Critical roles of tubular mitochondrial ATP synthase dysfunction in maleic acid-induced acute kidney injury.

Maleic acid (MA) induces renal tubular cell dysfunction directed to acute kidney injury (AKI). AKI is an increasing global health burden due to its association with mortality and morbidity. However, targeted therapy for AKI is lacking. Previously, we determined mitochondrial-associated proteins are MA-induced AKI affinity proteins. We hypothesized that mitochondrial dysfunction in tubular epithelial cells plays a critical role in AKI. In vivo and in vitro systems have been used to test this hypothesis. For the in vivo model, C57BL/6 mice were intraperitoneally injected with 400 mg/kg body weight MA. For the in vitro model, HK-2 human proximal tubular epithelial cells were treated with 2 mM or 5 mM MA for 24 h. AKI can be induced by administration of MA. In the mice injected with MA, the levels of blood urea nitrogen (BUN) and creatinine in the sera were significantly increased (p < 0.005). From the pathological analysis, MA-induced AKI aggravated renal tubular injuries, increased kidney injury molecule-1 (KIM-1) expression and caused renal tubular cell apoptosis. At the cellular level, mitochondrial dysfunction was found with increasing mitochondrial reactive oxygen species (ROS) (p < 0.001), uncoupled mitochondrial respiration with decreasing electron transfer system activity (p < 0.001), and decreasing ATP production (p < 0.05). Under transmission electron microscope (TEM) examination, the cristae formation of mitochondria was defective in MA-induced AKI. To unveil the potential target in mitochondria, gene expression analysis revealed a significantly lower level of ATPase6 (p < 0.001). Renal mitochondrial protein levels of ATP subunits 5A1 and 5C1 (p < 0.05) were significantly decreased, as confirmed by protein analysis. Our study demonstrated that dysfunction of mitochondria resulting from altered expression of ATP synthase in renal tubular cells is associated with MA-induced AKI. This finding provides a potential novel target to develop new strategies for better prevention and treatment of MA-induced AKI.

Strain-induced ferroelectric polarization reversal without undergoing geometric inversion in blue SiSe monolayer.

Ferroelectricity in two-dimensional (2D) systems generally arises from phonons and has been widely investigated. On the contrary, electronic ferroelectricity in 2D systems has been rarely studied. Using first-principles calculations, the ferroelectric behavior of the buckled blue SiSe monolayer under strain are explored. It is found that the direction of the out-of-plane ferroelectric polarization can be reversed by applying an in-plane strain. And such polarization switching is realized without undergoing geometric inversion. Besides, the strain-triggered polarization reversal emerges in both biaxial and uniaxial strain cases, indicating it is an intrinsic feature of such a system. Further analysis shows that the polarization switching is the result of the reversal of the magnitudes of the positive and negative charge center vectors. And the variation of buckling is found to play an important role, which results in the switch. Moreover, a non-monotonic variation of band gap with strain is revealed. Our findings throws light on the investigation of novel electronic ferroelectric systems.

Panax notoginseng Saponins Ameliorate Gamma Radiation-Mediated Damages in Human Peripheral Blood Monocytes and Swiss Albino Mice.

In this study, the protective effects of Panax notoginseng saponins (PNS) against gamma radiation-induced DNA damage and associated physiological alterations in Swiss albino mice were investigated. Exposure to gamma radiation led to a dose-dependent increase in cytokinesis-blocked micronuclei (CBMN) double-strand DNA breaks (DSBs), dicentric aberrations (DC), formation in peripheral blood mononuclear cells. However, pretreatment with PNS at concentrations of 1, 5, and 10 µg/mL significantly attenuated the frequencies of DC and CBMN in a concentration-dependent manner. PNS administration before radiation exposure also reduced radiation-induced DSBs in BL, indicating protection against reactive oxygen species generation and DNA damage. Notably, pretreatment with PNS at 10 µg/mL prevented the overexpression of γ-H2AX, proteins associated with DNA damage response, in irradiated mice. In addition, in vivo studies showed intraperitoneal administration of PNS (25 mg/kg body weight) for 1 h before radiation exposure mitigated lipid peroxidation levels and restored antioxidant status, countering oxidative damage induced by gamma radiation. Furthermore, PNS pretreatment reversed the decrease in hemoglobin (Hb) content, white blood cell count, and red blood cell count in irradiated mice, indicating preservation of hematological parameters. Overall, PNS demonstrated an anticlastogenic effect by modulating radiation-induced DSBs and preventing oxidative damage, thus highlighting its potential as a protective agent against radiation-induced DNA damage and associated physiological alterations. Clinically, PNS will be beneficial for cancer patients undergoing radiotherapy, but their pharmacological properties and toxicity profiles need to be studied.

How Progesterone Receptor Expression Impacts Platinum Sensitivity in Ovarian Clear Cell Carcinoma: Insights from Clinical and Experimental Perspectives.

Ovarian clear cell carcinoma (OCCC) is often considered a relatively platinum-resistant malignancy. The aim of this study was to explore the influence of progesterone receptor (PR) expression levels on platinum sensitivity and survival outcomes in people with OCCC. A retrospective analysis was conducted with 80 people with OCCC who underwent surgery followed by adjuvant chemotherapy. PR expression was assessed via immunohistochemical (IHC) staining and quantified using the H score. The platinum sensitivity and survival outcomes of patients with weak and strong PR expression were compared. Additionally, cisplatin viability and migration experiments were conducted with OCCC cell lines (ES-2 and TOV-21G) with varying PR isoform expressions. Among the 80 patients, 62 were classified as having platinum-sensitive disease, while 18 had platinum-resistant disease. The mean total PR H- score of platinum-sensitive tumors was significantly higher than that of platinum-resistant tumors (p = 0.002). Although no significant differences in progression-free and overall survival were observed between patients with high and low PR expression, those with high PR expression tended to have longer survival. While PR protein was only weakly detectable in ES-2 and TOV-21G cells, a transfection of the PR-A or PR-B gene resulted in a strong expression of PR-A or PR-B, which led to significantly reduced proliferation and migration in ES-2 and TOV-21G cells. Furthermore, overexpression of PR-A or PR-B enhanced cisplatin cytotoxicity in these cell lines. In conclusion, strong PR expression was associated with improved platinum sensitivity and survival outcomes, consistent with our experimental findings. The potential of PR as a tumor sensitizer to cisplatin in OCCC warrants further investigation.

6-shogaol is a potential treatment for Head and Neck Squamous Cell Carcinoma.

Objective: Natural products in diet have shown a potential role in the prevention and treatment of cancer. Ginger (Zingiber officinale Roscoe) is a great candidate because of its properties of anti-inflammatory, antioxidant, and anti-cancer, but little is known about its effect on head and neck cancer. 6-Shogaol is an active compound derived from Ginger. Thus, this study aimed to investigate the possible anticancer effects of 6-shogaol, a major ginger derivate, on head and neck squamous cell carcinomas (HNSCCs) and the underlying mechanisms. Material and Methods: Two HNSCC cell lines, SCC4 and SCC25, were used in this study. Both SCC4 and SCC25 cells were kept as control or treated with 6-shogaol for 8 and 24 hours and then the cell apoptosis and cell cycle progression of treated cells were examined by PI and Annexin V-FITC double stain and flow cytometry analysis. The Cleaved caspase 3, phosphorylations of ERK1/2 and p38 kinases were examined by Western blot analysis. Results: The results showed that 6-shogaol significantly initiated the G2/M phase arrest of the cell cycle and apoptosis to inhibit the survival of both cell lines. Moreover, these responses could be regulated by ERK1/2 and p38 signaling. And, finally, we also demonstrated that 6-shogaol could enhance the cytotoxicity of cisplatin in HNSCC cells. Conclusion: Our data provided new insights to understand the potential pharmaceutical efficacy of a ginger derivate, 6-shogaol, in antagonizing HNSCC survival. The present study suggests that 6-shogaol is a potential novel candidate for anti-HNSCCs therapy.

Functional and Molecular Markers for Hearing Loss and Vertigo Attacks in Meniere's Disease.

Meniere's disease (MD) is one of the most complicated diseases in the otologic clinic. The complexity of MD is partially due to the multifactorial etiological mechanisms and the heterogenous symptoms, including episodic vertigo, hearing loss, aural fullness and tinnitus. As a result, the diagnosis of MD and differentiating MD from other diseases with similar symptoms, such as vestibular migraine (VM), is challenging. In addition, it is difficult to predict the progression of hearing loss and the frequency of vertigo attacks. Detailed studies have revealed that functional markers, such as pure tone audiometry (PTA), electrocochleography (ECochG), vestibular evoked myogenic potential (VEMP), caloric test, video head impulse test (vHIT) and magnetic resonance imaging (MRI) could help to evaluate MD with different hearing levels and frequency of vertigo attacks. Investigations of molecular markers such as autoimmunity, inflammation, protein signatures, vasopressin and circadian clock genes in MD are still underway. This review will summarize these functional and molecular markers, address how these markers are associated with hearing loss and vertigo attacks in MD, and analyze the results of the markers between MD and VM.

Dihydroisotanshinone I and BMAL-SIRT1 Pathway in an In Vitro 6-OHDA-Induced Model of Parkinson's Disease.

Danshen has been widely used for the treatment of central nervous system diseases. We investigated the effect of dihydroisotanshinone I (DT), a compound extracted from Danshen, as well as the corresponding mechanisms in an in vitro-based 6-OHDA-induced Parkinson's disease (PD) model. SH-SY5Y human neuroblastoma cell lines were pretreated with 6-hydroxydopamine (6-OHDA) and challenged with DT. Subsequently, the cell viability and levels of reactive oxygen species (ROS) and caspase-3 were analyzed. The effect of DT on the 6-OHDA-treated SH-SY5Y cells and the expression of the core circadian clock genes were measured using a real-time quantitative polymerase chain reaction. Our results indicated that DT attenuated the 6-OHDA-induced cell death in the SH-SY5Y cells and suppressed ROS and caspase-3. Moreover, DT reversed both the RNA and protein levels of BMAL1 and SIRT1 in the 6-OHDA-treated SH-SY5Y cells. Additionally, the SIRT1 inhibitor attenuated the effect of DT on BMAL1 and reduced the cell viability. The DT and SIRT1 activators activated SIRT1 and BMAL1, and then reduced the death of the SH-SY5Y cells damaged by 6-OHDA. SIRT1 silencing was enhanced by DT and resulted in a BMAL1 downregulation and a reduction in cell viability. In conclusion, our investigation suggested that DT reduces cell apoptosis, including an antioxidative effect due to a reduction in ROS, and regulates the circadian genes by enhancing SIRT1 and suppressing BMAL1. DT may possess novel therapeutic potential for PD in the future, but further in vivo studies are still needed.

Clinical and Cellular Evidence of Glycyrrhiza glabra and Platycodon grandiflorus for Vocal Fold Nodules Complementary Treatment.

Vocal fold nodules (VFNs) are the most frequent cause of hoarseness. The management comprised medical, surgical and physical therapy but the effectiveness is not always satisfactory. In this study, we try to figure out an alternative treatment from our clinical experience summary. We retrospectively reviewed VFNs patients who received traditional Chinese medicine (TCM) treatments from July 2018 to August 2020 and traced their Chinese Voice Handicap Index-10 (VHI-C10) and multidimensional voice program (MDVP) analysis results. For further evaluation, we conducted an inflammatory response of porcine vocal fold epithelial (PVFE) cells with 50 ng/mL TNF-alpha. The inflamed PVFE cells were separately cultured in the aqueous extract of Glycyrrhiza glabra (G. glabra) and Platycodon grandifloras (P. grandifloras). In these VFNs patients (n = 22), the average VHI-C10 score decreased from 17.6 to 6.6 (p < 0.001). MDVP analysis revealed improvements in jitter, shimmer, noise-harmonic ratio, and GRBAS scoring system. Of the TCM prescription patterns, G. glabra and P. grandiflorus were used most frequently. In the MTT assay of PVFE cells, no adverse effects of our extracts were observed at doses of 1-200 µg/mL. Western blot analysis revealed downregulation of p65 and mitogen activated protein kinase pathway proteins. The results from both the clinical and in vitro aspects of this study revealed that the herbs G. glabra and P. grandiflorus may offer beneficial outcomes as alternative treatments for VFNs after precise diagnosis.

The effect of continuous adductor canal block combined with distal interspace between the popliteal artery and capsule of the posterior knee block for total knee arthroplasty: a randomized, double-blind, controlled trial.

BACKGROUND: The optimal analgesia for total knee arthroplasty (TKA) requires excellent analgesia while preserving muscle strength. This study aimed to determine the hypothesis that continuous adductor canal block (CACB) combined with the distal interspace between the popliteal artery and the posterior capsule of the knee (IPACK) block could effectively alleviate the pain of the posterior knee, decrease opioids consumption, and promote early recovery and discharge. METHODS: Patients undergoing unilateral, primary TKA were allocated into group CACB+SHAM (receiving CACB plus sham block) or group CACB+IPACK (receiving CACB plus IPACK block). The primary outcome was cumulative opioid consumption. Secondary outcomes included the incidence of postoperative pain originated from the posterior knee, visual analogue scale (VAS) score, range of motion, ambulation distance, and satisfaction for pain management. RESULTS: The incidence of moderate-severe pain of the posterior knee was lower in group CACB+IPACK than that of the group CACB+SHAM at 4 hours (17.1% vs. 42.8%; p = 0.019), 8 hours (11.4% vs. 45.7%; p = 0.001), and 24 hours (11.4% vs. 34.3%; p = 0.046) after TKA. The VAS scores of the posterior knee were lower in group CACB+IPACK than that of the group CACB+SHAM at 4 hours [2 (2) vs. 3 (2-4); p = 0.000], 8 hours [1 (1, 2) vs. 3 (2-4); p = 0.001], and 24 hours [1(0-2) vs. 2 (1-4); p = 0.002] after TKA. The overall VAS scores were lower in group CACB+IPACK than that of the group CACB+SHAM at 4 hours [3 (2, 3) vs. 3 (3, 4); p = 0.013] and 8 hours [2 (2, 3) vs. 3 (2-4); p = 0.032] at rest and 4 hours [3 (3, 4) vs. 4 (4, 5); p = 0.001], 8 hours [3 (2-4) vs. 4 (3-5); p = 0.000], 24 hours [2 (2, 3) vs. 3 (2-4); p = 0.001] during active flexion after TKA. The range of motion (59.11 ± 3.90 vs. 53.83 ± 5.86; p = 0.000) and ambulation distance (44.60 ± 4.87 vs. 40.83 ± 6.65; p = 0.009) were superior in group CACB+IPACK than that of the group CACB+SHAM in postoperative day 1. The satisfaction for pain management was higher in group CACB+IPACK than that of the group CACB+SHAM [9 (8, 9) vs. 8 (7-9); p = 0.024]. There was no difference in term of cumulative opioids consumption between group CACB+IPACK and group CACB+SHAM [120(84-135) vs. 120(75-135); p = 0.835]. CONCLUSION: The combination of CACB and distal IPACK block could decrease the incidences of moderate-severe posterior knee pain, improve the postoperative pain over the first 24 hours after TKA, as well as promoting recovery of motor function. However, the opioids consumption was not decreased by adding distal IPACK to CACB. TRIAL REGISTRATION: This study was registered at Chinese Clinical Trial Registry ( ChiCTR2200059139 ; registration date: 26/04/2022; enrollment date: 16/11/2020; http://www.chictr.org.cn ).

Standing genetic variation as the predominant source for adaptation of a songbird.

What kind of genetic variation contributes the most to adaptation is a fundamental question in evolutionary biology. By resequencing genomes of 80 individuals, we inferred the origin of genomic variants associated with a complex adaptive syndrome involving multiple quantitative traits, namely, adaptation between high and low altitudes, in the vinous-throated parrotbill (Sinosuthora webbiana) in Taiwan. By comparing these variants with those in the Asian mainland population, we revealed standing variation in 24 noncoding genomic regions to be the predominant genetic source of adaptation. Parrotbills at both high and low altitudes exhibited signatures of recent selection, suggesting that not only the front but also the trailing edges of postglacial expanding populations could be subjected to environmental stresses. This study verifies and quantifies the importance of standing variation in adaptation in a cohort of genes, illustrating that the evolutionary potential of a population depends significantly on its preexisting genetic diversity. These findings provide important context for understanding adaptation and conservation of species in the Anthropocene.