Performance of ChatGPT on the Taiwan urology board examination: insights into current strengths and shortcomings.

PURPOSE: To compare ChatGPT-4 and ChatGPT-3.5's performance on Taiwan urology board examination (TUBE), focusing on answer accuracy, explanation consistency, and uncertainty management tactics to minimize score penalties from incorrect responses across 12 urology domains. METHODS: 450 multiple-choice questions from TUBE(2020-2022) were presented to two models. Three urologists assessed correctness and consistency of each response. Accuracy quantifies correct answers; consistency assesses logic and coherence in explanations out of total responses, alongside a penalty reduction experiment with prompt variations. Univariate logistic regression was applied for subgroup comparison. RESULTS: ChatGPT-4 showed strengths in urology, achieved an overall accuracy of 57.8%, with annual accuracies of 64.7% (2020), 58.0% (2021), and 50.7% (2022), significantly surpassing ChatGPT-3.5 (33.8%, OR = 2.68, 95% CI [2.05-3.52]). It could have passed the TUBE written exams if solely based on accuracy but failed in the final score due to penalties. ChatGPT-4 displayed a declining accuracy trend over time. Variability in accuracy across 12 urological domains was noted, with more frequently updated knowledge domains showing lower accuracy (53.2% vs. 62.2%, OR = 0.69, p = 0.05). A high consistency rate of 91.6% in explanations across all domains indicates reliable delivery of coherent and logical information. The simple prompt outperformed strategy-based prompts in accuracy (60% vs. 40%, p = 0.016), highlighting ChatGPT's limitations in its inability to accurately self-assess uncertainty and a tendency towards overconfidence, which may hinder medical decision-making. CONCLUSIONS: ChatGPT-4's high accuracy and consistent explanations in urology board examination demonstrate its potential in medical information processing. However, its limitations in self-assessment and overconfidence necessitate caution in its application, especially for inexperienced users. These insights call for ongoing advancements of urology-specific AI tools.

Discovery of Oxidized p-Terphenyls as Phosphodiesterase 4 Inhibitors from Marine-Derived Fungi.

Four new p-terphenyl derivatives, talaroterphenyls A-D (1-4), together with three biosynthetically related known ones (5-7), were obtained from the mangrove sediment-derived Talaromyces sp. SCSIO 41412. Compounds 1-3 are rare p-terphenyls, which are completely substituted on the central benzene ring by oxygen atoms; this is the first report of their isolation from natural sources. Their structures were elucidated through NMR spectroscopy, HRESIMS, and X-ray diffraction. Genome sequence analysis revealed that 1-7 were biosynthesized from tyrosine and phenylalanine, involving four key biosynthetic genes (ttpB-ttpE). These p-terphenyls (1-7) and 36 marine-derived terphenyl analogues (8-43) were screened for phosphodiesterase 4 (PDE4) inhibitory activities, and 1-5, 14, 17, 23, and 26 showed notable activities with IC50 values of 0.40-16 µM. The binding pattern of p-terphenyl inhibitors 1-3 with PDE4 were explored by molecular docking analysis. Talaroterphenyl A (1), with a low cytotoxicity, showed obvious anti-inflammatory activity in LPS-stimulated RAW264.7 cells. Furthermore, in the TGF-ß1-induced medical research council cell strain-5 (MRC-5) pulmonary fibrosis model, 1 could down-regulate the expression levels of FN1, COL1, and α-SMA significantly at concentrations of 5-20 µM. This study suggests that the oxidized p-terphenyl 1, as a marine-derived PDE4 inhibitor, could be used as a promising antifibrotic agent.

Structural optimization of Moracin M as novel selective phosphodiesterase 4 inhibitors for the treatment of idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and high mortality lung disease. Although the antifibrotic drugs pirfenidone and nintedanib could slow the rate of lung function decline, the usual course of the condition is inexorably to respiratory failure and death. Therefore, new approaches and novel therapeutic drugs for the treatment of IPF are urgently needed. And the selective PDE4 inhibitor has in vivo and in vitro anti-fibrotic effects in IPF models. But the clinical application of most PDE4 inhibitors are limited by their unexpected and severe side effects such as nausea, vomiting, and diarrhea. Herein, structure-based optimizations of the natural product Moracin M resulted in a novel a novel series of 2-arylbenzofurans as potent PDE4 inhibitors. The most potent inhibitor L13 has an IC50 of 36 ± 7 nM with remarkable selectivity across the PDE families and administration of L13·citrate (10.0 mg/kg) exhibited comparable anti-pulmonary fibrosis effects to pirfenidone (300 mg/kg) in a bleomycin-induced IPF mice model, indicate that L13 is a potential lead for the treatment of IPF.

Bioactive Polyketides and Benzene Derivatives from Two Mangrove Sediment-Derived Fungi in the Beibu Gulf.

To discover bioactive natural products from mangrove sediment-derived microbes, a chemical investigation of the two Beibu Gulf-derived fungi strains, Talaromyces sp. SCSIO 41050 and Penicillium sp. SCSIO 41411, led to the isolation of 23 natural products. Five of them were identified as new ones, including two polyketide derivatives with unusual acid anhydride moieties named cordyanhydride A ethyl ester (1) and maleicanhydridane (4), and three hydroxyphenylacetic acid derivatives named stachylines H-J (10-12). Their structures were determined by detailed nuclear magnetic resonance (NMR) and mass spectroscopic (MS) analyses, while the absolute configurations were established by theoretical electronic circular dichroism (ECD) calculation. A variety of bioactive screens revealed three polyketide derivatives (1-3) with obvious antifungal activities, and 4 displayed moderate cytotoxicity against cell lines A549 and WPMY-1. Compounds 1 and 6 at 10 µM exhibited obvious inhibition against phosphodiesterase 4 (PDE4) with inhibitory ratios of 49.7% and 39.6%, respectively, while 5, 10, and 11 showed the potential of inhibiting acetylcholinesterase (AChE) by an enzyme activity test, as well as in silico docking analysis.

Identify potent SARS-CoV-2 main protease inhibitors via accelerated free energy perturbation-based virtual screening of existing drugs.

The COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a global crisis. There is no therapeutic treatment specific for COVID-19. It is highly desirable to identify potential antiviral agents against SARS-CoV-2 from existing drugs available for other diseases and thus repurpose them for treatment of COVID-19. In general, a drug repurposing effort for treatment of a new disease, such as COVID-19, usually starts from a virtual screening of existing drugs, followed by experimental validation, but the actual hit rate is generally rather low with traditional computational methods. Here we report a virtual screening approach with accelerated free energy perturbation-based absolute binding free energy (FEP-ABFE) predictions and its use in identifying drugs targeting SARS-CoV-2 main protease (Mpro). The accurate FEP-ABFE predictions were based on the use of a restraint energy distribution (RED) function, making the practical FEP-ABFE-based virtual screening of the existing drug library possible. As a result, out of 25 drugs predicted, 15 were confirmed as potent inhibitors of SARS-CoV-2 Mpro The most potent one is dipyridamole (inhibitory constant Ki = 0.04 µM) which has shown promising therapeutic effects in subsequently conducted clinical studies for treatment of patients with COVID-19. Additionally, hydroxychloroquine (Ki = 0.36 µM) and chloroquine (Ki = 0.56 µM) were also found to potently inhibit SARS-CoV-2 Mpro We anticipate that the FEP-ABFE prediction-based virtual screening approach will be useful in many other drug repurposing or discovery efforts.

Finite element analysis after rod fracture of the spinal hybrid elastic rod system.

BACKGROUND: The spinal hybrid elastic (SHE) rod dynamic stabilization system can provide sufficient spine support and less adjacent segment stress. This study aimed to investigate the biomechanical effects after the internal fracture of SHE rods using finite element analysis. METHODS: A three-dimensional nonlinear finite element model was developed. The SHE rod comprises an inner nitinol stick (NS) and an outer polycarbonate urethane (PCU) shell (PS). The fracture was set at the caudal third portion of the NS, where the maximum stress occurred. The resultant intervertebral range of motion (ROM), intervertebral disc stress, facet joint contact force, screw stress, NS stress, and PCU stress were analyzed. RESULTS: When compared with the intact spine model, the overall trend was that the ROM, intervertebral disc stress, and facet joint force decreased in the implanted level and increased in the adjacent level. When compared with the Ns-I, the trend in the Ns-F decreased and remained nearly half effect. Except for torsion, the PS stress of the Ns-F increased because of the sharing of NS stress after the NS fracture. CONCLUSIONS: The study concluded the biomechanical effects still afford nearly sufficient spine support and gentle adjacent segment stress after rod fracture in a worst-case scenario of the thinnest PS of the SHE rod system.

Varifocal Metalens for Optical Sectioning Fluorescence Microscopy.

Fluorescence microscopy with optical sectioning capabilities is extensively utilized in biological research to obtain three-dimensional structural images of volumetric samples. Tunable lenses have been applied in microscopy for axial scanning to acquire multiplane images. However, images acquired by conventional tunable lenses suffer from spherical aberration and distortions. Here, we design, fabricate, and implement a dielectric Moiré metalens for fluorescence imaging. The Moiré metalens consists of two complementary phase metasurfaces, with variable focal length, ranging from ∼10 to ∼125 mm at 532 nm by tuning mutual angles. In addition, a telecentric configuration using the Moiré metalens is designed for high-contrast multiplane fluorescence imaging. The performance of our system is evaluated by optically sectioned images obtained from HiLo illumination of fluorescently labeled beads, as well as ex vivo mice intestine tissue samples. The compact design of the varifocal metalens may find important applications in fluorescence microscopy and endoscopy for clinical purposes.

Therapeutic targets and potential agents for the treatment of COVID-19.

The outbreak of coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, has become a global crisis. As of November 9, COVID-19 has already spread to more than 190 countries with 50,000,000 infections and 1,250,000 deaths. Effective therapeutics and drugs are in high demand. The structure of SARS-CoV-2 is highly conserved with those of SARS-CoV and Middle East respiratory syndrome-CoV. Enzymes, including RdRp, Mpro /3CLpro , and PLpro , which play important roles in viral transcription and replication, have been regarded as key targets for therapies against coronaviruses, including SARS-CoV-2. The identification of readily available drugs for repositioning in COVID-19 therapy is a relatively rapid approach for clinical treatment, and a series of approved or candidate drugs have been proven to be efficient against COVID-19 in preclinical or clinical studies. This review summarizes recent progress in the development of drugs against SARS-CoV-2 and the targets involved.

Simultaneous multi-color optical sectioning fluorescence microscopy with wavelength-coded volume holographic gratings.

Optical sectioning fluorescence microscopy provides high contrast images of volumetric samples and has been widely used for many biological applications. However, simultaneously acquiring multi-color fluorescence images require additional optical elements and devices, which are bulky, wavelength specific, and not cost-effective. In this paper, wavelength-coded volume holographic gratings (WC-VHGs) based optical sectioning fluorescence microscopy is proposed to simultaneously offer multi-color fluorescence images with fine out-of-focus background rejection. Due to wavelength degeneracy, multiplexed WC-VHGs are capable of acquiring multi-wavelength fluorescence images in a single shot, and displaying the laterally separated multi-wavelength images onto CCD. In our system optical sectioning capability is achieved through speckle illumination and HiLo imaging method. To demonstrate imaging characteristics of our system, dual-wavelength fluorescence images of both standard fluorescent microspheres and ex vivo mT/mG mice cardiac tissue are presented. Current results may find important applications in hyperspectral imaging for biomedical research.

The use of micro-needle arrays to deliver cells for cellular therapies.

Cell therapy is used to treat various diseases and to repair injuries. Cell delivery is a crucial process that delivers cells to target sites. Cells must be precisely delivered to a target site and the cells that are delivered must be localized to the target site to repair damaged tissue. For stem cell therapy, the most convenient method of cell delivery involves directly injecting cells into damaged tissue. Other strategies use carriers to transplant stem cells into damaged tissue. These are termed, stem cell delivery systems (SCDSs). Micro-needle arrays are minimally invasive transdermal delivery systems. The devices can pass through the stratum corneum barrier and deliver macromolecules into the skin. They can also access the microcirculation system in the skin. This study fabricates PMMA micro-needle using a two-stage micro-molding method. Cells are seeded on the micro-needle arrays and then transferred into the target tissue. Collagen hydrogel is used as a model biomimetic tissue. Cells are efficiently delivered to regions of interest, collagen hydrogel, by using this system. The delivery rate is about 83.2%. This demonstrates that micro-needle arrays allow very efficient delivery of cells.

In vivo imaging of insulin-secreting human pancreatic ductal cells using MRI reporter gene technique: A feasibility study.

PURPOSE: The purpose of this study was to investigate the feasibility of in vivo imaging of human pancreatic ductal cells by OATP1B3 reporter gene under MRI. METHODS: A human cell line (PANC-1) derived from the pancreatic ductal epithelium was used in this study. After transduction of OATP1B3, the cellular physiological functions and the ability of intracellular uptake of the MRI contrast medium (Gd-EOB-DTPA) were examined. Induced differentiation of the PANC-1 cells into hormone-secreting cells were performed to simulate pancreatic ß-like cells. The hormone-secreting cells were implanted into rats and in vivo MRI was evaluated. RESULTS: The mRNA and proteins of OATP1B3 were highly expressed. No significant change of cellular physiological functions was found after the expression. After induced differentiation, the hormone secretion capacities of the OATP1B3-expressing PANC-1 cells were confirmed. Intra-cellular uptake of Gd-EOB-DTPA was determined in vitro by inductively coupled plasma mass spectrometry and MRI. In vivo MRI of the OATP1B3-expressing xenograft revealed an increased signal intensity after contrast enhancement. CONCLUSION: OATP1B3 can be used as a safe and feasible in vivo MRI gene reporter for human pancreatic ductal cells.

Multi-wavelength quantitative differential phase contrast imaging by radially asymmetric illumination.

A new approach for achieving isotropic differential phase contrast imaging by applying multi-wavelength asymmetric illumination is demonstrated. Multi-wavelength isotropic differential phase contrast scheme (MW-iDPC) can be implemented using an add-on module in any commercial inverted microscope. Isotropy of intensity transfer function is achieved using three axis measurements. The expression for MW-iDPC imaging is presented, and detailed mathematical analysis is performed for transfer function. By applying color leakage correction, image sensor responses can be calibrated. Asymmetric illumination masks are designed, and simulation studies for intensity of the transfer function are performed. We utilize the MW-iDPC system to reconstruct quantitative phase images of standard microspheres and live breast cancer cells. The optical thickness of cells can be measured with high accuracy and image acquisition time is reduced significantly.

Organic anion-transporting polypeptide 1B3 as a dual reporter gene for fluorescence and magnetic resonance imaging.

Reporter proteins have broad applications in visualizing molecular events at the cellular, tissue and whole-body levels. Transmembrane transporters recognizing specific molecular domains are of particular interest because they enable the migration of signal-source molecules from the extracellular space to the cytoplasm for subsequent application in multimodality imaging. Organic anion-transporting polypeptides (OATPs) have demonstrated their MRI reporter efficacy. We further expanded their use as a dual-modality reporter in MRI and noninvasive in vivo imaging system (IVIS). We overexpressed OATP1B3 in the HT-1080 sarcoma cell line. Both Gd-EOB-DTPA, an MRI contrast agent, and indocyanine green (ICG), a near-infrared fluorescent dye that provides better deep-tissue detection because of its long wavelength, could be delivered to the intracellular space and imaged in a tumor-bearing nude mouse model. Our in vivo dual-imaging reporter system achieved high sensitivity in MRI and observation periods lasting as long as 96 h in IVIS. Because of the superior temporal and spatial resolutions and the clinical availability of both ICG and Gd-EOB-DTPA, this dual-imaging OATP1B3 system will find biomedical use in tumor biology, stem cell trafficking, and tissue engineering.-Wu, M.-R., Liu, H.-M., Lu, C.-W., Shen, W.-H., Lin, I.-J., Liao, L.-W., Huang, Y.-Y., Shieh, M.-J., Hsiao, J.-K. Organic anion-transporting polypeptide 1B3 as a dual reporter gene for fluorescence and magnetic resonance imaging.

Use of Indocyanine Green (ICG), a Medical Near Infrared Dye, for Enhanced Fluorescent Imaging-Comparison of Organic Anion Transporting Polypeptide 1B3 (OATP1B3) and Sodium-Taurocholate Cotransporting Polypeptide (NTCP) Reporter Genes.

Molecular and cellular imaging in living organisms have ushered in an era of comprehensive understanding of intracellular and intercellular events. Currently, more efforts have been focused on the infrared fluorescent dyes that facilitate deeper tissue visualization. Both sodium taurocholate cotransporting polypeptide (NTCP) and organic-anion-transporting polypeptide 1B3 (OATP1B3) are capable of carrying indocyanine green (ICG) into the cytoplasm. We compared the feasibility of NTCP and OATP1B3 as reporter genes in combination with ICG. NTCP and OATP1B3 were transduced into HT-29 cells. Genetically modified HT-29 cells were inoculated into nude mice. ICG was administered in vitro and in vivo and the signals were observed under confocal microscopy, flow cytometry, multimode microplate reader, and an in vivo imaging system. Both NTCP- and OATP1B3-expressing cells and xenografts had higher ICG intensities. The OATP1B3-expressing xenograft has a higher ICG uptake than the NTCP-expressing xenograft. NTCP or OATP1B3 combined with ICG could serve as a noninvasive imaging modality for molecular and cellular imaging. OATP1B3 outperforms NTCP in terms of in vivo imaging.

Leading Comorbidity associated with 30-day post-anesthetic mortality in geriatric surgical patients in Taiwan: a retrospective study from the health insurance data.

BACKGROUND: Elderly patients with aged physical status and increased underlying disease suffered from more postoperative complication and mortality. We design this retrospective cohort study to investigate the relationship between existing comorbidity of elder patients and 30 day post-anesthetic mortality by using International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM) from Health Insurance Database. METHODS: Patients aged above 65 years old who received anesthesia between 2000 and 2010 were included from 1 million Longitudinal Health Insurance Database in (LHID) 2005 in Taiwan. We use age, sex, type of surgery to calculate propensity score and match death group and survival one with 1:4 ratio (death: survival = 1401: 5823). Multivariate logistic model with stepwise variable selection was employed to investigate the factors affecting death 30 days after anesthesia. RESULTS: Thirty seven comorbidities can independently predict the post-anesthetic mortality. In our study, the leading comorbidities predict post-anesthetic mortality is chronic renal disease (OR = 2.806), acute myocardial infarction (OR = 4.58), and intracranial hemorrhage (OR = 3.758). CONCLUSIONS: In this study, we present the leading comorbidity contributing to the postoperative mortality in elderly patients in Taiwan from National Health Insurance Database. Chronic renal failure is the leading contributing comorbidity of 30 days mortality after anesthesia in Taiwan which can be explained by the great number of hemodialysis and prolong life span under National Taiwan Health Insurance. Large scale database can offer enormous information which can help to improve quality of medical care.

Optimized decellularization protocol including α-Gal epitope reduction for fabrication of an acellular porcine annulus fibrosus scaffold.

Recent advances in tissue engineering have led to potential new strategies, especially decellularization protocols from natural tissues, for the repair, replacement, and regeneration of intervertebral discs. This study aimed to validate our previously reported method for the decellularization of annulus fibrosus (AF) tissue and to quantify potentially antigenic α-Gal epitopes in the decellularized tissue. Porcine AF tissue was decellularized using different freeze-thaw temperatures, chemical detergents, and incubation times in order to determine the optimal method for cell removal. The integrity of the decellularized material was determined using biochemical and mechanical tests. The α-Gal epitope was quantified before and after decellularization. Decellularization with freeze-thaw in liquid nitrogen, an ionic detergent (0.1% SDS), and a 24 h incubation period yielded the greatest retention of GAG and collagen relative to DNA reduction when tested as single variables. Combined, these optimal decellularization conditions preserved more GAG while removing the same amount of DNA as the conditions used in our previous study. Components and biomechanical properties of the AF matrix were retained. The decellularized AF scaffold exhibited suitable immune-compatibility, as evidenced by successful in vivo remodeling and a decrease in the α-Gal epitope. Our study defined the optimal conditions for decellularization of porcine AF tissues while preserving the biological composition and mechanical properties of the scaffold. Under these conditions, immunocompatibility was evidenced by successful in vivo remodeling and reduction of the α-Gal epitope in the decellularized material. Decellularized AF scaffolds are potential candidates for clinical applications in spinal surgery.

Treatment of critically sized femoral defects with recombinant BMP-2 delivered by a modified mPEG-PLGA biodegradable thermosensitive hydrogel.

BACKGROUND: Reconstruction of a segmental fracture with massive bone loss is still a challenge for orthopaedic surgeons. The aim of our study was to develop a suitable biodegradable thermosensitive hydrogel system as a carrier for bone morphogenetic protein (BMP)-2 delivery in the treatment of critical-sized femoral defects. METHODS: A block copolymer composed of monomethoxypoly(ethylene glycol) (mPEG), poly(lactic-co-glycolic acid) (PLGA) and 2, 2'-Bis (2-oxazolin) (Box) was synthesized by ring opening polymerization. The synthesized block copolymer was characterized by (1)H-NMR spectroscopy and gel permeation chromatography (GPC). Different biophysical and biochemical properties of the synthesized copolymer, including temperature-induced structure changes, degradation rate, pH changes during hydrolytic degradation, cell toxicity, and the release profile of BMP-2, were also evaluated and/or were compared with those of a well-characterized mPEG-PLGA copolymer. In animal testing, rabbits (n = 36) that received critically sized (10 mm) femoral defects were divided into 6 groups. These experimental groups included an untreated group, autograft, and groups treated with the synthesized copolymer carrying different concentrations of BMP-2 (0, 5, 10, and 20 µg/ml). Bone repair was evaluated using X-ray radiography, histological staining, micro-computed tomography (µCT), biomarker examination and biomechanical testing in a 12-week treatment period. RESULTS: A new thermosensitive mPEG-PLGA/Box/mPEG-PLGA block copolymer, or named as BOX copolymer, was successfully prepared. Compared to the reported mPEG-PLGA in vitro, the prepared BOX copolymer at the same weight percent concentrations exhibited wider temperature ranges of gelation, slower degradation rates, higher the pH values, as well as less cytotoxicity. Furthermore, the BMP-2 release from BOX hydrogel exhibited a near-linear release profile in vitro. In animal experiments, treatment of critical-sized bony defects with 25 wt% BOX hydrogel carrying BMP-2 effectively promoted fracture healing during the 12-week trial period and higher concentrations of BMP-2 treatment correlated with better bone quality. Most importantly, clinical outcome and bone healing in the BOX-hydrogel group with 20 µg/ml BMP-2 were nearly equivalent to those in the autograft group in a 12-week treatment course. CONCLUSION: These data support that the use of BOX hydrogel (25 wt%) as a drug delivery system is a promising method in the treatment of large bone defects.

Prenylated coumarins: natural phosphodiesterase-4 inhibitors from Toddalia asiatica.

Bioassay-guided fractionation of the ethanolic extract of the roots of Toddalia asiatica led to the isolation of seven new prenylated coumarins (1-7) and 14 known analogues (8-21). The structures of 1-7 were elucidated by spectroscopic analysis, and their absolute configurations were determined by combined chemical methods and chiral separation analysis. Compounds 1-5, named toddalin A, 3‴-O-demethyltoddalin A, and toddalins B-D, represent an unusual group of phenylpropenoic acid-coupled prenylated coumarins. Compounds 1-21 and four modified analogues, 10a, 11a, 13a, and 17a, were screened by using tritium-labeled adenosine 3',5'-cyclic monophosphate ([3H]-cAMP) as substrate for their inhibitory activity against phosphodiesterase-4 (PDE4), which is a drug target for the treatment of asthma and chronic obstructive pulmonary disease. Compounds 3, 8, 10, 10a, 11, 11a, 12, 13, 17, and 21 exhibited inhibition with IC50 values less than 10 µM. Toddacoumalone (8), the most active compound (IC50=0.14 µM), was more active than the positive control, rolipram (IC50=0.59 µM). In addition, the structure-activity relationship and possible inhibitory mechanism of the active compounds are also discussed.

Design, Synthesis, and Evaluation of Dihydropyrimidine Derivatives as Selective PDE1 Inhibitors for the Treatment of Liver Fibrosis.

Liver fibrosis is a common pathological feature of most chronic liver diseases with no effective drugs available. Phosphodiesterase 1 (PDE1), a subfamily of the PDE super enzyme, might work as a potent target for liver fibrosis by regulating the concentration of cAMP and cGMP. However, there are few PDE1 selective inhibitors, and none has been investigated for liver fibrosis treatment yet. Herein, compound AG-205/1186117 with the dihydropyrimidine scaffold was selected as the hit by virtual screening. A hit-to-lead structural modification led to a series of dihydropyrimidine derivatives. Lead 13h exhibited the IC50 of 10 nM against PDE1, high selectivity over other PDEs, as well as good safety properties. Administration of 13h exerted significant anti-liver fibrotic effects in bile duct ligation-induced fibrosis rats, which also prevented TGF-ß-induced myofibroblast differentiation in vitro, confirming that PDE1 could work as a potential target for liver fibrosis.