecular dynamics (MD) simulations. Remarkably, our simulations identified nine compounds that exhibited significant and sustained binding affinity compared to the co-crystallized Empagliflozin. Collectively, considering the anticipated pharmacokinetic profiles and toxicity assessments, several of these compounds emerged as promising candidates for further in-depth evaluation.

Influence of habitat features on the colonisation of native and non-indigenous species

Marine artificial structures provide substrates on which organisms can settle and grow. These structures facilitate establishment and spread of non-indigenous species, in part due to their distinct physical features (substrate material, movement, orientation) compared to natural habitat analogues such as rocky shores, and because following construction, they have abundant resources (space) for species to colonise. Despite the perceived importance of these habitat features, few studies have directly compared distributions of native and non-indigenous species or considered how functional identity and associated environmental preferences drive associations. We undertook a meta-analysis to investigate whether colonisation of native and non-indigenous species varies between artificial structures with features most closely resembling natural habitats (natural substrates, fixed structures, surfaces oriented upwards) and those least resembling natural habitats (artificial materials, floating structures, downfacing or vertical surfaces), or whether functional identity is the primary driver of differences. Analyses were done at global and more local (SE Australia) scales to investigate if patterns held regardless of scale. Our results suggest that functional group (i.e., algae, ascidians. barnacles, bryozoans, polychaetes) rather than species classification (i.e., native or non-indigenous) are the main drivers of differences in communities between different types of artificial structures. Specifically, there were differences in the abundance of ascidians, barnacles, and polychaetes between (1) upfacing and downfacing/vertical surfaces, and (2) floating and fixed substrates. When differences were detected, taxa were most abundant on features least resembling natural habitats. Results varied between global and SE Australian analyses, potentially due to reduced variability across studies in the SE Australian dataset. Thus, the functional group and associated preferences of the highest threat NIS in the area should be considered in design strategies (e.g., ecological engineering) to limit their establishment on newly built infrastructure.

Correction to “Synthesis and Insecticidal Activity Evaluation of Potential Insecticidal Natural Product Borrelidin Analogs Toward New Pesticides”

Correction to “Synthesis and Insecticidal Activity Evaluation of Potential Insecticidal Natural Product Borrelidin Analogs Toward New Pesticides”

Predictive coding with spiking neurons and feedforward gist signaling.

Predictive coding (PC) is an influential theory in neuroscience, which suggests the existence of a cortical architecture that is constantly generating and updating predictive representations of sensory inputs. Owing to its hierarchical and generative nature, PC has inspired many computational models of perception in the literature. However, the biological plausibility of existing models has not been sufficiently explored due to their use of artificial neurons that approximate neural activity with firing rates in the continuous time domain and propagate signals synchronously. Therefore, we developed a spiking neural network for predictive coding (SNN-PC), in which neurons communicate using event-driven and asynchronous spikes. Adopting the hierarchical structure and Hebbian learning algorithms from previous PC neural network models, SNN-PC introduces two novel features: (1) a fast feedforward sweep from the input to higher areas, which generates a spatially reduced and abstract representation of input (i.e., a neural code for the gist of a scene) and provides a neurobiological alternative to an arbitrary choice of priors; and (2) a separation of positive and negative error-computing neurons, which counters the biological implausibility of a bi-directional error neuron with a very high baseline firing rate. After training with the MNIST handwritten digit dataset, SNN-PC developed hierarchical internal representations and was able to reconstruct samples it had not seen during training. SNN-PC suggests biologically plausible mechanisms by which the brain may perform perceptual inference and learning in an unsupervised manner. In addition, it may be used in neuromorphic applications that can utilize its energy-efficient, event-driven, local learning, and parallel information processing nature.

Fracture smectites in bedrock at the Kivetty and Romuvaara sites, Finland, as natural analogues for radioactive waste repository buffers

Bentonite is used in various geological repository designs for highly radioactive and low- and intermediate-level waste. Stability of such materials has been evaluated in long-term safety assessments, with recent emphasis on potential chemical erosion of these clays in fresh groundwater conditions. The fracture-filling mineralogy at two investigation sites, Kivetty and Romuvaara, in Finland shows the existence of different types of smectites characterized by their respective dominant elements, such as Mg-, Fe- and Na–Ca-rich smectites. Of these, Ca- and Na-smectites are likely to be montmorillonites that provide potential natural analogues for the bentonite buffers and their long-term performance in fractured bedrock environments. The smectite minerals observed reflect the local parent rock mineral composition, suggesting in situ formation during hydrothermal alteration, well predating the current freshwater conditions in the fractured bedrock. These observations support the stability of smectites, including Na- and Ca-montmorillonites, in the fractured bedrock of glaciated terrain with fresh continental groundwater extending to repository-relevant depths. Further, no erosion or sedimentation processes have been observed to have taken place in the fracture systems studied. However, uncertainties remain related to detailed exchangeable cation compositions of the smectite. Current groundwater systems at both sites would alter the composition of montmorillonite towards the Ca-rich form, and more detailed investigations are required to assess the stability of Na-montmorillonite in connection to open fractures. In general, bentonite alteration in fractures to Ca-montmorillonite would be beneficial in repository scenarios that consider potential chemical erosion by dilute groundwater. Supplementary material: Supplementary material 1 (XCT data for fracture smectite samples from Kivetty and Romuvaara) are available at https://doi.org/10.23729/1ce75faa-d52a-43cd-af40-3961b3081f70 [last accessed 5 July 2023] and Supplementary material 2 (XRD diffractogram data) and Supplementary material 3 (SEM-EDS data) are available at https://doi.org/10.6084/m9.figshare.c.7126477 Thematic collection: This article is part of the Sustainable geological disposal and containment of radioactive waste collection available at: https://www.lyellcollection.org/topic/collections/radioactive

An efficient and concise method to 2-methylmycoleptodiscin A from (−)-sclareol

Natural product analogue 2-methylmycoleptodiscin A has been simply synthesized from commercially available (−)-sclareol in 36 % overall yield. The crucial step was the intramolecular Friedel − Crafts reaction at C-4 of the indole ring using optimized catalyst Eaton's reagent under benign and solvent free reaction conditions.

Natural product inspired diastereoselective synthesis of sugar-derived pyrano[3,2-c]quinolones and their in-silico studies

Herein, we report the development of a diastereoselective and efficient route to construct sugar-derived pyrano[3,2-c]quinolones utilizing 1-C-formyl glycal and 4-hydroxy quinolone annulation. This methodology will open a route to synthesize nature inspired pyrano[3,2-c]quinolones. This is the first report for the stereoselective synthesis of sugar-derived pyrano[3,2-c]quinolones, where 100% stereoselectivity was observed. A total of sixteen compounds have been synthesized in excellent yields with 100% stereoselectivity. The molecular docking of the synthesized novel natural product analogues demonstrated their binding modes within the active site of type II topoisomerase. The results of the in-silico studies displayed more negative binding energies for the all the synthesized compounds in comparison to the natural product huajiosimuline A, indicating their affinity for the active pocket. Ten out of the sixteen novel synthesized compounds were found to have comparative or relatively more negative binding energy in comparison to the standard anti-cancer drug, doxorubicin. Additionally, the scalability and viability of this protocol was illustrated by the gram scale synthesis.

Acceleration of Deep Subsurface Fluid Fluxes in the Anthropocene

AbstractThe Anthropocene has been framed around humanity's impact on atmospheric, biologic, and near‐surface processes, such as land use and vegetation change, greenhouse gas emissions, and the above‐ground hydrologic cycle. Groundwater extraction has lowered water tables in many key aquifers but comparatively little attention has been given to the impacts in the deeper subsurface. Here, we show that fluid fluxes from the extraction and injection of fluids associated with oil and gas production and inflow of water into mines likely exceed background flow rates in deep (&gt;500 m) groundwater systems at a global scale. Projected carbon capture and sequestration (CCS), geothermal energy production, and lithium extraction to facilitate the energy transition will require fluid production rates exceeding current oil and co‐produced water extraction. Natural analogs and geochemical modeling indicate that subsurface fluid manipulation in the Anthropocene will likely appear in the rock record. The magnitude and importance of these changes are unclear, due to a lack of understanding of how deep subsurface hydrologic and geochemical cycles and associated microbial life interact with the rest of the Earth system.

Assessing the performance of a radioactive waste repository over geological timescales: past experience and the way forward

The successful implementation of plans to develop a repository for radioactive waste in the United Kingdom will require an assessment of the ability of the facility to meet appropriate regulatory safety criteria at all stages during its construction, operation and after closure. As part of this assessment, an environmental safety case (ESC) will be presented and this will contain a collection of claims, arguments and evidence which collectively demonstrate that long-term safety can be achieved and maintained. Natural analogues (NA) can be helpful in demonstrating understanding of aspects of repository performance by, for example, providing evidence that certain materials can survive for long periods. Appropriate NAs can be critical to providing long-term practical demonstrations to support the theoretical and mathematical arguments of the ESC and they may have a significant role in the overall process understanding. As part of the ongoing repository development programme in the UK, an updated version of an existing catalogue of NA studies (focussed on the requirements of the ESC) has been produced and the background to NA studies in general, and to the catalogue in particular, are presented here. Thematic collection: This article is part of the Sustainable geological disposal and containment of radioactive waste collection available at: https://www.lyellcollection.org/topic/collections/radioactive

LC-MS/MS analysis of 11-nor-9-carboxy-hexahydrocannabinol (HHC-COOH) and 11-hydroxy-hexahydrocannabinol (HHC-OH) for verification of hexahydrocannabinol (HHC) intake

Natural and semi-synthetic cannabinoid analogs are getting increasing media attention for their recreative use as an alternative to traditional cannabis, in Sweden as well as internationally. To investigate an increasing number of urine samples incoming to our clinical laboratory that were screening positive, using a CEDIA THC-COOH immunoassay from ThermoFisher Scientific, but then testing negative using GC-MS based verification analysis, we developed an LC-MS/MS-method for verification of hexahydrocannabinol (HHC) and Δ8-tetrahydrocannabinol. Assessment of HHC intake was based on identification of the following four metabolites: 11-nor-9(R)-carboxy-hexahydrocannabinol (R-HHC-COOH), 11-nor-9(S)-carboxy-hexahydrocannabinol (S-HHC-COOH), 11-hydroxy-9(R)-hexahydrocannabinol (R-HHC-OH) and 11-hydroxy-9(S)-hexahydrocannabinol (S-HHC-OH). Out of 46 urine samples analysed in this study, 44 showed presence of HHC-metabolites, which indicate HHC as the main explanation for an increased number of negative verifications for THC-COOH. In these samples, the HHC-OH metabolites occurred at a higher concentration than R-HHC-COOH while S-HHC-COOH was only detected in few samples at low concentrations. R-HHC-COOH and S-HHC-COOH can easily be added to a pre-existing verification method for THC-COOH, and still show acceptable results, while HHC-OH requires an enzyme capable of hydrolysing the ether glucuronide bond.

“Nuclear Winter” Hypothesis Research and Responsibilities in Nuclear Policy

In the 1980s, one of the fundamental topics of scientific debate was the discussion of the global consequences of nuclear war. At that time, the hypothesis of “nuclear winter” emerged, in which scientists attempted to analyse the theoretical possibility of a sharp cooling of the Earth after mass fires, and to find natural analogues of a potential climatic catastrophe. In the following decades, the “nuclear winter” hypothesis went through various stages of criticism and reassessment. In the early 2000s, studies of the problem became regional in nature, focusing mainly on the possible consequences of local nuclear conflicts. In this article, the authors analyse the stages of development of research on the “nuclear winter” hypothesis, focusing on the Russian and American approaches, and conclude that the body of work produced by American and Soviet scientists in 1983–1985 represents the first attempts by the scientific community to conceptualise the problem of responsible nuclear policy.

Phosphatidylserine synthase in the endoplasmic reticulum of Toxoplasma is essential for its lytic cycle in human cells

Glycerophospholipids have emerged as a significant contributor to the intracellular growth of pathogenic protist Toxoplasma gondii. Phosphatidylserine (PtdSer) is one such lipid, attributed to the locomotion and motility-dependent invasion and egress events in its acutely infectious tachyzoite stage. However, the de novo synthesis of PtdSer and the importance of the pathway in tachyzoites remain poorly understood. We show that a base-exchange-type PtdSer synthase (PSS) located in the parasite’s endoplasmic reticulum produces PtdSer, which is rapidly converted to phosphatidylethanolamine (PtdEtn) by PtdSer decarboxylase (PSD) activity. The PSS-PSD pathway enables the synthesis of several lipid species, including PtdSer (16:0/18:1) and PtdEtn (18:2/20:4, 18:1/18:2 and 18:2/22:5). The PSS-depleted strain exhibited a lower abundance of the major ester-linked PtdEtn species and concurrent accrual of host-derived ether-PtdEtn species. Most phosphatidylthreonine (PtdThr) species—an exclusive natural analog of PtdSer, also made in the endoplasmic reticulum—were repressed. PtdSer species, however, remained largely unaltered, likely due to the serine-exchange reaction of PtdThr synthase in favor of PtdSer upon PSS depletion. Not least, the loss of PSS abrogated the lytic cycle of tachyzoites, impairing the cell division, motility, and egress. In a nutshell, our data demonstrate a critical role of PSS in the biogenesis of PtdSer and PtdEtn species and its physiologically essential repurposing for the asexual reproduction of a clinically relevant intracellular pathogen.

GSWORD: GPU-accelerated Sampling for Subgraph Counting

Subgraph counting is a fundamental component for many downstream applications such as graph representation learning and query optimization.Since obtaining the exact count is often intractable,there have been a plethora of approximation methods on graph sampling techniques. Nonetheless, the state-of-the-art sampling methods still require massive samples to produce accurate approximations on large data graphs.We propose gSWORD, a GPU framework that leverages the massive parallelism of GPUs to accelerate iterative sampling algorithms for subgraph counting. Despite the embarrassingly parallel nature of the samples, there are unique challenges in accelerating subgraph counting due to its irregular computation logic. To address these challenges, we introduce two GPU-centric optimizations: (1) sample inheritance, enabling threads to inherit samples from neighboring threads to avoid idling, and (2) warp streaming, effectively distributing workloads among threads through a streaming process. Moreover, we propose a CPU-GPU co-processing pipeline that overlaps the sampling and enumeration processes to mitigate the underestimation issue. Experimental results demonstrate that deploying state-of-the-art sampling algorithms on gSWORD can perform millions of samples per second. The co-processing pipeline substantially improves the estimation accuracy in the cases where existing methods encounter severe underestimations with negligible overhead.

AKR1C3 in carcinomas: from multifaceted roles to therapeutic strategies.

Aldo-Keto Reductase Family 1 Member C3 (AKR1C3), also known as type 5 17β-hydroxysteroid dehydrogenase (17β-HSD5) or prostaglandin F (PGF) synthase, functions as a pivotal enzyme in androgen biosynthesis. It catalyzes the conversion of weak androgens, estrone (a weak estrogen), and PGD2 into potent androgens (testosterone and 5α-dihydrotestosterone), 17β-estradiol (a potent estrogen), and 11β-PGF2α, respectively. Elevated levels of AKR1C3 activate androgen receptor (AR) signaling pathway, contributing to tumor recurrence and imparting resistance to cancer therapies. The overexpression of AKR1C3 serves as an oncogenic factor, promoting carcinoma cell proliferation, invasion, and metastasis, and is correlated with unfavorable prognosis and overall survival in carcinoma patients. Inhibiting AKR1C3 has demonstrated potent efficacy in suppressing tumor progression and overcoming treatment resistance. As a result, the development and design of AKR1C3 inhibitors have garnered increasing interest among researchers, with significant progress witnessed in recent years. Novel AKR1C3 inhibitors, including natural products and analogues of existing drugs designed based on their structures and frameworks, continue to be discovered and developed in laboratories worldwide. The AKR1C3 enzyme has emerged as a key player in carcinoma progression and therapeutic resistance, posing challenges in cancer treatment. This review aims to provide a comprehensive analysis of AKR1C3's role in carcinoma development, its implications in therapeutic resistance, and recent advancements in the development of AKR1C3 inhibitors for tumor therapies.

Antimicrobial activity of a natural compound and analogs against multi-drug-resistant Gram-positive pathogens.

The rapid emergence of methicillin-resistant Staphylococcus aureus (MRSA) isolates has precipitated a critical need for novel antibiotics. We have developed a one-pot synthesis method for naturally occurring compounds such as MC21-A (C58) and its chloro-analog, C59. Our findings demonstrate that these compounds kill MRSA isolates at lower or comparable concentrations to standard-of-care (SoC) antimicrobials. C59 eradicates MRSA cells in biofilms, which are notoriously difficult to treat with SoC antibiotics. Additionally, the lack of resistance development observed with C59 treatment is a significant advantage when compared to currently available antibiotics. Furthermore, these compounds are non-toxic to mammalian cell lines at effective concentrations. Our findings indicate the potential of these compounds to treat MRSA infections and underscore the importance of exploring natural products for novel antibiotics. Further investigation will be essential to fully realize the therapeutic potential of these next-generation antimicrobials to address the critical issue of antimicrobial resistance.

Pterostilbene: a potential therapeutic agent for fibrotic diseases.

Fibrosis is a prevailing pathology in chronic diseases and accounts for 45% of deaths in developed countries. This condition is primarily identified by the transformation of fibroblasts into myofibroblasts and the overproduction of extracellular matrix (ECM) by myofibroblasts. Pterostilbene (PTS) is a natural analogue of resveratrol and is most commonly found in blueberries. Research has shown that PTS exerts a wide range of pharmacological effects, such as antioxidant, anti-inflammatory, and anticancer effects. As a result, PTS has the potential to prevent and cure numerous diseases. Emerging evidence has indicated that PTS can alleviate myocardial fibrosis, renal fibrosis, pulmonary fibrosis, hepatic fibrosis, and colon fibrosis via the inhibition of inflammation, oxidative stress, and fibrogenesis effects in vivo and in vitro, and the potential mechanisms are linked to various pathways, including transforming growth factor-β1 (TGF-β1)/small mother against decapentaplegic proteins (Smads) signalling, the reactive oxygen species (ROS)-driven Pitx2c/mir-15b pathway, nuclear factor kappa B (NF-κB) signalling, Kelch-like epichlorohydrin-associated protein-1 (Keap-1)/NF-E2-related factor-2 (Nrf2) cascade, the NLR family pyridine structure domain 3 (NLRP3) pathway, theJanus kinase-2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) pathway,and the Src/STAT3 pathway. In this review, we comprehensively summarize the antifibrotic effects of PTS both in vivo and in vitro and the pharmacological mechanisms, pharmacokinetics, and toxicology of PTS and provide insights into and strategies for exploring promising agents for the treatment of fibrosis.