Enhancer Reprogramming Promotes Pancreatic Cancer Metastasis.

Pancreatic ductal adenocarcinoma (PDA) is one of the most lethal human malignancies, owing in part to its propensity for metastasis. Here, we used an organoid culture system to investigate how transcription and the enhancer landscape become altered during discrete stages of disease progression in a PDA mouse model. This approach revealed that the metastatic transition is accompanied by massive and recurrent alterations in enhancer activity. We implicate the pioneer factor FOXA1 as a driver of enhancer activation in this system, a mechanism that renders PDA cells more invasive and less anchorage-dependent for growth in vitro, as well as more metastatic in vivo. In this context, FOXA1-dependent enhancer reprogramming activates a transcriptional program of embryonic foregut endoderm. Collectively, our study implicates enhancer reprogramming, FOXA1 upregulation, and a retrograde developmental transition in PDA metastasis.

NRF2 Promotes Tumor Maintenance by Modulating mRNA Translation in Pancreatic Cancer.

Pancreatic cancer is a deadly malignancy that lacks effective therapeutics. We previously reported that oncogenic Kras induced the redox master regulator Nfe2l2/Nrf2 to stimulate pancreatic and lung cancer initiation. Here, we show that NRF2 is necessary to maintain pancreatic cancer proliferation by regulating mRNA translation. Specifically, loss of NRF2 led to defects in autocrine epidermal growth factor receptor (EGFR) signaling and oxidation of specific translational regulatory proteins, resulting in impaired cap-dependent and cap-independent mRNA translation in pancreatic cancer cells. Combined targeting of the EGFR effector AKT and the glutathione antioxidant pathway mimicked Nrf2 ablation to potently inhibit pancreatic cancer ex vivo and in vivo, representing a promising synthetic lethal strategy for treating the disease.

Systematic review of fatigue severity in ME/CFS patients: insights from randomized controlled trials.

BACKGROUND: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a debilitating illness medically unexplained, affecting approximately 1% of the global population. Due to the subjective complaint, assessing the exact severity of fatigue is a clinical challenge, thus, this study aimed to produce comprehensive features of fatigue severity in ME/CFS patients. METHODS: We systematically extracted the data for fatigue levels of participants in randomized controlled trials (RCTs) targeting ME/CFS from PubMed, Cochrane Library, Web of Science, and CINAHL throughout January 31, 2024. We normalized each different measurement to a maximum 100-point scale and performed a meta-analysis to assess fatigue severity by subgroups of age, fatigue domain, intervention, case definition, and assessment tool, respectively. RESULTS: Among the total of 497 relevant studies, 60 RCTs finally met our eligibility criteria, which included a total of 7088 ME/CFS patients (males 1815, females 4532, and no information 741). The fatigue severity of the whole 7,088 patients was 77.9 (95% CI 74.7-81.0), showing 77.7 (95% CI 74.3-81.0) from 54 RCTs in 6,706 adults and 79.6 (95% CI 69.8-89.3) from 6 RCTs in 382 adolescents. Regarding the domain of fatigue, 'cognitive' (74.2, 95% CI 65.4-83.0) and 'physical' fatigue (74.3, 95% CI 68.3-80.3) were a little higher than 'mental' fatigue (70.1, 95% CI 64.4-75.8). The ME/CFS participants for non-pharmacological intervention (79.1, 95% CI 75.2-83.0) showed a higher fatigue level than those for pharmacological intervention (75.5, 95% CI 70.0-81.0). The fatigue levels of ME/CFS patients varied according to diagnostic criteria and assessment tools adapted in RCTs, likely from 54.2 by ICC (International Consensus Criteria) to 83.6 by Canadian criteria and 54.2 by MFS (Mental Fatigue Scale) to 88.6 by CIS (Checklist Individual Strength), respectively. CONCLUSIONS: This systematic review firstly produced comprehensive features of fatigue severity in patients with ME/CFS. Our data will provide insights for clinicians in diagnosis, therapeutic assessment, and patient management, as well as for researchers in fatigue-related investigations.

Determination of the Combined Effects of Asian Herbal Medicine with Calcium and/or Vitamin D Supplements on Bone Mineral Density in Primary Osteoporosis: A Systematic Review and Meta-Analysis.

Our review of 52 RCTs from 5 databases suggests a tendency for notable improvement in BMD when combining herbal medicine with supplements (calcium and vitamin D variants) compared to supplement monotherapy in primary osteoporosis. However, caution is needed in interpreting results due to substantial heterogeneity among included studies. PURPOSE: To conduct a systematic review and meta-analysis to determine whether herbal medicine (HM) plus supplements such as calcium (Ca) or vitamin D (Vit.D) improves bone mineral density (BMD) compared to supplements alone in primary osteoporosis (OP) patients. METHODS: We searched 5 databases for randomized controlled trials (RCTs) using HMs with supplements (Ca or Vit.D variants) as interventions for primary OP patients published until August 31, 2022. Meta-analysis using BMD score as the primary outcome was performed using RevMan 5.4 version. Risk of bias in the included studies was assessed useing RoB 2.0 tool. RESULTS: In total, 52 RCTs involving 4,889 participants (1,408 men, 3,481 women) were included, with average BMD scores of 0.690 ± 0.095 g/cm2 (lumbar) and 0.625 ± 0.090 g/cm2 (femoral neck). As a result of performing meta-analysis using BMD scores for all 52 RCTs included in this review, combination of HMs with Ca and Vit.D variants improved the BMD score by 0.08 g/cm2 (lumbar, 38 RCTs, 95% CI: 0.06-0.10, p < 0.001, I2 = 97%) and 0.06 g/cm2 (femoral neck, 19 RCTs, 95% CI: 0.04-0.08, p < 0.001, I2 = 92%)compared to controls. However, statistical significance of the lumbar BMD improvement disappeared after adjusting for potential publication bias. CONCLUSION: Our data suggest that combining of HM and supplements tends to be more effective in improving BMD in primary OP than supplements alone. However, caution is needed in interpretation due to the reporting bias and high heterogeneity among studies, and well-designed RCTs are required in the future.

Injectable Peptide Hydrogels Loaded with Murine Embryonic Stem Cells Relieve Ischemia In Vivo after Myocardial Infarction.

Myocardial infarction (MI) is a major cause of morbidity and mortality worldwide, especially in aging and metabolically unhealthy populations. A major target of regenerative tissue engineering is the restoration of viable cardiomyocytes to preserve cardiac function and circumvent the progression to heart failure post-MI. Amelioration of ischemia is a crucial component of such restorative strategies. Angiogenic ß-sheet peptides can self-assemble into thixotropic nanofibrous hydrogels. These syringe aspiratable cytocompatible gels were loaded with stem cells and showed excellent cytocompatibility and minimal impact on the storage and loss moduli of hydrogels. Gels with and without cells were delivered into the myocardium of a mouse MI model (LAD ligation). Cardiac function and tissue remodeling were evaluated up to 4 weeks in vivo. Injectable peptide hydrogels synergized with loaded murine embryonic stem cells to demonstrate enhanced survival after intracardiac delivery during the acute phase post-MI, especially at 7 days. This approach shows promise for post-MI treatment and potentially functional cardiac tissue regeneration and warrants large-scale animal testing prior to clinical translation.

The effects of long-pulsed alexandrite laser therapy on facial redness and skin microbiota compositions in rosacea: A prospective, multicentre, single-arm clinical trial.

BACKGROUND: Rosacea is a chronic skin disorder characterised by abnormal neurovasculature and inflammation in the central region of the face. The efficacy of pulsed-dye laser and intense pulsed light treatments for rosacea have been demonstrated in several clinical trials. However, there is currently no research on the efficacy of long-pulsed alexandrite laser (LPAL) therapy alone for rosacea-related facial redness and its effect on skin microbiota. AIM: To evaluate the efficacy of LPAL therapy on facial redness in rosacea and assess changes in skin microbiota composition. METHODS: Subjects with rosacea (n = 21, mean age: 39.2 ± 11.3 years) were recruited from two medical institutions and received monthly LPAL treatments (Clarity II™, Lutronic Corp.) for 3 months. At each visit, clinical photographs were taken, and erythema was measured using a spectrometer. At the initial and final visits, the Dermatology Life Quality Index (DLQI) and Skin Sensitivity Questionnaire (SSQ) were evaluated. Skin swabs were obtained at the initial and final visit, and facial microbiome composition was analysed using 16S rRNA amplicon sequencing. RESULTS: After three LPAL treatment sessions, the average facial erythema index, measured using Mexameter® decreased significantly from 360.0 ± 96.7 at baseline to 312.0 ± 94.5 at the final visit (p < .05). The DLQI and SSQ showed significant improvement of symptoms. Skin microbiome diversity and relative abundance were altered significantly, particularly in the genera Clostridium, Lawsonella, Bacteroides, and Lactobacillus. CONCLUSIONS: LPAL therapy alone showed favourable efficacy for the treatment of facial redness in rosacea, with some impacts on the skin microbiota composition.

Interleukin-24: A molecular mediator of particulate matter's impact on skin aging.

Air pollution, a global health concern, has been associated with adverse effects on human health. In particular, particulate matter (PM), which is a major contributor to air pollution, impacts various organ systems including the skins. In fact, PM has been suggested as a culprit for accelerating skin aging and pigmentation. In this study, using single-cell RNA sequencing, IL-24 was found to be highly upregulated among the differentially expressed genes commonly altered in keratinocytes and fibroblasts of ex vivo skins exposed to PM. It was verified that PM exposure triggered the expression of IL-24 in keratinocytes, which subsequently led to a decrease in type I procollagen expression and an increase in MMP1 expression in fibroblasts. Furthermore, long-term treatment of IL-24 induced cellular senescence in fibroblasts. Through high-throughput screening, we identified chemical compounds that inhibit the IL-24-STAT3 signaling pathway, with lovastatin being the chosen candidate. Lovastatin not only effectively reduced the expression of IL24 induced by PM in keratinocytes but also exhibited a capacity to restore the decrease in type I procollagen and the increase in MMP1 caused by IL-24 in fibroblasts. This study provides insights into the significance of IL-24, illuminating mechanisms behind PM-induced skin aging, and proposes IL-24 as a promising target to mitigate PM-associated skin aging.

Real-Time Live Imaging of Osteoclast Activation via Cathepsin K Activity in Bone Diseases.

Intravital fluorescence imaging of functional osteoclasts within their intact disease context provides valuable insights into the intricate biology at the microscopic level, facilitating the development of therapeutic approaches for osteoclast-associated bone diseases. However, there is a lack of studies investigating osteoclast activity within deep-seated bone lesions using appropriate fluorescent probes, despite the advantages offered by the multi-photon excitation system in enhancing deep tissue imaging resolution. In this study, we report on the intravital tracking of osteoclast activity in three distinct murine bone disease models. We utilized a cathepsin K (CatK)-responsive two-photon fluorogenic probe (CatKP1), which exhibited a notable fluorescence turn-on response in the presence of active CatK. By utilizing CatKP1, we successfully monitored a significant increase in osteoclast activity in hindlimb long bones and its attenuation through pharmacological intervention without sacrificing mice. Thus, our findings highlight the efficacy of CatKP1 as a valuable tool for unraveling pathological osteoclast behavior and exploring novel therapeutic strategies.

Evaluation of viral infection as an etiology of ME/CFS: a systematic review and meta-analysis.

BACKGROUND: Myalgic encephalitis/chronic fatigue syndrome (ME/CFS) is a long-term disabling illness without a medically explained cause. Recently during COVID-19 pandemic, many studies have confirmed the symptoms similar to ME/CFS in the recovered individuals. To investigate the virus-related etiopathogenesis of ME/CFS, we conducted a systematic assessment of viral infection frequency in ME/CFS patients. METHODS: We conducted a comprehensive search of PubMed and the Cochrane Library from their inception through December 31, 2022, using selection criteria of viral infection prevalence in ME/CFS patients and controls. Subsequently, we performed a meta-analysis to assess the extent of viral infections' contribution to ME/CFS by comparing the odds ratio between ME/CFS patients and controls (healthy and/or diseased). RESULTS: Finally, 64 studies met our eligibility criteria regarding 18 species of viruses, including a total of 4971 ME/CFS patients and 9221 control subjects. The participants included healthy subjects and individuals with one of 10 diseases, such as multiple sclerosis or fibromyalgia. Two DNA viruses (human herpes virus (HHV)-7 and parvovirus B19, including their co-infection) and 3 RNA viruses (borna disease virus (BDV), enterovirus and coxsackie B virus) showed odds ratios greater than 2.0 compared with healthy and/or diseased subjects. Specifically, BDV exceeded the cutoff with an odds ratio of ≥ 3.47 (indicating a "moderate association" by Cohen's d test) compared to both healthy and diseased controls. CONCLUSION: This study comprehensively evaluated the risk of viral infections associated with ME/CFS, and identified BDV. These results provide valuable reference data for future studies investigating the role of viruses in the causation of ME/CFS.

Nephrin expression in human epidermal keratinocytes and its implication in poor wound closure.

Nephrin is a type-1 transmembrane protein and a component of the slit diaphragm renal-filtration barrier. It has several functions in actin remodeling and cell-cell adhesion. Nephrin is principally located in the kidney glomerulus, but several studies have reported that nephrin is found in the pancreas, brain, and placenta. However, nephrin expression and its role in human skin have not yet been reported. First, using single-cell RNA sequencing, immunohistochemistry, and immuno-electron microscopy, nephrin expression was confirmed in human-skin epidermal keratinocytes. Nephrin expression colocalized with the expression of zonula occludens-1 in keratinocytes and was closely related to keratinocyte cell density, proliferation, and migration. High glucose treatment decreased nephrin expression and compromised keratinocyte cell migration without yes-associated protein nuclear entry. This reduced cell migration under high glucose conditions was improved in nephrin-overexpressing keratinocytes. Nephrin was highly expressed on the margins of re-epithelized epidermis based on in vivo mice and ex vivo human skin wound models. The results demonstrate that nephrin is expressed in human-skin keratinocytes and functions in cell adhesion, proliferation, and migration. In conclusion, this study suggests that nephrin may have a variety of physiological roles in human skin.

Periodontitis is associated with the development of fungal sinusitis: A nationwide 12-year follow-up study.

AIM: The incidence of fungal sinusitis is increasing; however, its pathophysiology has not been investigated previously. We investigate the effect of periodontitis on the incidence of fungal sinusitis over a 12-year follow-up period using nationwide population-based data. MATERIALS AND METHODS: The periodontitis group was randomly selected from the National Health Insurance Service database. The non-periodontitis group was obtained by propensity score matching considering several variables. The primary end point was the diagnosis of sinonasal fungal balls (SFBs) and invasive fungal sinusitis (IFS). RESULTS: The periodontitis and non-periodontitis groups included 12,442 and 12,442 individuals, respectively. The overall adjusted hazard ratio (aHR) for SFBs in the periodontitis group was 1.46 (p = .002). In subgroup analysis, the aHR for SFBs was 1.59 (p = 0.008) for those with underlying chronic kidney disease (CKD), 1.58 (p = .022) for those with underlying atopic dermatitis, 1.48 (p = .019) for those with chronic obstructive pulmonary disease (COPD), and 1.36 (p = .030) for those with diabetes mellitus (DM), but these values are applicable only when considering the relationship between periodontitis and SFB. The aHR for IFS in the periodontitis group was higher than in the non-periodontitis group (2.80; p = .004). CONCLUSIONS: The risk of SFBs and IFS increased after diagnosis of periodontitis. This trend is often more severe in patients with DM, COPD, or CKD, but this association with underlying diseases is applicable only when considering the association between periodontitis and fungal sinusitis.

The role of Eustachian tubography and Valsalva CT in Eustachian tube balloon dilation.

BACKGROUND: Not many imaging techniques have been reported in Eustachian tube imaging. PURPOSE: To investigate the role of selective Eustachian tubography (SET) and Valsalva computed tomography (CT) in patients who underwent Eustachian tube balloon dilation (ETBD). MATERIAL AND METHODS: Eligible patients were aged 18 years and older with chronic Eustachian tube dysfunction who had failed medical treatment. On the day of the procedure, Valsalva CT and SET were performed. Participants underwent fluoroscopic ETBD with a 6×20-mm balloon catheter. Clinical examinations to check for the ability to perform the Valsalva maneuver and ETDQ-7 score change were conducted at one week and then at one, two, and six months. Follow-up Valsalva CT was performed in the one-month follow-up. RESULTS: A total of 30 ears in 23 patients (16 right ears, 14 left ears; 10 women, 13 men) underwent ETBD from August 2018 to November 2019. Positive CT patency was higher in follow-up Valsalva CT than baseline Valsalva CT (40% and 23.3%, respectively) (P = 0.006). In SET, positive patency was observed in 13 of 25 ears. Response to balloon dilation was observed in 18 of 25 patients. Clinical success was achieved in 16 of 27 ears. Response to balloon dilation was the only significant predictor of clinical success (P = 0.012). CONCLUSION: SET depicted the lumen of the Eustachian tube; thereby, it could be a potentially valuable tool in ETBD. Valsalva CT provides additional information about the cartilaginous portion of the Eustachian tube.

Dual-wavelength long-pulsed 755-nm alexandrite/1,064-nm Nd:YAG laser versus Nd:YAG alone for treatment of palmoplantar verruca.

We compared the effectiveness and safety of the long-pulsed neodymium-doped yttrium-aluminum-garnet (Nd:YAG) laser alone and combined with a 755-nm alexandrite laser for treating palmoplantar warts. We divided patients into two groups to receive up to four monthly treatments with Nd:YAG alone (single-wavelength) or combined with the alexandrite laser (dual-wavelength). We assessed treatment responses (according to clearance rate), vascular/hyperkeratosis grades, and patient satisfaction and pain ratings. The differences in treatment response (p = .348), patient satisfaction (p = .560), and pain ratings (p = .728) between the groups were not significant. The single- and dual-wavelength treatment options were equally effective in treating recalcitrant palmoplantar warts.

Effect of high hydrostatic pressure treatment on the inactivation and sublethal injury of foodborne pathogens and quality of apple puree at different pH.

The objectives of this study were to evaluate the survival of high hydrostatic pressure (HHP)-treated Salmonella Typhimurium, Escherichia coli O157:H7, and Listeria monocytogenes in apple puree, as well as to determine the levels of HHP-induced cell injury according to the pressure level, holding time, and pH of apple puree. Apple puree was inoculated with three foodborne pathogens and treated at pressures of 300-600 MPa for up to 7 min at 22 °C using HHP equipment. Increasing the pressure level and lowering the pH of apple puree led to larger microbial reductions, and E. coli O157:H7 showed higher resistance compared to S. Typhimurium and L. monocytogenes. Besides, approximately 5-log injured cells of E. coli O157:H7 were induced in apple puree at pH 3.5 and 3.8. HHP treatment at 500 MPa for 2 min effectively achieved complete inactivation of the three pathogens in apple puree at pH 3.5. For apple puree at pH 3.8, more than 2 min treatment of HHP at 600 MPa is seemingly needed to achieve complete inactivation of the three pathogens. Transmission electron microscopy analysis was conducted to identify ultrastructural changes in the injured or dead cells after HHP treatment. Plasmolysis and uneven cavities in the cytoplasm were observed in injured cells, and additional deformations, such as distorted and rough cell envelopes, and cell disruption occurred in dead cells. No changes in solid soluble content (SSC) and color of apple puree were observed after HHP treatment, and no differences were detected between control and HHP-treated samples during 10 d of storage at 5 °C. The results of this study could be useful in determining the acidity of apple purees or the treatment time at specific acidity levels when applying the HHP processing.

Clinical features of chronic fungal rhinosinusitis in Korean geriatric and non-geriatric patients.

PURPOSE: Worldwide, the incidence of chronic fungal rhinosinusitis (CFRS) has increased. Although ageing leads to weakening of the immune system, which increases susceptibility to CFRS, the CFRS characteristics in geriatric patients are unclear. Therefore, we comparatively analysed the clinical characteristics of CFRS in geriatric and non-geriatric patients. METHODS: This retrospective analysis compared the demographics, rhinologic symptoms, multiple allergen simultaneous tests, olfactory function tests, paranasal sinus computed tomography findings, and outcomes of 131 patients with CFRS who underwent functional endoscopic sinus surgery and 131 enrolled patients were divided in geriatric (> 65 years) and non-geriatric (≤ 65 years) groups. RESULTS: Among the geriatric and non-geriatric participants (n = 65, 49.6% and n = 66, 50.4%, respectively), hypertension and diabetes mellitus were more common in the geriatric group. Demographics, including symptoms, showed no significant intergroup differences. Normosmia and hyposmia were significantly less prevalent, whereas phantosmia and parosmia were more prevalent in the geriatric group than in the non-geriatric group (p = 0.03 and p = 0.01, respectively). Sphenoidal sinus involvement was significantly higher in geriatric patients than in non-geriatric patients (p = 0.02). CONCLUSION: Based on greater sphenoidal sinus involvement, a deeper anatomical area is more vulnerable to fungal infection in the geriatric group than in the non-geriatric group. Increasing clinicians' awareness of CFRS in geriatric patients with olfactory dysfunction, including phantosmia and parosmia, is important for early intervention.

Association between poly-sensitisation and sensitisation to staphylococcal enterotoxin A and B affecting allergic severity in children.

PURPOSE: Accumulating evidence suggests that Staphylococcus aureus plays a significant role as a disease modifier in upper and lower airway diseases. We aimed to assess the association between staphylococcal enterotoxins (SEs) with allergic diseases and the degree of allergen sensitisation in children, which remains unclear. METHODS: We retrospectively reviewed the medical records of 455 patients aged 3-18 years between March 2018 and March 2022. Clinical history and demographic data were obtained. The baseline study included paranasal sinus X-ray scan, multiple allergen simultaneous test, and ImmunoCAP® for measuring serum total and specific immunoglobulin E (IgE) levels to allergens and staphylococcal enterotoxin A and B (SEA and SEB). RESULTS: The mean age was 9.77 ± 4.3 years. 133 patients (29.2%) were sensitised to one inhalant allergen, and 188 patients (41.3%) showed polysensitisation. Patients sensitised to SEs showed higher total and specific IgE levels and total eosinophil counts compared to non-SE-sensitised patients. Sensitisation to SEs is closely associated with polysensitisation to inhalant allergens and allergic multimorbidity. When the SE-IgE value was 0.35 or higher, the odds ratio for allergen polysensitisation was significantly higher than when the SE-IgE value was lower than 0.35. CONCLUSIONS: Association between polysensitisation and sensitisation to SEs in children shows the higher the specific IgE levels for SEs, the higher the likelihood of polysensitisation. Considering the relationship between polysensitisation, high IgE levels, and the severity of allergic morbidity, sensitisation to SEs is thought to be related to allergy severity.

Drainage of a Pterygopalatine Fossa Abscess With Chronic Sinusitis via an Endoscopic Nasal Approach.

The pterygopalatine fossa is a clinically inaccessible space deep in the face, and reports of pterygopalatine fossa abscesses are rare. The authors present the case of a 63-year-old woman presenting with a severe headache owing to an abscess involving the pterygopalatine fossa. On a computed tomography scan, inflammation of the right pterygopalatine fossa associated with right maxillary sinusitis and periapical inflammation and a cystic lesion around the tooth were observed. After administering appropriate antibiotics, the headache improved considerably, and endoscopic nasal surgery resulted in adequate abscess drainage. To the authors' knowledge, this case study is one of the few reporting the successful treatment of an abscess in the pterygopalatine fossa through an endoscopic transnasal approach.

Extended Suprabrow Lift with Relief of Glabellar Wrinkles.

BACKGROUND: Eyebrows define one's facial appearance; brow ptosis, which can occur with aging, can convey a negative expression. Various methods have been used to correct eyebrow position and shape. We endeavored to repair brow ptosis and glabellar wrinkles and present the outcome. METHODS: This retrospective study reviewed 40 patients who underwent extended suprabrow lift accompanied by relief of glabellar wrinkles between January 2018 and August 2020. The procedure was considered when patients exhibited brow ptosis, glabellar wrinkles, and a wide forehead. Fat graft was implemented after glabellar muscle division. The results were assessed based on measurements performed preoperatively and at 6 and 18 months postoperatively. RESULTS: Overall, patients were satisfied with the outcomes. To assess glabellar wrinkles, the Modified Fitzpatrick Wrinkle Assessment score revealed adequate correction during neutral and furrowed gazes (P < 0.05). The forehead and brow heights were also analyzed after repair, exhibiting decreased forehead height and elevated brow position (P < 0.05). At 6 and 18 months after surgery, adequate maintenance of the repair was evident (P < 0.05). A visible scar was observed in two patients, which was managed using a fractional ablative laser procedure. CONCLUSION: Extended suprabrow lift, when based on preoperative measurements, led to the correction of brow ptosis, glabellar wrinkles, and a wide forehead. For periorbital rejuvenation, it is imperative to decide locations where the skin and soft tissues should be preserved or removed. The use of fat grafts for wrinkle repair effectively maintains the repair postoperatively. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

A Mixture of Cervus elaphus sibiricus and Glycine max (L.) Merrill Inhibits Ovariectomy-Induced Bone Loss Via Regulation of Osteogenic Molecules in a Mouse Model.

Osteoporosis is a metabolic skeletal disease characterized by lowered bone mineral density and quality, which lead to an increased risk of fracture. The aim of this study was to evaluate the anti-osteoporosis effects of a mixture (called BPX) of Cervus elaphus sibiricus and Glycine max (L.) Merrill and its underlying mechanisms using an ovariectomized (OVX) mouse model. BALB/c female mice (7 weeks old) were ovariectomized. From 12 weeks of ovariectomy, mice were administered BPX (600 mg/kg) mixed in a chow diet for 20 weeks. Changes in bone mineral density (BMD) and bone volume (BV), histological findings, osteogenic markers in serum, and bone formation-related molecules were analyzed. Ovariectomy notably decreased the BMD and BV scores, while these were significantly attenuated by BPX treatment in the whole body, femur, and tibia. These anti-osteoporosis effects of BPX were supported by the histological findings for bone microstructure from H&E staining, increased activity of alkaline phosphatase (ALP), but a lowered activity of tartrate-resistant acid phosphatase (TRAP) in the femur, along with other parameters in the serum, including TRAP, calcium (Ca), osteocalcin (OC), and ALP. These pharmacological actions of BPX were explained by the regulation of key molecules in the bone morphogenetic protein (BMP) and mitogen-activated protein kinase (MAPK) pathways. The present results provide experimental evidence for the clinical relevance and pharmaceutical potential of BPX as a candidate for anti-osteoporosis treatment, especially under postmenopausal conditions.

Intravitreal Administration of Retinal Organoids-Derived Exosomes Alleviates Photoreceptor Degeneration in Royal College of Surgeons Rats by Targeting the Mitogen-Activated Protein Kinase Pathway.

Increasing evidence suggests that exosomes are involved in retinal cell degeneration, including their insufficient release; hence, they have become important indicators of retinopathies. The exosomal microRNA (miRNA), in particular, play important roles in regulating ocular and retinal cell functions, including photoreceptor maturation, maintenance, and visual function. Here, we generated retinal organoids (ROs) from human induced pluripotent stem cells that differentiated in a conditioned medium for 60 days, after which exosomes were extracted from ROs (Exo-ROs). Subsequently, we intravitreally injected the Exo-RO solution into the eyes of the Royal College of Surgeons (RCS) rats. Intravitreal Exo-RO administration reduced photoreceptor apoptosis, prevented outer nuclear layer thinning, and preserved visual function in RCS rats. RNA sequencing and miRNA profiling showed that exosomal miRNAs are mainly involved in the mitogen-activated protein kinase (MAPK) signaling pathway. In addition, the expression of MAPK-related genes and proteins was significantly decreased in the Exo-RO-treated group. These results suggest that Exo-ROs may be a potentially novel strategy for delaying retinal degeneration by targeting the MAPK signaling pathway.