The male reproductive toxicity after 5-Fluorouracil exposure: DNA damage, oxidative stress, and mitochondrial dysfunction in vitro and in vivo.

5-Fluorouracil (5-FU), a chemotherapeutic drug used to treat a variety of cancers, can enter the environment through different routes, causing serious public health and environmental concerns. It has been reported that 5-FU exposure adversely affects male reproductive function, and its effects on this system cannot be avoided. In this study, using western blotting and quantitative polymerase chain reaction studies, we found that 5-FU promoted testicular injury by inducing oxidative stress, which was accompanied by the inhibition of nuclear factor erythroid 2-related factor 2/antioxidant response element signaling. Accumulation of reactive oxygen species (ROS) aggravated 5-FU-mediated mitochondrial dysfunction and apoptosis in murine cell lines and testes, indicating oxidative stress and mitochondrial-dependent apoptotic signaling play crucial roles in the damage of spermatogenic cells caused. N-Acetyl-L-cysteine, an antioxidant that scavenges intracellular ROS, protected spermatogenic cells from 5-FU-induced oxidative damage and mitochondrial dysfunction, revealing the important role of ROS in testicular dysfunction caused by 5-FU. We found that 5-FU exposure induces testicular cell apoptosis through ROS-mediated mitochondria pathway in mice. In summary, our findings revealed the reproductive toxicological effect of 5-FU on mice and its mechanism, provided basic data reference for adverse ecological and human health outcomes associated with 5-FU contamination or poisoning.

Effect of connexin 43 in LPS/IL-4-induced macrophage M1/M2 polarization: An observational study.

Lipopolysaccharide (LPS) and interleukin-4 (IL-4) play important roles in inducing M1 and M2 macrophage polarization. Studies have shown that LPS can promote the polarization of macrophages to M1-type and produce many pro-inflammatory cytokines, while IL-4 can promote the polarization of macrophages to M2-type and produce many anti-inflammatory cytokines. Moreover, Connexin 43 (Cx43) is widely expressed in macrophages and has various regulatory functions. However, whether Cx43 is involved in the regulation of macrophage M1/M2 polarization has not been fully studied. This study examined the role of Cx43 and M2 polarization markers using Western blot, immunofluorescence, flow cytometry. Cx43 overexpression was induced using Cx43 overexpressing lentivirus. The statistical software SPSS 20.0 (IBM Corp.) and GraphPad Prism 8.0 (GraphPad Software, La Jolla, CA, United States) were used to analyze the results. P values < .05 were considered to indicate statistically significant differences. Our results showed that LPS promotes the polarization of macrophages to M1-type, which is accompanied by an increase in Cx43 expression from 0 to 24 hours. Moreover, the application of the Cx43-specific blockers Gap19 and Gap26 reduces the expression of macrophage M1-type polarization markers. Thus, the expression of Cx43 increases first, and then, due to the initiation of intracellular autophagy during LPS-induced macrophage M1 polarization. Cx43 is degraded and the expression of Cx43 decreases from 24 hours to 48 hours. IL-4 decreases the expression of Cx43 from 24 hours to 48 hours and promotes the transformation of macrophages to M2-type. The application of Cx43 overexpression lentivirus leads to a reduction in the expression of M2 polarization markers. IL-4-induced M2 polarization of macrophages inhibits cell autophagy, reducing Cx43 degradation and leading to an increase in Cx43 from 24 hours to 48 hours. Thus, Cx43 expression in M2-type polarization experiences a reduction at first and then an increase from 24 hours to 48 hours. The direction of macrophage polarization can be controlled by regulating the expression of Cx43, thus providing a theoretical basis for treating atherosclerosis, tumors, and other diseases associated with macrophage polarization.

Population-based BRCA germline mutation screening in the Han Chinese identifies individuals at risk of BRCA mutation-related cancer: experience from a clinical diagnostic center from greater Shanghai area.

BACKGROUND: Deleterious BRCA1/2 (BRCA) mutation raises the risk for BRCA mutation-related malignancies, including breast, ovarian, prostate, and pancreatic cancer. Germline variation of BRCA exhibits substantial ethnical diversity. However, there is limited research on the Chinese Han population, constraining the development of strategies for BRCA mutation screening in this large ethnic group. METHODS: We profile the BRCA mutational spectrum, including single nucleotide variation, insertion/deletion, and large genomic rearrangements in 2,080 apparently healthy Chinese Han individuals and 522 patients with BRCA mutation-related cancer, to determine the BRCA genetic background of the Chinese Han population, especially of the East Han. Incident cancer events were monitored in 1,005 participants from the healthy group, comprising 11 BRCA pathogenic/likely pathogenic (PLP) variant carriers and 994 PLP-free individuals, including 3 LGR carriers. RESULTS: Healthy Chinese Han individuals demonstrated a distinct BRCA mutational spectrum compared to cancer patients, with a 0.53% (1 in 189) prevalence of pathogenic/likely pathogenic (PLP) variant, alongside a 3 in 2,080 occurrence of LGR. BRCA1 c. 5470_5477del demonstrated high prevalence (0.44%) in the North Han Chinese and penetrance for breast cancer. None of the 3 LGR carriers developed cancer during the follow-up. We calculated a relative risk of 135.55 (95% CI 25.07 to 732.88) for the development of BRCA mutation-related cancers in the BRCA PLP variant carriers (mean age 42.91 years, median follow-up 10 months) compared to PLP-free individuals (mean age 48.47 years, median follow-up 16 months). CONCLUSION: The unique BRCA mutational profile in the Chinese Han highlights the potential for standardized population-based BRCA variant screening to enhance BRCA mutation-related cancer prevention and treatment.

Chinese surgical robot-assisted surgery for parotid tumor: a case report.

Robotic surgery is known as the "third technological revolution" in the field of surgery, and is an important milestone in the development of modern surgery. However, our country's innovative surgical robot industry is still in its early stages, and it is only being utilized in certain surgical fields. To explore the effectiveness of the application of domestic surgical robot in oral and maxillofacial surgery, the author successfully completed a case of benign parotid tumor resection with the assistance of a domestic autonomous robot. The operation was successful, facial nerve function was preserved, and postoperative wound healing was good.

Targeted Delivery of Catalase and Photosensitizer Ce6 by a Tumor-Specific Aptamer Is Effective against Bladder Cancer In Vivo.

Photodynamic therapy (PDT) is often applied in a clinical setting to treat bladder cancer. However, current photosensitizers report drawbacks such as low efficacy, low selectivity, and numerous side effects, which have limited the clinical values of PDT for bladder cancer. Previously, we developed the first bladder cancer-specific aptamer that can selectively bind to and be internalized by bladder tumor cells versus normal uroepithelium cells. Here, we use an aptamer-based drug delivery system to deliver photosensitizer chlorine e6 (Ce6) into bladder tumor cells. In addition to Ce6, we also incorporate catalase into the drug complex to increase local oxygen levels in the tumor tissue. Compared with free Ce6, an aptamer-guided DNA nanotrain (NT) loaded with Ce6 and catalase (NT-Catalase-Ce6) can specifically recognize bladder cancer cells, produce oxygen locally, induce ROS in tumor cells, and cause mitochondrial apoptosis. In an orthotopic mouse model of bladder cancer, the intravesical instillation of NT-Catalase-Ce6 exhibits faster drug internalization and a longer drug retention time in tumor tissue compared with that in normal urothelium. Moreover, our modified PDT significantly inhibits tumor growth with fewer side effects such as cystitis than free Ce6. This aptamer-based photosensitizer delivery system can therefore improve the selectivity and efficacy and reduce the side effects of PDT treatment in mouse models of bladder cancer, bearing a great translational value for bladder cancer intravesical therapy.

Clinical, Diagnostic, and Treatment Characteristics of Orbital Liposarcoma.

PURPOSE: To clarify the clinical, diagnostic, and treatment characteristics of orbital liposarcoma. DESIGN: Retrospective observational case series. METHODS: A review was performed of electronic medical records, histopathology, radiological images, and follow-up information for 21 patients with orbital liposarcoma. RESULTS: The predominant clinical manifestation of this disease was painless exophthalmos. The most frequently encountered pathological types were well-differentiated and myxoid liposarcoma. Preoperative radiological images from 15 patients showed that orbital liposarcoma initially developed in extraocular muscle in 9 patients. Furthermore, all well-differentiated liposarcomas exhibited the radiographic characteristics of irregular and ill-defined adipose tissue, whereas only 12.5% of myxoid liposarcomas had the imaging characteristics. For the patients who exclusively underwent surgery, all of those with subtotal excisions experienced recurrence, 63.6% of marginal excisions recurred, and 50% of wide excisions resulted in recurrence. However, none of the patients who underwent marginal excisions or wide excisions combined with adjuvant radiotherapy exhibited recurrence. The analysis of magnetic resonance imaging findings in 3 patients who underwent neoadjuvant radiotherapy revealed that the tumor size remained stable in a patient with well-differentiated liposarcoma, whereas another patient with the same type of tumor exhibited a gradual increase in size. Conversely, a patient with myxoid liposarcoma experienced a significant reduction in tumor size following neoadjuvant radiotherapy. CONCLUSION: Orbital liposarcoma demonstrated a propensity for developing in the extraocular muscle. The radiological images of orbital well-differentiated liposarcomas were characterized by irregular and ill-defined adipose tissue. Surgery combined with radiotherapy demonstrated potential in reducing recurrence rates. Notably, orbital myxoid liposarcoma exhibited greater sensitivity to radiotherapy compared to well-differentiated liposarcoma.

Fiber configuration determines foreign body response of electrospun scaffolds:in vitroandin vivoassessments.

Biomaterial scaffolds boost tissue repair and regeneration by providing physical support, delivering biological signals and/or cells, and recruiting endogenous cells to facilitate tissue-material integration and remodeling. Foreign body response (FBR), an innate immune response that occurs immediately after biomaterial implantation, is a critical factor in determining the biological outcomes of biomaterial scaffolds. Electrospinning is of great simplicity and cost-effectiveness to produce nanofiber scaffolds with well-defined physicochemical properties and has been used in a variety of regenerative medicine applications in preclinical trials and clinical practice. A deep understanding of causal factors between material properties and FBR of host tissues is beneficial to the optimal design of electrospun scaffolds with favorable immunomodulatory properties. We herein prepared and characterized three electrospun scaffolds with distinct fiber configurations and investigated their effects on FBR in terms of immune cell-material interactions and host responses. Our results show that electrospun yarn scaffold results in greater cellular immune reactions and elevated FBR inin vivoassessments. Although the yarn scaffold showed aligned fiber bundles, it failed to induce cell elongation of macrophages due to its rough surface and porous grooves between yarns. In contrast, the aligned scaffold showed reduced FBR compared to the yarn scaffold, indicating a smooth surface is also a contributor to the immunomodulatory effects of the aligned scaffold. Our study suggests that balanced porousness and smooth surface of aligned fibers or yarns should be the key design parameters of electrospun scaffolds to modulate host responsein vivo.

ATF5-regulated Mitochondrial Unfolded Protein Response Attenuates Neuronal Damage in Epileptic Rat by Reducing Endoplasmic Reticulum Stress Through Mitochondrial ROS.

Endoplasmic reticulum (ER) dysfunction caused by excessive ER stress is a crucial mechanism underlying seizures-induced neuronal injury. Studies have shown that mitochondrial reactive oxygen species (ROS) are closely related to ER stress, and our previous study showed that activating transcription factor 5 (ATF5)-regulated mitochondrial unfolded protein response (mtUPR) modulated mitochondrial ROS generation in a hippocampal neuronal culture model of seizures. However, the effects of ATF5-regulated mtUPR on ER stress and the underlying mechanisms remain uncertain in epilepsy. In this study, ATF5 upregulation by lentivirus infection attenuated seizures-induced neuronal damage and apoptosis in a rat model of pilocarpine-induced epilepsy, whereas ATF5 downregulation by lentivirus infection had the opposite effects. ATF5 upregulation potentiated mtUPR by increasing the expression of mitochondrial chaperone heat shock protein 60 (HSP60) and caseinolytic protease proteolytic subunit (ClpP) and reducing mitochondrial ROS generation in pilocarpine-induced seizures in rats. Additionally, upregulation of ATF5 reduced the expression of glucose-regulated protein 78 (GRP78), protein kinase RNA-like endoplasmic reticulum kinase (PERK), activating transcription factor 4 (ATF4), and C/EBP homologous protein (CHOP), suggesting suppression of ER stress; Moreover, ATF5 upregulation attenuated apoptosis-related proteins such as B-cell lymphoma-2 (BCL2) downregulation, BCL2-associated X (BAX) and cleaved-caspase-3 upregulation. However, ATF5 downregulation exerted the opposite effects. Furthermore, pretreatment with the mitochondria-targeted antioxidant mito-TEMPO attenuated the harmful effects of ATF5 downregulation on ER stress and neuronal apoptosis by reducing mitochondrial ROS generation. Overall, our study suggested that ATF5-regulated mtUPR exerted neuroprotective effects against pilocarpine-induced seizures in rats and the underlying mechanisms might involve mitochondrial ROS-mediated ER stress.

Interfering TRIB3 protects the blood brain barrier through PI3K/Akt pathway to alleviate cerebral ischemia-reperfusion injury in diabetes mellitus mice.

This study aimed to treat diabetic cerebral ischemia-reperfusion injury (CI/RI) by affecting blood brain barrier (BBB) permeability and integrity. The CI/RI model in DM mice and a high glucose (HG) treated oxygen and glucose deprivation/reoxygenation (OGD/R) brain endothelial cell model were established for the study. Evans blue (EB) staining was used to evaluate the permeability of BBB in vivo. TTC staining was used to analyze cerebral infarction. The location and expression of tribbles homolog 3 (TRIB3) in endothelial cells were detected by immunofluorescence. Western blotting was used to detect the protein expressions of TRIB3, tight junction molecules, adhesion molecules, phosphorylated protein kinase B (p-AKT) and AKT. The levels of pro-inflammatory cytokines were detected by qRT-PCR. Trans-epithelial electrical resistance (TEER) and fluorescein isothiocyanate (FITC)-dextran were used to measure vascular permeability in vitro. TRIB3 ubiquitination and acetylation levels were detected. Acetyltransferase bound to TRIB3 were identified by immunoprecipitation. TRIB3 was localized in cerebral endothelial cells and was highly expressed in diabetic CI/R mice. The BBB permeability in diabetic CI/R mice and HG-treated OGD/R cells was increased, while the junction integrity was decreased. Interference with TRIB3 in vitro reduces BBB permeability and increases junction integrity. In vivo interfering with TRIB3 reduced cerebral infarction volume, BBB permeability and inflammation levels, and upregulated p-AKT levels. The phosphatidylinositol 3-kinase (PI3K) inhibitor wortmannin reversed the effects of TRIB3-interfering plasmid. In vitro HG treatment induced TRIB3 acetylation through acetyltransferase p300, which in turn reduced ubiquitination and stabilized TRIB3. Interfering TRIB3 protects BBB by activating PI3K/AKT pathway and alleviates brain injury, which provides a new target for diabetic CI/RI.

Chanling Gao suppresses colorectal cancer via PI3K/Akt/mTOR pathway modulation and enhances quality of survival.

The Chinese medicine formula Chanling Gao (CLG) exhibits significant tumor inhibitory effects in colorectal cancer (CRC) nude mice. However, the detailed mechanisms remain elusive. CRC in situ nude mouse models were treated with CLG. Small animal magnetic resonance imaging (MRI) tracked tumor progression, and overall health metrics such as food and water intake, body weight, and survival were monitored. Posttreatment, tissues and blood were analyzed for indicators of tumor inhibition and systemic effects. Changes in vital organs were observed via stereoscope and hematoxylin-eosin staining. Immunohistochemistry quantified HIF-1α and P70S6K1 protein expression in xenografts. Double labeling was used to statistically analyze vascular endothelial growth factor (VEGF) and CD31 neovascularization. Enzyme-linked immunosorbent assay was used to determine the levels of VEGF, MMP-2, MMP-9, IL-6, and IL-10 in serum, tumors, and liver. Western blotting was used to assess the expression of the PI3K/Akt/mTOR signaling pathway-related factors TGF-ß1 and smad4 in liver tissues. CLG inhibited tumor growth, improved overall health metrics, and ameliorated abnormal blood cell counts in CRC nude mice. CLG significantly reduced tumor neovascularization and VEGF expression in tumors and blood. It also suppressed HIF-1α, EGFR, p-PI3K, Akt, p-Akt, and p-mTOR expression in tumors while enhancing PTEN oncogene expression. Systemic improvements were noted, with CLG limiting liver metastasis, reducing pro-inflammatory cytokines IL-6 and IL-10 in liver tissues, decreasing MMP-2 in blood and MMP-2 and MMP-9 in tumors, and inhibiting TGF-ß1 expression in liver tissues. CLG can enhance survival quality and inhibit tumor growth in CRC nude mice, likely through the regulation of the PI3K/Akt/mTOR signaling pathway.

Clinical characteristics and prognosis of laryngeal tuberculosis combined with respiratory tuberculosis.

PURPOSE: To investigate the clinical characteristics, diagnosis and prognosis of patients with laryngeal tuberculosis (LTB) combined with respiratory tuberculosis. MATERIALS AND METHODS: A retrospective analysis was conducted on 134 patients who underwent endoscopy and were eventually diagnosed with LTB. The patients' demographic characteristics, clinical manifestations, endoscopic features, auxiliary examination, imaging examination and prognostic characteristics were analyzed. RESULTS: LTB patients had a median age of 45.5 years (range from 12 to 87 years) and a median course of 3.0 months (range from 0.1 to 72 months). The patients' symptoms mainly presented as hoarseness (97.0 %), abnormal sensation of pharyngeal (49.3 %), cough and sputum (41.0 %), pharyngalgia (39.6 %), dysphagia (10.4 %) and dyspnea (8.2 %). The positive rate of tuberculous symptoms was 25.4 %. Endoscopic features showed that the lesions mainly involved the glottis (87.3 %), presenting as unilateral lesions (66.7 %), near-full-length involvement (88.0 %), with mucosal waves significantly reduced (86.3 %), followed by supraglottis (43.3 %), subglottis (24.6 %) and the pharynx (15.7 %). The lesions may present as granulomatous proliferation (66.4 %), ulceration (65.7 %) or swelling and exudation (51.5 %). A total of 75 patients (56.0 %) were finally diagnosed with combined pulmonary tuberculosis (PTB), with a positive chest X-ray rate of 25.6 % and a positive chest CT rate of 71.2 %. A total of 42 patients who received anti-tuberculosis treatment were followed up, and 73.8 % of patients had significant improvement in symptoms. The morphology of the pharyngeal and laryngeal mucosa returned to basically normal (59.4 %) or scar-like (34.4 %). CONCLUSIONS: LTB is usually found in middle-aged men, and patients' symptoms are mainly hoarseness, abnormal sensation of pharyngeal, pharyngalgia, cough and sputum, and can be combined with tuberculous symptoms. These lesions mainly involve multiple subregions, mainly in the glottis, and can be combined with pharyngeal involvement. There were various types of lesions. Half of the patients were complicated with PTB, and chest CT was superior to X-ray in the detection of pulmonary lesions. After regular anti-tuberculosis treatment, the symptoms and morphology of the pharyngeal and laryngeal mucosa of most patients were significantly improved.

Aldehyde dehydrogenase 2-mediated aldehyde metabolism promotes tumor immune evasion by regulating the NOD/VISTA axis.

BACKGROUND: Aldehyde dehydrogenase 2 (ALDH2) is a crucial enzyme involved in endogenous aldehyde detoxification and has been implicated in tumor progression. However, its role in tumor immune evasion remains unclear. METHODS: Here, we analyzed the relationship between ALDH2 expression and antitumor immune features in multiple cancers. ALDH2 knockout tumor cells were then established using CRISPR/Cas9 system. In immunocompetent breast cancer EMT6 and melanoma B16-F10 mouse models, we investigated the impact of ALDH2 blockade on cytotoxic T lymphocyte function and tumor immune microenvironment by flow cytometry, mass cytometry, Luminex liquid suspension chip detection, and immunohistochemistry. Furthermore, RNA sequencing, flow cytometry, western blot, chromatin immunoprecipitation assay, and luciferase reporter assays were employed to explore the detailed mechanism of ALDH2 involved in tumor immune evasion. Lastly, the synergistic therapeutic efficacy of blocking ALDH2 by genetic depletion or its inhibitor disulfiram in combination with immune checkpoint blockade (ICB) was investigated in mouse models. RESULTS: In our study, we uncovered a positive correlation between the expression level of ALDH2 and T-cell dysfunction in multiple cancers. Furthermore, blocking ALDH2 significantly suppressed tumor growth by enhancing cytotoxic activity of CD8+ T cells and reshaping the immune landscape and cytokine milieu of tumors in vivo. Mechanistically, inhibiting ALDH2-mediated metabolism of aldehyde downregulated the expression of V-domain Ig suppressor of T-cell activation (VISTA) via inactivating the nucleotide oligomerization domain (NOD)/nuclear factor kappa-B (NF-κB) signaling pathway. As a result, the cytotoxic function of CD8+ T cells was revitalized. Importantly, ALDH2 blockade markedly reinforced the efficacy of ICB treatment. CONCLUSIONS: Our data delineate that ALDH2-mediated aldehyde metabolism drives tumor immune evasion by activating the NOD/NF-κB/VISTA axis. Targeting ALDH2 provides an effective combinatorial therapeutic strategy for immunotherapy.

The TRIM21-FOXD1-BCL-2 axis underlies hyperglycaemic cell death and diabetic tissue damage.

Chronic hyperglycaemia is a devastating factor that causes diabetes-induced damage to the retina and kidney. However, the precise mechanism by which hyperglycaemia drives apoptotic cell death is incompletely known. Herein, we found that FOXD1, a FOX family transcription factor specifically expressed in the retina and kidney, regulated the transcription of BCL-2, a master regulator of cell survival. Intriguingly, the protein level of FOXD1, which responded negatively to hyperglycaemic conditions, was controlled by the TRIM21-mediated K48-linked polyubiquitination and subsequent proteasomal degradation. The TRIM21-FOXD1-BCL-2 signalling axis was notably active during diabetes-induced damage to murine retinal and renal tissues. Furthermore, we found that tartary buckwheat flavonoids effectively reversed the downregulation of FOXD1 protein expression and thus restored BCL-2 expression and facilitated the survival of retinal and renal tissues. In summary, we identified a transcription factor responsible for BCL-2 expression, a signalling axis (TRM21-FOXD1-BCL-2) underlying hyperglycaemia-triggered apoptosis, and a potential treatment for deleterious diabetic complications.

Capecitabine-based chemotherapy in early-stage triple-negative breast cancer: a meta-analysis.

Introduction: The efficacy and safety of adjuvant capecitabine in early-stage triple-negative breast cancer remains undefined. A meta-analysis was conducted to elucidate whether capecitabine-based regimens could improve survival in early-stage triple-negative breast cancer (TNBC). Methods: The current study searched Medline, Embase, Cochrane Library, Web of Science, and ClinicalTrials.gov proceedings up to 2023.9. Disease-free survival (DFS), overall survival (OS), and grade 3-4 adverse events (AEs) were assessed. Extracted or calculated hazard ratios (HRs) and odds ratios (ORs) with 95% confidence intervals (CIs) were pooled. Results: The capecitabine-based regimens showed significant advantages in DFS (HR = 0.81, 95% CI: 0.73-0.90; P <.001) and OS (HR = 0.75, 95% CI: 0.65-0.87; P <.001) from 12 randomized controlled trials (RCTs) with 5,390 unselected participants. Subgroup analysis of DFS showed analogous results derived from patients with lymph node negative (HR = 0.68, 95% CI: 0.50-0.92; P = .006) and capecitabine duration no less than six cycles (HR = 0.73; 95% CI: 0.62-0.86; P <.001). Improvement of DFS in the addition group (HR = 0.77, 95% CI: 0.68-0.87; P <.001) and adjuvant setting (HR = 0.79, 95% CI: 0.70-0.89; P <.001) was observed. As to safety profile, capecitabine was associated with more frequent stomatitis (OR = 5.05, 95% CI: 1.45-17.65, P = .011), diarrhea (OR = 6.11, 95% CI: 2.12-17.56; P =.001), and hand-foot syndrome (OR = 31.82, 95% CI: 3.23-313.65, P = .003). Conclusions: Adjuvant capecitabine-based chemotherapy provided superior DFS and OS to early-stage TNBC. The benefits to DFS in selected patients with lymph node negative and the addition and extended duration of capecitabine were demonstrated.

Effect of sunitinib against Echinococcus multilocularis through inhibition of VEGFA-induced angiogenesis.

BACKGROUND: Alveolar echinococcosis (AE) is a lethal zoonosis caused by the fox tapeworm Echinococcus multilocularis. The disease is difficult to treat, and an effective therapeutic drug is urgently needed. Echinococcus multilocularis-associated angiogenesis is required by the parasite for growth and metastasis; however, whether antiangiogenic therapy is effective for treating AE is unclear. METHODS: The in vivo efficacy of sunitinib malate (SU11248) was evaluated in mice by secondary infection with E. multilocularis. Enzyme-linked immunosorbent assays (ELISAs) were used to evaluate treatment effects on serum IL-4 and vascular endothelial growth factor A (VEGFA) levels after SU11248 treatment. Gross morphological observations and immunohistochemical staining were used to evaluate the impact of SU11248 on angiogenesis and the expression of pro-angiogenic factors VEGFA and VEGF receptor 2 (VEGFR2) in the metacestode tissues. Furthermore, the anthelmintic effects of SU11248 were tested on E. multilocularis metacestodes in vitro. The effect of SU11248 on the expression of VEGFA, VEGFR2, and phosphorylated VEGFR2 (p-VEGFR2) in liver cells infected with protoscoleces in vitro was detected by western blotting, reverse transcription quantitative polymerase chain reaction (RT-qPCR), and enzyme-linked immunosorbent assay (ELISA). The influence of SU11248 on endothelial progenitor cell (EPC) proliferation and migration was determined using CCK8 and transwell assays. RESULTS: In vivo, SU11248 treatment markedly reduced neovascular lesion formation and substantially inhibited E. multilocularis metacestode growth in mice. Further, it exhibited high anti-hydatid activity as efficiently as albendazole (ABZ), and the treatment resulted in reduced protoscolex development. In addition, VEGFA, VEGFR2, and p-VEGFR2 expression was significantly decreased in the metacestode tissues after SU11248 treatment. However, no effect of SU11248 on serum IL-4 levels was observed. In vitro, SU11248 exhibited some anthelmintic effects and damaged the cellular structure in the germinal layer of metacestodes at concentrations below those generally considered acceptable for treatment (0.12-0.5 µM). Western blotting, RT-qPCR, and ELISA showed that in co-cultured systems, only p-VEGFR2 levels tended to decrease with increasing SU11248 concentrations. Furthermore, SU11248 was less toxic to Reuber rat hepatoma (RH) cells and metacestodes than to EPCs, and 0.1 µM SU11248 completely inhibited EPC migration to the supernatants of liver cell and protoscolex co-cultures. CONCLUSIONS: SU11248 is a potential candidate drug for the treatment of AE, which predominantly inhibits parasite-induced angiogenesis. Host-targeted anti-angiogenesis treatment strategies constitute a new avenue for the treatment of AE.

Proliferative glomerulonephritis with monoclonal IgG Lambda deposits caused by plasmablastic lymphoma: a case report.

INTRODUCTION: As a very rare form of B-cell lymphoma, plasmablastic lymphoma (PBL) typically occurs in patients with underlying immunosuppression, including human immunodeficiency virus (HIV), organ transplantation, and autoimmune diseases. For HIV-positive patients, PBL normally originates in the gastrointestinal tract, especially from the oral cavity in most cases. It is extremely rare to find abdominal cavity involvement in PBL, and there has been no previously reported instance of proliferative glomerulonephritis with monoclonal immunoglobulin deposits (PGNMID) attributed to monoclonal IgG (MIgG) lambda secreted by PBL. CASE PRESENTATION: We report the case of an HIV-negative female with nephrotic syndrome, renal insufficiency, and multiple swollen lymph nodes. Ascitic fluid cytology revealed a high level of plasmablast-like lymphocytes with the restriction of lambda light chains. Besides, the renal biopsy revealed PGNMID, which could presumably be secondary to MIgG-lambda-secreting by PBL. MIgG-lambda-restricted expression was discovered earlier in the kidney tissue than in the blood. CONCLUSION: The diagnostic landscape for PBL is notoriously intricate, necessitating a multifaceted and nuanced approach to mitigate the risks of erroneous identification.

Experimental and theoretical studies on inhibition against tyrosinase activity and melanin biosynthesis by antioxidant ergothioneine.

Ergothioneine, a natural derivative of histidine with a thiol/thine tautomeric structure, exhibits exceptional antioxidant properties and inhibition activities on tyrosinase. In this study, enzyme kinetics experiments and chromatographic spectral analysis revealed that ergothioneine inhibited tyrosinase in a reversible and non-competitive manner, with an inhibition constant of 0.554 mg/mL (2.41 mM). As the concentration of ergothioneine increased, the extremely flexible loop structure of tyrosinase extended from 40.1 % to 41.0 %, effectively covering the active center or binding site. Theoretical molecular docking simulation results show that ergothioneine forms complexes with tyrosinase through hydrogen bonding and salt bridges in the active center of Cu ions. Additionally, it was observed that ergothioneine's antioxidant had a stronger reducing impact on dopaquinone, an intermediate in melanin production, than the effect of ascorbic acid at an equivalent concentration (0.5 mg/mL). Ergothioneine reduced the intracellular reactive oxygen species to lower levels than the control group without UVA radiation and regulated the proliferation and differentiation in B16-F10 melanocytes. Clinical trials have shown that a 0.1 % concentration of ergothioneine can effectively suppress melanin production in irradiated skin. The significant reduction in melanin index and an increase in the individual type angle (ITA°) degree were measured after 4 weeks. These results collectively suggest that ergothioneine may be a promising inhibitor of natural antioxidant tyrosinase. Furthermore, due to its safety and efficacy, ergothioneine could be considered one of the bioactive substances for further study on diseases related to melanin production and tyrosinase activity which is of great significance for the cosmetics, medicine and food industries.

Case report: Remarkable response to a novel combination of mitotane, etoposide, paraplatin, and sintilimab in a patient with metastatic adrenocortical carcinoma.

Background: Adrenocortical carcinoma (ACC) is a rare malignancy with a poor prognosis and limited treatment options for metastases. However, new effective regimens are emerging for specific conditions in metastatic ACC. Case presentation: We report a case of a 36-year-old man diagnosed with metastatic ACC who had a large left adrenal mass (158 mm × 112 mm) and multiple metastases in the liver and lungs. Genetic testing revealed a microsatellite instability-high (MSI-H) tumor, a splice mutation in MLH1, and a high tumor mutational burden (TMB). After the left adrenalectomy, he received sequential treatment with a combination of mitotane, etoposide, paraplatin (EP-M), and sintilimab. His condition has been assessed as a stable disease since the sixth cycle of the combined regimen. Conclusion: This case highlights the remarkable response of our patient's ACC with MSI-H tumor, MLH1 spice mutation, and high TMB to treatment with a novel combination of EP-M and sintilimab. Our findings suggest a promising therapeutic option for patients with similar molecular profiles.

Clinicopathological characteristics and its association with digestive system tumors of 1111 patients with Schistosomiasis japonica.

Schistosomiasis japonicum can cause different degrees of organ damage and complex human immune pathological reactions, which often invade the intestine and liver. The purpose of this study was to explore the pathological types and pathological changes of Schistosomiasis and their correlation with some digestive system tumors. Hematoxylin eosin staining was performed on the diseased tissues of 1111 Schistosomiasis cases. We counted the deposition sites of Schistosoma eggs, analyzed the pathological characteristics, and compared the clinicopathological characteristics of Schistosomiasis associated digestive system tumors and non-Schistosomiasis digestive system tumors. We found that Schistosoma japonicum can cause multi organ and multi system damage, with 469 cases of inflammation, 47 cases of adenoma, and 519 cases of adenocarcinoma. Other types include cysts, stromal tumors, malignant lymphomas, and neuroendocrine tumors. Schistosomiasis associated tumors, including gastric cancer, liver cancer, colon cancer and rectal cancer, were compared with non-Schistosomiasis tumors. There were significant differences in age, gender and tumor differentiation between the two groups. Our study shows Schistosomiasis is a systemic disease, causing multiple organ and system damage in the human body. Its clinicopathological types are diverse, and there may be a pathological change process of "Inflammation-adenoma-carcinoma". Schistosomiasis associated digestive system tumors differ from non-Schistosomiasis tumors in some clinicopathological features.