The Dynamic Role of Endoplasmic Reticulum Stress in Chronic Liver Disease.

Chronic liver disease (CLD) is a major worldwide public health threat, with an estimated prevalence of 1.5 billion individuals with CLD in 2020. Chronic activation of endoplasmic reticulum (ER) stress-related pathways is recognized as substantially contributing to the pathologic progression of CLD. The ER is an intracellular organelle that folds proteins into their correct three-dimensional shapes. ER-associated enzymes and chaperone proteins highly regulate this process. Perturbations in protein folding lead to misfolded or unfolded protein accumulation in the ER lumen, resulting in ER stress and concomitant activation of the unfolded protein response (UPR). The adaptive UPR is a set of signal transduction pathways evolved in mammalian cells that attempts to reestablish ER protein homeostasis by reducing protein load and increasing ER-associated degradation. However, maladaptive UPR responses in CLD occur due to prolonged UPR activation, leading to concomitant inflammation and cell death. This review assesses the current understanding of the cellular and molecular mechanisms that regulate ER stress and the UPR in the progression of various liver diseases and the potential pharmacologic and biological interventions that target the UPR.

Visual Outcomes and Risk of Endophthalmitis in Open Globe Injuries without Intraocular Foreign Bodies with Delayed Repair.

OBJECTIVE: To assess and compare the rate of endophthalmitis and visual outcomes in cases of OGI's without intraocular foreign bodies repaired within and greater than 24 hours from the time of injury. DESIGN: A retrospective review of 2,002 cases of OGI's presenting to a single institution. SUBJECTS, PARTICIPANTS, AND/OR CONTROLS: Patients with OGI's were admitted and managed according to a standardized protocol. METHODS, INTERVENTION, OR TESTING: The impact of timing of repair was assessed between those undergoing OGI repair within (i) 24 hours, (ii) 25-36 hours, and (iii) greater than 36 hours from the time of injury. MAIN OUTCOME AND MEASURE: Rates of endophthalmitis and postoperative visual acuity of logMAR 1.3, logMAR 1.0, and logMAR 0.3 at 180 days and 1 year following open globe repair. RESULTS: 1,382 patients with OGI's were included, of which 75% were male with an average age of 41 years. Maximal zone of injury was zone 1 for 468 patients, zone 2 for 529 patients and zone 3 for 508 patients. 84% of all OGI's underwent repair within 24 hours from the time of injury, 9% from 25-36 hours, and 7% greater than 36 hours. Average preoperative visual acuity was hand motion. Risk factors associated with repair performed greater than 36 hours from the time of injury included female sex (p=0.042). Endophthalmitis was associated with time to repair greater than 36 hours (p=0.049) but not with 25-36 hours or zone of injury (p=0.111). Time to repair had no significant impact on visual acuity outcomes. CONCLUSIONS: Although repair of OGI's within 24 hours is the current standard of care, this study found no statistically significant difference in rates of endophthalmitis or visual outcomes in eyes undergoing repair within 24 hours of injury compared to repair extending to 25 to 36 hours . Endophthalmitis rates did increase after 36 hours. We recommend urgent repair of open globe injuries, but in certain circumstances, it may be reasonable to delay repair beyond 24 hours to optimize operating conditions.

Implementation of anterior segment ophthalmic telemedicine.

PURPOSE OF REVIEW: The growing push to integrate telemedicine into ophthalmic practices requires physicians to have a thorough understanding of ophthalmic telemedicine's applications, limitations, and recent advances in order to provide well tolerated and appropriate clinical care. This review aims to provide an overview of recent advancements in the use of ophthalmic telemedicine for anterior segment eye examinations. RECENT FINDINGS: Virtual care for anterior segment evaluation relies on appropriate technology, novel workflows, and appropriate clinical case selection. Recent advances, particularly in the wake of the COVID-19 pandemic, have highlighted the utility of home-based assessments for visual acuity, external evaluation, tonometry, and refraction. Additionally, innovative workflows incorporating office-based testing into virtual care, termed 'hybrid telemedicine', enable high-quality ophthalmic testing to inform clinical decision-making. SUMMARY: Novel digital tools and workflows enable high-quality anterior segment evaluation and management for select ophthalmic concerns. This review highlights the clinical tools and workflows necessary to enable anterior segment telehealth.

A Novel Ophthalmic Telemedicine Program for Follow-Up of Minor Ophthalmic Emergencies.

Background: Near-term follow-up for minor ophthalmic emergencies is important to ensure positive patient outcomes but can impose logistical challenges for patients and ophthalmology practices. While ophthalmic telemedicine has been used for screening and triage, its feasibility and safety for follow-up care for minor ophthalmic emergencies have not been reported. The objective of this study was to report initial results of a novel virtual emergency department (ED) follow-up clinic. Methods: Retrospective cross-sectional study of patients discharged from the ophthalmic ED who required near-term follow-up and carried diagnoses suitable for virtual evaluation, between December 6, 2021, and June 26, 2022, at a single tertiary eye care center. Main outcome measures included missed appointment rate, time interval between ED encounter and virtual follow-up, clinical diagnoses, and referrals after telemedicine follow-up (including for urgent ambulatory and ED evaluation). Results: A total of 145 virtual visits were scheduled with 99 (68.3%) completed appointments, yielding a no-show rate of 31.7%. Of the completed visits, the mean time interval between ED evaluation and virtual follow-up was 8.3 days (standard deviation ±3.9). Eighty-four (84.9%) visits were video-based and 15 (15.1%) were audio-only. Seventy-nine (94%) had at least one aspect of the ophthalmic examination documented. The most common diagnoses were chalazion (18), conjunctivitis (13), corneal abrasion (12), and encounter after corneal foreign body removal (7). After virtual follow-up, 23 patients (23.2%) had subsequent referrals, and no patients re-presented to the ophthalmic ED. Conclusions: Ophthalmic telemedicine may be a safe and feasible modality for providing timely post-acute near-term follow-up care for patients with appropriate ophthalmic diagnoses.

Outcomes of Zone 3 Open Globe Injuries by Wound Extent: Subcategorization of Zone 3 Injuries Segregates Visual and Anatomic Outcomes.

PURPOSE: Open globe injuries (OGIs) are categorized by zone, with zone 3 (Z3) comprising wounds > 5 mm beyond the limbus. Outcomes of Z3 OGIs are highly heterogeneous. Open globe injuries with far posterior Z3 (pZ3) wounds were hypothesized to have worse visual and anatomic outcomes. DESIGN: Single-center retrospective cohort study. PARTICIPANTS: A total of 258 eyes with Z3 OGIs. METHODS: A retrospective review of Z3 OGIs treated at a tertiary center over 12 years. Wounds ≥ 10 mm posterior to the limbus were defined as pZ3. Outcomes were compared between pZ3 and anterior Z3 (aZ3) eyes. MAIN OUTCOME MEASURES: Visual acuity on a logarithm of the minimum angle of resolution (logMAR) scale. Secondary outcomes included anatomic outcomes, development of retinal detachment and proliferative vitreoretinopathy, and the number of secondary surgeries. RESULTS: A total of 258 Z3 OGI eyes with > 30 days follow-up were assessed; 161 (62%) were pZ3. At 3-month follow-up, pZ3 OGIs were more likely to exhibit no light perception (pZ3: 38%; aZ3: 17%; P < 0.003), lack count fingers vision (pZ3: 72%; aZ3: 43%; P < 0.002), and fail to read a letter on the eye chart (pZ3: 83%; aZ3: 64%; P < 0.001). The visual acuity distribution at 3 months was significantly worse for pZ3 compared with aZ3 injuries (P < 0.004). Similar results were found at final follow-up. Multiple linear regression showed that pZ3 location was independently associated with worse visual acuity (ß = 0.29, 95% confidence interval [CI], 0.09-0.50, P < 0.006) in addition to presenting acuity, age, vitreous hemorrhage, uveal prolapse, and afferent pupillary defect. Far posterior wounds injuries were more likely to develop retinal detachments (pZ3: 87%; aZ3: 71%; P < 0.01) and proliferative vitreoretinopathy (pZ3 66%; aZ3 47%; P < 0.03). Patients with pZ3 OGIs were significantly more likely to reach poor anatomic outcome (phthisis, enucleation, need for keratoprosthesis) compared with patients with aZ3 OGI (pZ3: 56%; aZ3: 40%; P < 0.03). CONCLUSIONS: Posterior OGI extension independently portends worse visual and anatomic outcomes. The effect on visual outcome was durable and clinically relevant compared with established predictors of OGI outcomes. Application of these findings improves the prognostic precision and will guide future research efforts to optimize surgical decision-making in severe OGI cases. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

Early Postoperative Magnetic Resonance Imaging Findings Related to Electrocauterization for Cerebellar Reduction During Chiari Decompression Surgery.

BACKGROUND: Cerebellar tonsillar reduction or resection can be performed as part of the surgical management of Chiari type 1 malformation when it is accompanied by symptomatic brainstem compression or syringomyelia. The purpose of this study is to characterize the early postoperative magnetic resonance imaging (MRI) findings in patients with Chiari type 1 malformations who undergo cerebellar tonsillar reduction via electrocautery. METHODS: The extent of cytotoxic edema and microhemorrhages demonstrated on MRI scans obtained within 9 days following surgery was assessed and correlated with neurological symptoms. RESULTS: Cytotoxic edema was found on all postoperative MRI examinations included in this series, with superimposed hemorrhage in 12 of 16 patients (75%) and was primarily located along the margins of the cauterized inferior cerebellum. Cytotoxic edema was present beyond the margins of the cauterized cerebellar tonsils in 5 of 16 patients (31%) and was associated with new focal neurological deficits in 4 of 5 patients (80%). CONCLUSION: Cytotoxic edema and hemorrhages along the cerebellar tonsil cautery margins can be expected findings in early postoperative MRI in patients who undergo Chiari decompression accompanied by tonsillar reduction. However, the presence of cytotoxic edema beyond these regions can be associated with new focal neurological symptoms.

Optimization and Scale Up of Spray Dried CPZEN-45 Aerosol Powders for Inhaled Tuberculosis Treatment.

PURPOSE: Tuberculosis (TB) remains one of the most serious diseases caused by a single organism. Multiple (MDR) and extensively (XDR) drug resistant disease poses a threat to global health and requires new drugs and/or innovative approaches to treatment. A number of drugs have been proposed as inhaled therapy for TB, frequently prepared by spray drying. CPZEN-45 is a novel anti-tubercular drug that has poor oral bioavailability but has shown promise when administered via inhalation. METHODS: Excipient-free CPZEN-45 HCl has been spray dried into a powder with physicochemical characteristics, aerodynamic particle size distribution, and delivered dose suitable for consideration as an inhaled product. RESULTS: The mass median aerodynamic diameter (MMAD) and geometric standard deviation (GSD) of the powder delivered using a RS01 inhaler were 2.62 ± 0.04 µm and 1.76 ± 0.09, respectively. Additionally, the powder was physically and chemically stable after storage at ambient conditions for >1.5 years with particle size similar to freshly manufactured product. Overages in spray dried powder were recycled the powder and resprayed into drug product likewise resulting in negligible change in quality thus allowing for further preclinical characterization as necessary. CPZEN-45 was scaled up using pilot-scale manufacturing equipment where the density of the powder was increased to facilitate larger delivered doses without affecting the aerodynamic performance properties. CONCLUSION: The spray dried powders were suitable for pharmacokinetics, efficacy and preclinical toxicology studies. The final method of manufacture may be used directly for CGMP particle manufacture to support IND and Phase I clinical trials and beyond.

Private Equity in Ophthalmology and Optometry: Analysis of Acquisitions from 2012 through 2019 in the United States.

PURPOSE: To identify temporal and geographic trends in private equity (PE)-backed acquisitions of ophthalmology and optometry practices in the United States. DESIGN: A cross-sectional study using private equity acquisition and investment data from January 1, 2012, through October 20, 2019. PARTICIPANTS: A total of 228 PE acquisitions of ophthalmology and optometry practices in the United States between 2012 and 2019. METHODS: Acquisition and financial investment data were compiled from 6 financial databases, 4 industry news outlets, and publicly available press releases from PE firms or platform companies. MAIN OUTCOME MEASURES: Yearly trends in ophthalmology and optometry acquisitions, including number of total acquisitions, clinical locations, and providers of acquired practices as well as subsequent sales, median holding period, geographic footprint, and financing status of each platform company. RESULTS: A total of 228 practices associated with 1466 clinical locations and 2146 ophthalmologists or optometrists were acquired by 29 PE-backed platform companies. Of these acquisitions, 127, 9, and 92 were comprehensive or multispecialty, retina, and optometry practices, respectively. Acquisitions increased rapidly between 2012 and 2019: 42 practices were acquired between 2012 and 2016 compared to 186 from 2017 through 2019. Financing rounds of platform companies paralleled temporal acquisition trends. Three platform companies, comprising 60% of platforms formed before 2016, were subsequently sold or recapitalized to new PE investors by the end of this study period with a median holding period of 3.5 years. In terms of geographic distribution, acquisitions occurred in 40 states with most PE firms developing multistate platform companies. New York and California were the 2 states with the greatest number of PE acquisitions with 22 and 19, respectively. CONCLUSIONS: Private equity-backed acquisitions of ophthalmology and optometry practices have increased rapidly since 2012, with some platform companies having already been sold or recapitalized to new investors. Additionally, private equity-backed platform companies have developed both regionally focused and multistate models of add-on acquisitions. Future research should assess the impact of PE investment on patient, provider, and practice metrics, including health outcomes, expenditures, procedural volume, and staff employment.

Association of the Affordable Care Act Medicaid Expansion with Dilated Eye Examinations among the United States Population with Diabetes.

PURPOSE: To evaluate the association between Medicaid expansion and diabetic dilated eye examinations. DESIGN: A retrospective difference in differences (DiD) analysis using individual-level survey response data from January 1, 2009, to December 31, 2017. PARTICIPANTS: A total of 52 392 survey responses from 50 states and the District of Columbia between 2009 and 2017. Responders were adults aged 18 to 64 years reporting a previous diagnosis of diabetes and a household income below 138% of the US federal poverty line (FPL). METHODS: The Centers for Disease Control and Prevention's Behavioral Risk Factor Surveillance System data were used to identify survey responders who were asked about the presence of dilated eye examinations from years before and after Medicaid expansion implementation. MAIN OUTCOME MEASURES: The DiD in proportion of dilated eye examinations among diabetic persons aged 18 to 64 years with household incomes below 138% of the FPL between states that did and did not implement Medicaid expansion. RESULTS: Implementation of Medicaid expansion policies was associated with a 1.3% (95% confidence interval [CI], -3.8 to 6.4; P = 0.61), 6.3% (95% CI, 1.3-11.3; P = 0.016), 4.1% (95% CI, -0.8 to 9.0; P = 0.11), and 2.3% (95% CI, -1.6 to 6.2; P = 0.23) increase in the proportion of diabetic persons aged 18 to 64 years with incomes below 138% of the FPL receiving a dilated eye examination within the past year due to Medicaid expansion 1, 2, 3, and 4 cumulative years after expansion, respectively. CONCLUSIONS: Medicaid expansion policies were significantly associated with an increase in dilated eye examination rates within the first 2 years after implementation. However, this increase did not persist beyond this period, with nonsignificant increases 3 and 4 cumulative years after implementation. Healthcare policymakers should be aware that additional measures beyond expanding insurance coverage may be necessary to increase and sustain the rate of dilated eye examinations among diabetic populations.

Biofabrication of multiscale bone extracellular matrix scaffolds for bone tissue engineering.

Interconnected porosity is critical to the design of regenerative scaffolds, as it permits cell migration, vascularisation and diffusion of nutrients and regulatory molecules inside the scaffold. 3D printing is a promising strategy to achieve this as it allows the control over scaffold pore size, porosity and interconnectivity. Thus, the aim of the present study was to integrate distinct biofabrication strategies to develop a multiscale porous scaffold that was not only mechanically functional at the time of implantation, but also facilitated rapid vascularisation and provided stem cells with appropriate cues to enable their differentiation into osteoblasts. To achieve this, polycaprolactone (PCL) was functionalised with decellularised bone extracellular matrix (ECM), to produce osteoinductive filaments for 3D printing. The addition of bone ECM to the PCL not only increased the mechanical properties of the resulting scaffold, but also increased cellular attachment and enhanced osteogenesis of mesenchymal stem cells (MSCs). In vivo, scaffold pore size determined the level of vascularisation, with a larger filament spacing supporting faster vessel in-growth and more new bone formation. By freeze-drying solubilised bone ECM within these 3D-printed scaffolds, it was possible to introduce a matrix network with microscale porosity that further enhanced cellular attachment in vitro and increased vessel infiltration and overall levels of new bone formation in vivo. To conclude, an "off-the-shelf" multiscale bone-ECM-derived scaffold was developed that was mechanically stable and, once implanted in vivo, will drive vascularisation and, ultimately, lead to bone regeneration.

Remineralization of demineralized dentin using a dual analog system.

OBJECTIVE: Improved methods are needed to remineralize dentin caries in order to promote conservation of dentin tissue and minimize the surgical interventions that are currently required for clinical treatment. Here, we test the hypothesis that bulk substrates can be effectively mineralized via a dual analog system proposed by others, using a tripolyphosphate (TPP) "templating analog" and a poly(acrylic acid) (PAA) or poly(aspartic acid) (pAsp) "sequestration analog," the latter of which generates the polymer-induced liquid-precursor (PILP) mineralization process studied in our laboratory. MATERIAL & METHODS: Demineralized human dentin slices were remineralized with and without pre-treatment with TPP, using either PAA or pAsp as the PILP process-directing agent. A control experiment with no polymer present was used for comparison. RESULTS: No mineralization was observed in any of the PAA groups. In both the pAsp and no polymer groups, TPP inhibited mineralization on the surfaces of the specimens but promoted mineralization within the interiors. Pre-treatment with TPP enhanced overall mineralization of the pAsp group. However, when analysed via TEM, regions with little mineral were still present. CONCLUSION: Poly(acrylic acid) was unable to remineralize demineralized dentin slices under the conditions employed, even when pre-treated with TPP. However, pre-treatment with TPP enhanced overall mineralization of specimens that were PILP-remineralized using pAsp.

Bilateral multiple evanescent white dot syndrome.

PURPOSE: To present a single case of bilateral multiple evanescent white dot syndrome (MEWDS). METHODS: A single case with three months of follow-up using imaging studies including fundus color photography (FP), fluorescein angiography (FA), indocyanine green angiography (ICGA), fundus autofluorescence (FAF), spectral-domain optical coherence tomography (SD-OCT), en face SD-OCT and optical coherence tomography angiography (OCTA) is presented. RESULTS: The patient presented with bilateral MEWDS, ultimately with complete resolution of symptoms. FP revealed foveal granularity and white punctate deep retinal spots, FA found early wreath-like hyperfluorescence, while ICGA showed hypofluorescent dots and spots in the early and late stages. FAF showed areas of hyperautofluorescence. SD-OCT revealed disruption of the ellipsoid zone (EZ) and accumulation of hyperreflective material of variable size and shape. En face SD-OCT demonstrated hyporeflective areas corresponding to areas of EZ disruption as well as hyperreflective dots in the outer nuclear layer. OCTA showed areas of photoreceptor slab black-out corresponding to areas of EZ disruption and light areas of flow void or flow disturbance in the choriocapillaris slab. CONCLUSIONS: This case represents an unusual case of bilateral MEWDS with complete resolution within three months.

Review of Management and Outcomes of Delayed Repair Open Globe Injuries.

The standard of care for open globe injuries is prompt surgical closure, as delay in repair is a reported risk factor for post-traumatic endophthalmitis and is associated with worse visual outcomes. This article serves as a review of the current management and outcomes of open globe injuries repaired greater than 24 hours from the time of injury, specifically evaluating the rates of endophthalmitis in cases with and without intraocular foreign bodies, visual outcomes and rates of primary enucleation or evisceration.

Novel all-arthroscopic biceps tenodesis technique incorporated into rotator cuff repair-two hundred cases with minimum 2-year follow-up.

Background: Biceps tendon pathology is a common source of pain in the shoulder. It is frequently seen in conjunction with symptomatic rotator cuff tears. Biceps tendon management during arthroscopic rotator cuff repairs can be achieved via tenodesis with various techniques or tenotomy. Tenodesis of the biceps generally results in less deformity and reduced exertion-related cramping. However, most techniques require the addition of some type of hardware to provide fixation for the biceps tendon, which adds cost, time, and complexity. This study presents a technique for an all-arthroscopic bicep tenodesis performed in conjunction with a double-row rotator cuff repair, requiring no additional hardware. Methods: This study is a retrospective review of data that were prospectively collected for 200 consecutive patients for whom the procedure was performed. Patients were seen postoperatively at 2 weeks, 6 weeks, 4 months, and 6 months and in addition massive rotator cuff repairs were seen at 8 months. Additionally all patients were contacted at a minimum 2-year follow-up to access for the presence deformity, the American Shoulder and Elbow Surgeons (ASES) score, and SANE score. Descriptive statistics and comparisons to known minimal clinical important differences (MCIDs) for the patient recorded outcome measures were recorded. Results: Two hundred patients were included in the study and 152 responded to the telephone interviews. The mean age of the patients at the time of surgery was 65.3 year old (standard deviation ± 9.1, range of 46-84), and the mean postoperative phone interview was 3.2 years postsurgery (standard deviation of ± 1.0, range of 2-5 years). The average ASES score improved from 52.6 to 94.6, which is 3 times greater than the minimal clinical important difference. The average postoperative SANE score was 94. Seven procedures out of the 200 were labeled as failures due to 1 patient's nonsatisfaction with the procedure and 3 for a Popeye deformity and 3 that had a revision RCR. Discussion: The described method of an arthroscopic biceps tenodesis performed with a rotator cuff repair uses no extra hardware, requires minimal additional operative time, and is clinically effective. At a minimum 2-year follow-up, the all-arthroscopic biceps tenodesis in conjunction with a double-row rotator cuff repair resulted in a marked improvement in their ASES score with a 3.5% failure rate. Conclusion: The all-arthroscopic bicep tenodesis performed in conjunction with a double-row rotator cuff repair demonstrated improved clinical outcome, without requiring any additional hardware to tenodese the biceps, at a minimum 2-year follow-up.

Recovery of Vision in Open Globe Injury Patients with Initial No Light Perception Vision.

PURPOSE: To identify clinical characteristics of injured eyes associated with visual recovery in patients with open globe injuries (OGIs) and presenting with no light perception (NLP) vision. DESIGN: Retrospective chart review. SUBJECTS: All patients presenting to Massachusetts Eye and Ear with OGI and NLP vision from January 1999 to March 2022. METHODS: Manual data extraction to collect patient demographic characteristics, preoperative, intraoperative, and postoperative characteristics of OGI injury, laceration versus rupture, history of intraocular surgery, time from injury to repair, timing of vitrectomy, lensectomy, choroidal drainage, and silicone oil placement, visual acuity (VA) at last follow-up, and subsequent B-scan ultrasound findings of retinal detachment, choroidal hemorrhage, vitreous hemorrhage, and disorganized intraocular contents. Patients with >1 week of follow-up and a documented VA at most recent follow-up were included. Exclusion criteria included age <10 years. Multivariable regression was performed. MAIN OUTCOME MEASURES: Visual acuity recovery defined as light perception or better in patients with OGI and initial NLP vision. RESULTS: One hundred forty-seven eyes with NLP vision after OGI were included. Twenty-five (17%) eyes regained vision at last follow-up. The majority of patients recovered light perception vision (n = 15, 60%) followed by 20/500 or better (n = 5, 20%), hand motions (n = 3, 12%), and counting fingers (n = 2, 8%). Most injuries were zone III (n = 102, 69%) and presented with rupture (n = 127, 86%). The mean time from OGI to surgical repair was 0.85 ± 1.7 days. B-scan was obtained in 104 (71%) cases. Pars plana vitrectomy was performed in 9 eyes (6%) with NLP at time of vitrectomy. Disorganized intraocular contents on B-scan (odd ratio, 0.170; 95% confidence interval, 0.042-0.681; P = 0.012) was the only clinical variable significantly associated with visual recovery, corresponding to a lack of visual improvement. CONCLUSIONS: Recovery of vision in OGI with NLP vision at presentation cannot be predicted based on presenting clinical features. B-scan findings of disorganized intraocular contents after initial OGI repair was the only factor negatively associated with vision recovery in this patient population. Therefore, all eyes presenting with an OGI and NLP vision should undergo primary repair in hopes of subsequent visual recovery. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Therapeutic potential of berberine in attenuating cholestatic liver injury: insights from a PSC mouse model.

BACKGROUND AND AIMS: Primary sclerosing cholangitis (PSC) is a chronic liver disease characterized by progressive biliary inflammation and bile duct injury. Berberine (BBR) is a bioactive isoquinoline alkaloid found in various herbs and has multiple beneficial effects on metabolic and inflammatory diseases, including liver diseases. This study aimed to examine the therapeutic effect of BBR on cholestatic liver injury in a PSC mouse model (Mdr2-/- mice) and elucidate the underlying mechanisms. METHODS: Mdr2-/-mice (12-14 weeks old, both sexes) received either BBR (50 mg/kg) or control solution daily for eight weeks via oral gavage. Histological and serum biochemical analyses were used to assess fibrotic liver injury severity. Total RNAseq and pathway analyses were used to identify the potential signaling pathways modulated by BBR in the liver. The expression levels of key genes involved in regulating hepatic fibrosis, bile duct proliferation, inflammation, and bile acid metabolism were validated by qRT-PCR or Western blot analysis. The bile acid composition and levels in the serum, liver, small intestine, and feces and tissue distribution of BBR were measured by LC-MS/MS. Intestinal inflammation and injury were assessed by gene expression profiling and histological analysis. The impact on the gut microbiome was assessed using 16S rRNA gene sequencing. RESULTS: BBR treatment significantly ameliorated cholestatic liver injury, evidenced by decreased serum levels of AST, ALT, and ALP, and reduced bile duct proliferation and hepatic fibrosis, as shown by H&E, Picro-Sirius Red, and CK19 IHC staining. RNAseq and qRT-PCR analyses indicated a substantial inhibition of fibrotic and inflammatory gene expression. BBR also mitigated ER stress by downregulating Chop, Atf4 and Xbp-1 expression. In addition, BBR modulated bile acid metabolism by altering key gene expressions in the liver and small intestine, resulting in restored bile acid homeostasis characterized by reduced total bile acids in serum, liver, and small intestine and increased fecal excretion. Furthermore, BBR significantly improved intestinal barrier function and reduced bacterial translocation by modulating the gut microbiota. CONCLUSION: BBR effectively attenuates cholestatic liver injury, suggesting its potential as a therapeutic agent for PSC and other cholestatic liver diseases.