Effects of oridonin on sperm function and the PI3K/PDK1/AKT signaling pathway: Implications for reproductive toxicity.

Oridonin, a natural terpenoid isolated from the leaves of Isodon rubescens (Hemsley) H.Hara, is widely used in oriental medicine for its anticancer properties across various cancer types. Despite its prevalent use, the toxic effects of oridonin on male reproduction, particularly its impact on sperm functions and the mechanisms involved, are not well understood. This study aimed to explore the effects and underlying mechanisms of oridonin on sperm functions. We initially treated Duroc boar spermatozoa with varying concentrations of oridonin (0, 5, 50, 75, 100, and 150 µM) and incubated them to induce capacitation. We then assessed cell viability and several sperm functions, including sperm motility and motion kinematics, capacitation status, and ATP levels. We also analyzed the expression levels of proteins associated with the phosphatidylinositol 3-kinase (PI3K)/phosphoinositide-dependent kinase-1 (PDK1)/protein kinase B (AKT) signaling pathway and phosphotyrosine proteins. Our results indicate that oridonin adversely affects most sperm functions in a dose-dependent manner. We observed significant decreases in AKT, p-AKT (Thr308), phosphatase and tensin homolog (PTEN), p-PDK1, and p-PI3K levels following oridonin treatment, alongside an abnormal increase in phosphotyrosine proteins. These findings suggest that oridonin may disrupt normal levels of tyrosine-phosphorylated proteins by inhibiting the PI3K/PDK1/AKT signaling pathway, which is crucial for cell proliferation, metabolism, and apoptosis, thus potentially harming sperm functions. Consequently, we recommend considering the reproductive toxicity of oridonin when using it as a therapeutic agent.

Adverse Effects of Avobenzone on Boar Sperm Function: Disruption of Protein Kinase A Activity and Tyrosine Phosphorylation.

Avobenzone (AVO), an ultraviolet (UV) filter, is frequently used as an ingredient in personal cosmetics. This UV filter has been found to be easily exposed in swimming pools and beaches, and it has been detected in human urine and blood. Moreover, numerous studies have demonstrated that AVO exhibits endocrine-disrupting properties. Nevertheless, the effects of AVO on male fertility have not yet fully understood. Therefore, this study aimed to assess the effects of AVO on various sperm functions during capacitation. First, boar spermatozoa were treated with various AVO concentrations. After treatment, sperm motility and kinetic characteristics, capacitation status, intracellular adenosine triphosphate (ATP) levels, and sperm viability were evaluated. Moreover, Western blot analysis w.as conducted to evaluate protein kinase A (PKA) activity and tyrosine phosphorylation. As a result, AVO treatment significantly decreased total motility, progressive motility, and several kinetic characteristics at high concentrations (50 and 100 µM). Furthermore, the capacitation status dose-dependently decreased. Conversely, no significant differences in acrosome reaction, cell viability, and intracellular ATP levels were observed. However, the intracellular ATP level tended to decrease. In addition, AVO dose-dependently induced abnormal changes in PKA activity and tyrosine phosphorylation. Although AVO did not directly exert a toxic effect on cell viability, it ultimately negatively affected sperm functions through abnormal alterations in PKA activity and tyrosine phosphorylation. Thus, the potential implications on male fertility must be considered when contemplating the safe utilization of AVO.

Application of sperm motion kinematics and motility-related proteins for prediction of male fertility.

The selection of superior sires is paramount for enhancing the efficiency of animal production in the livestock industry. However, semen quality assessment still relies on conventional semen analysis techniques in both animals and humans. Despite extensive efforts to develop various biomarkers for more accurate and precise predictions of male fertility potential, more effective physiological indicators and advance potential biomarkers are needed. Herein, we aimed to develop new potential biomarkers related to sperm motion kinematics for male fertility prediction. We first evaluated sperm motion kinematic parameters and expression levels of sperm motility-related proteins of 30 Duroc boars. We then explored the correlation between litter size, sperm motion kinematics parameters, and sperm motility-related proteins. Progressive sperm motility (%), rapid sperm motility (%), slow sperm motility (%), straight-line velocity (µm/s), linearity (%), beat cross frequency (Hz), mean angular displacement (degree), wobble (%) were correlated with litter size. Furthermore, the expression of axonemal dynein light intermediate polypeptide 1 (DNALI1) and radial spoke head protein 9 homolog (RSPH9) correlated with litter size. The overall accuracy exceeded 60% for predicting litter size using these sperm motion parameters and proteins. Notably, our study observed an increase in litter size after predicting litter size using these parameters and proteins. Thus, sperm motion kinematic parameters and protein expression, particularly of DNALI1 and RSPH9, could serve as new biomarkers for male fertility. These results may contribute to improved understanding of the mechanisms underlying sperm motility.

Effect of 4-nonylphenol (4-NP) on sperm function: Insights into the PI3K/PDK1/AKT signaling pathway during capacitation.

4-Nonylphenol (4-NP) is an endocrine-disrupting chemical that impairs animal and human reproduction. However, the mechanisms underlying male reproductive dysfunction by 4-NP have not been fully understood. Herein, we demonstrated the effects of 4-NP on boar sperm functions and molecular mechanisms. Spermatozoa were treated with various concentrations of 4-NP (0, 10, 25, 50, 75, and 100 µM) during capacitation. Then, we evaluated sperm motility, capacitation status, intracellular ATP level, and cell viability. Finally, we measured the expression of phosphorylated protein kinase A (PKA), tyrosine phosphorylation, and proteins related to the phosphatidylinositol 3 kinase (PI3K)/phosphoinositide-dependent kinase-1 (PDK1)/protein kinase B (AKT) signaling pathways following exposure to 4-NP. Sperm motility and motion kinematics were reduced by 4-NP, whereas intracellular ATP levels were increased significantly in a dose-dependent manner. Furthermore, the expression levels of p-PI3K, PTEN, p-PDK1, AKT, and p-AKT exhibited a significant dose-dependent increase. Moreover, abnormal activation of PKA and tyrosine phosphorylation were observed. Specifically, the ∼24 kDa p-PKA substrate demonstrated a significant reduction following exposure to 4-Np. In addition, the ∼18 kDa p-PKA substrate and tyrosine-phosphorylated proteins displayed a significant dose-dependent increase after exposure to 4-NP. Our results suggest that 4-NP may induce detrimental effects on sperm functions through abnormal changes in PKA activity and tyrosine phosphorylation during capacitation, possibly through unusual alteration of the PI3K/PDK1/AKT signaling pathway. Therefore, 4-NP must be cautiously used considering its reproductive toxicity.

Ritonavir Has Reproductive Toxicity Depending on Disrupting PI3K/PDK1/AKT Signaling Pathway.

Ritonavir (RTV) is an antiviral and a component of COVID-19 treatments. Moreover, RTV demonstrates anti-cancer effects by suppressing AKT. However, RTV has cytotoxicity and suppresses sperm functions by altering AKT activity. Although abnormal AKT activity is known for causing detrimental effects on sperm functions, how RTV alters AKT signaling in spermatozoa remains unknown. Therefore, this study aimed to investigate reproductive toxicity of RTV in spermatozoa through phosphoinositide 3-kinase/phosphoinositide-dependent protein kinase-1/protein kinase B (PI3K/PDK1/AKT) signaling. Duroc spermatozoa were treated with various concentrations of RTV, and capacitation was induced. Sperm functions (sperm motility, motion kinematics, capacitation status, and cell viability) and expression levels of tyrosine-phosphorylated proteins and PI3K/PDK1/AKT pathway-related proteins were evaluated. In the results, RTV significantly suppressed sperm motility, motion kinematics, capacitation, acrosome reactions, and cell viability. Additionally, RTV significantly increased levels of phospho-tyrosine proteins and PI3K/PDK1/AKT pathway-related proteins except for AKT and PI3K. The expression level of AKT was not significantly altered and that of PI3K was significantly decreased. These results suggest RTV may suppress sperm functions by induced alterations of PI3K/PDK1/AKT pathway through abnormally increased tyrosine phosphorylation. Therefore, we suggest people who use or prescribe RTV need to consider its male reproductive toxicity.

Comparison between arthroscopic suture anchor fixation and open plate fixation in the greater tuberosity fracture of the proximal humerus.

INTRODUCTION: The purpose of this study is to compare the clinical and radiological outcomes of patients undergoing open reduction and internal fixation (OR/IF) using a plate or patients undergoing an arthroscopic suture anchor fixation for the greater tuberosity (GT) fracture of the proximal humerus. The purpose of this study is to compare the clinical and radiological outcomes of patients undergoing OR/IF or an arthroscopic suture anchor fixation for the GT fracture. MATERIALS AND METHODS: Between January, 2010 and December, 2020, 122 patients with GT fracture underwent operative fixation. Either OR/IF using proximal humeral locking plate (50 patients) or arthroscopic suture anchor (72 patients) fixation was performed. Fourteen patients were lost to follow-up and finally, 108 patients were enrolled in this study. We divided these patients into two groups: (1) OR/IF group (Group I: 44 patients) and arthroscopic anchor fixation group (Group II: 64 patients). The primary outcome was subjective shoulder function (shoulder functional scale). Secondary outcomes were range of motion, and complications including GT fixation failure, fracture migration, or neurologic complication. Also, age, sex, BMI, operation time, shoulder dislocation, fracture comminution, AP (anteroposterior), SI (superoinferior) size and displacement were evaluated and compared between two groups. RESULTS: Both groups showed satisfactory clinical and radiological outcomes at mid-term follow-up. Between 2 groups, there were no significant differences in age, sex, BMI, presence of shoulder dislocation or comminution. Group II showed higher clinical scores except VAS score (p < 0.05) and longer surgical times (95.3 vs. 61.5 min). Largest fracture displacement (Group I vs. II: SI displacement: 40 vs. 13 mm, and AP displacement: 49 vs. 11 mm) and higher complication rate (p = 0.049) was found in Group I. CONCLUSIONS: Both arthroscopic anchor fixation and open plate fixation methods showed satisfactory outcomes at mid-term follow-up. Among them, OR/IF is preferred for larger fracture displacement (> 5 mm) and shorter operation time However, arthroscopic anchor fixation group showed better clinical outcomes and less complications than the OR/IF group. LEVEL OF EVIDENCE: Level 4, Case series with subgroup analysis.

Perfluorooctanoic acid suppresses sperm functions via abnormal Protein Kinase B activation during capacitation.

Perfluorooctanoic acid (PFOA) is a perfluorinated compound, a synthesized chemical, and has been used in several industrial products for more than 70 years. Although PFOA is known to exert toxic effects in normal cells, there is no detailed information on its reproductive toxicity and its effects on sperm functions related to protein kinase B (AKT). Therefore, this study was conducted to explore the effects of PFOA on sperm functions via AKT. Boar spermatozoa were incubated with different concentrations of PFOA (0, 0.1, 1, 10, and 100 µM) to induce capacitation. Sperm functions (sperm motility, motion kinematic parameters, capacitation status, cell viability, and intracellular ATP levels) were evaluated. In addition, the expression levels of AKT, phospho-AKT, phospho-PKA, and tyrosine phosphorylated proteins were evaluated by western blotting. Results showed significant decreases in sperm motility and motion kinematic parameters. PFOA treatment significant suppressed spermatozoa capacitation and intracellular ATP levels. Furthermore, it significantly decreased the levels of phospho-PKA and tyrosine phosphorylated proteins. The levels of AKT phosphorylation at Thr308 and Ser473 also significantly decreased. These findings suggest that PFOA diminishes sperm functions during capacitation and induces unnatural phosphorylation in AKT, leading to reproductive toxicity. Therefore, people should be aware of reproductive toxicity when using PFOA.

Metallosis-Induced Conversion Shoulder Arthroplasty: A Unique Experience and Literature Review.

BACKGROUND: Total shoulder arthroplasty (TSA) can fail for several reasons, such as component loosening, periprosthetic fracture, instability, infection, soft tissue failure, or joint overstuffing. Severe metallosis without loose glenoid components after TSA may result in the need for revision to reverse TSA. CASE PRESENTATION: Four years before the current presentation, an 86-year-old woman suffered from right shoulder pain and swelling. The initial diagnosis was osteoarthritis of the shoulder joint, for which she underwent TSA. Four years later, she complained of shoulder joint pain, swelling, and limited range of motion. On sonography, subscapularis and supraspinatus tendon tears were identified. Plain radiographs and computed tomography (CT) scans showed metallosis around the shoulder joint. Due to the rocking horse mechanism, wear of the upper portion of the glenoid component and bearing caused a foreign-body reaction and severe metallosis around the joint. Due to a massive rotator cuff tear combined with glenoid component wear, the patient eventually underwent reverse TSA (RTSA) and was satisfied with the final results. CONCLUSIONS: Severe metallosis due to glenoid component wear combined with a massive rotator cuff tear in TSA may cause the need for revision to RTSA.

Comparative analysis and human health risk assessment of contamination with heavy metals of Central Asian rivers.

The study focuses on heavy metals contamination, drinking water quality, and associated health risks for adults and children by consuming water from Central Asian Rivers (Syr-Darya, Nura, and Ili Rivers). Water samples were collected from three rivers within the 2014-2019 period by the RMS "Kazhydromet" and analyzed for various physicochemical parameters. The study revealed that the concentrations of Fe, Cd, Cr (VI), Hg, Mn, and As significantly exceeded local and international drinking water standards in at least one water body. The lowest total water quality index (55.1%) was observed in the Nura River ("marginal water category"). Coal, soil, non-ferrous metals, and iron ore industries were found to be the major sources of heavy metals in the regions. Deterministic risk assessment revealed serious cancer risks (>1E-5) in rivers due to As and Cr (VI) exposure by oral and dermal contact for adults and children. Stochastic risk assessment confirmed high cancer risks (>1E-4) due to Cr (VI) contamination of the Syr-Darya River. The study results indicate the serious lifetime cancer risk to the residents due to the use of river water for drinking and household activities. Therefore, the study area urgently and continuously requires heavy metal removal, effective monitoring, and good quality drinking water supply.

The natural flavonoid compound deguelin suppresses sperm (Sus Scrofa) functions through abnormal activation of the PI3K/AKT pathway.

Deguelin is a natural flavonoid extracted from plants belonging to the Lonchocarpus, Derris, or Tephrosia genera. It inhibits AKT activity in tumors and has the potential to be used as a treatment for malignant tumors. However, the risks associated with the use of deguelin on male fertility have not yet been explained in detail. Therefore, this study was conducted to investigate the effects of deguelin on sperm functions during capacitation. First, boar spermatozoa were exposed to different concentrations of deguelin (0.1, 1, 10, 50, and 100 µM). Next, sperm functional assessments, such as sperm motility, capacitation status, intracellular ATP level, and cell viability, were performed. The expression levels of PI3K/AKT-related proteins and the phosphorylation of their tyrosine residues were also evaluated by western blotting. No significant difference was observed in cell viability; however, deguelin considerably decreased sperm motility and motion kinematics in a dose-dependent manner. Although no significant difference was observed in the capacitation status, acrosome reaction decreased at high concentrations of deguelin (50 and 100 µM). Furthermore, intracellular ATP levels were significantly decreased in all deguelin treatment groups compared with those in the control group. Results of western blotting revealed that deguelin substantially diminished tyrosine phosphorylation. Interestingly, in contrast to previous studies showing that deguelin inhibits AKT activity, our results showed that it increased the expression of PI3K/AKT pathway-related proteins. Collectively, these findings indicate that deguelin exerts negative effects on sperm functions due to abnormal PI3K/AKT signaling activation. We believe that this is the first study to provide evidence that deguelin can regulate sperm functions independent of PI3K/AKT pathway inhibition. Furthermore, its detrimental effects on male fertility should be considered while developing or using deguelin as a therapeutic agent.

Anticancer Effect of Cold Atmospheric Plasma in Syngeneic Mouse Models of Melanoma and Colon Cancer.

Cold atmospheric plasma (CAP) may have applications in treating various types of malignant tumors. This study assessed the anticancer effects of CAP using melanoma and colon cancer cell lines. CAP treatment significantly reduced the in vitro viability of melanoma and colon cancer cell lines and had a negligible effect on the viability of normal human melanocytes. Additionally, CAP and epidermal growth factor receptor (EGFR) inhibitor had an additive anticancer effect in a CAP-resistant melanoma cell line. Reactive oxygen and nitrogen species known to be generated by CAP enhanced the anticancer effects of CAP and EGFR inhibitors. The in vivo anticancer activities of CAP were evaluated by testing its effects against syngeneic tumors induced in mice by melanoma and colon cancer cells. CAP treatment reduced tumor volume and weight in both cancer models, with the extent of tumor reduction dependent on the duration and number of CAP treatments. Histologic examination also revealed the tumoricidal effects of CAP in both tumor models. In conclusion, CAP inhibits the growth of mouse melanoma and colon cancer cell lines in vitro and shows tumoricidal effects against mouse models of melanoma and colon cancer in vivo.

Reduced radiation exposure to circulating blood cells in proton therapy compared with X-ray therapy in locally advanced lung cancer: Computational simulation based on circulating blood cells.

Background: We estimated the dose of circulating blood cells (CBCs) in patients with locally advanced non-small cell lung cancer for predicting severe radiation-induced lymphopenia (SRIL) and compared pencil-beam scanning proton therapy (PBSPT) and intensity-modulated (photon) radiotherapy (IMRT). Materials and methods: After reviewing 325 patients who received definitive chemoradiotherapy with PBSPT (n = 37) or IMRT (n = 164). SRIL was diagnosed when two or more events of an absolute lymphocyte count < 200 µL occurred during the treatment course. Dose information for the heart and lungs was utilized for the time-dependent computational dose calculation of CBCs. Results: The dose distribution of CBCs was significantly lesser in the PBSPT group than that in the IMRT group. Overall, 75 (37.3%) patients experienced SRIL during the treatment course; 72 and 3 patients were treated with IMRT and PBSPT, respectively. SRIL was associated with poor progression-free and overall survival outcomes. Upon incorporating the dose information of CBCs for predicting SRIL, CBC D90% > 2.6 GyE was associated with the development of SRIL with the baseline lymphocyte count and target volume. Furthermore, PBSPT significantly reduced the dose of CBC D90% (odds ratio = 0.11; p = 0.004) compared with IMRT. Conclusion: The results of this study demonstrate the significance of the dose distribution of CBCs in predicting SRIL. Furthermore, reducing the dose of CBCs after PBSPT minimized the risk of SRIL. Lymphocyte-sparing radiotherapy in PBSPT could improve outcomes, particularly in the setting of maintenance immunotherapy.

MOG antibody-associated encephalitis in adult: clinical phenotypes and outcomes.

BACKGROUND: We investigated the clinical characteristics and outcomes of myelin oligodendrocyte glycoprotein (MOG) antibody-associated autoimmune encephalitis (MOGAE) in adult patients. METHODS: From an institutional cohort, we analysed adult patients with MOGAE followed-up for more than 1 year. Disease severity was assessed using the modified Rankin scale (mRS) and Clinical Assessment Scale in Autoimmune Encephalitis scores. Immunotherapy profiles, outcomes and disease relapses were evaluated along with serial brain MRI data. RESULTS: A total of 40 patients were enrolled and categorised into cortical encephalitis (18 patients), limbic encephalitis (LE, 5 patients) and acute disseminated encephalomyelitis (ADEM, 17 patients). 80.0% of patients achieved good clinical outcomes (mRS 0‒2) and 40.0% relapsed. The LE subtype was associated with an older onset age (p=0.004) and poor clinical outcomes (p=0.014) than the other subtypes but with a low rate of relapse (0.0%). 21/25 (84.0%) relapse attacks were associated with an absence or short (≤6 months) immunotherapy maintenance. On MRI, the development of either diffuse cerebral or medial temporal atrophy within the first 6 month was correlated with poor outcomes. MOG-antibody (MOG-Ab) was copresent with anti-N-methyl-D-aspartate receptor (NMDAR)-antibody in 13 patients, in whom atypical clinical presentation (cortical encephalitis or ADEM, p<0.001) and disease relapse (46.2% vs 0.0%, p<0.001) were more frequent compared with conventional NMDAR encephalitis without MOG-Ab. CONCLUSIONS: Outcomes are different according to the three phenotypes in MOGAE. Short immunotherapy maintenance is associated with relapse, and brain atrophy was associated with poor outcomes. Patients with dual antibodies of NMDAR and MOG have a high relapse rate.

Classification of white matter lesions and characteristics of small vessel disease markers.

OBJECTIVES: Radiological markers for cerebral small vessel disease (SVD) may have different biological underpinnings in their development. We attempted to categorize SVD burden by integrating white matter signal abnormalities (WMSA) features and secondary presence of lacunes, microbleeds, and enlarged perivascular spaces. METHODS: Data were acquired from 610 older adults (aged > 40 years) who underwent brain magnetic resonance imaging exam as part of a health checkup. The WMSA were classified individually by the number and size of non-contiguous lesions, distribution, and contrast. Age-detrended lacunes, microbleeds, and enlarged perivascular space were quantified to further categorize individuals. Clinical and laboratory values were compared across the individual classes. RESULTS: Class I was characterized by multiple, small, deep WMSA but a low burden of lacunes and microbleeds; class II had large periventricular WMSA and a high burden of lacunes and microbleeds; and class III had limited juxtaventricular WMSA and lacked lacunes and microbleeds. Class II was associated with older age, diabetes, and a relatively higher neutrophil-to-lymphocyte ratio. Smoking and higher uric acid levels were associated with an increased risk of class I. CONCLUSION: The heterogeneity of SVD was categorized into three classes with distinct clinical correlates. This categorization will improve our understanding of SVD pathophysiology, risk stratification, and outcome prediction. KEY POINTS: • Classification of white matter signal abnormality (WMSA) features was associated with different characteristic of lacunes, microbleeds, and enlarged perivascular space and clinical variability. • Class I was characterized by multiple, small, deep WMSA but a low burden of lacunes and microbleeds. Class II had large periventricular WMSA and a high burden of lacunes and microbleeds. Class III had limited juxtaventricular WMSA and lacked lacunes and microbleeds. • Class II was associated with older age, diabetes, and higher neutrophil-to-lymphocyte ratio. Smoking and higher uric acid levels were associated with an increased risk of class I.

Reproductive toxicity of ritonavir in male: Insight into mouse sperm capacitation.

Since COVID-19 began in 2019, therapeutic agents are being developed for its treatment. Among the numerous potential therapeutic agents, ritonavir (RTV), an anti-viral agent, has recently been identified as an important element of the COVID-19 treatment. Moreover, RTV has also been applied in the drug repurposing of cancer cells. However, previous studies have shown that RTV has toxic effects on various cell types. In addition, RTV regulates AKT phosphorylation within cancer cells, and AKT is known to control sperm functions (motility, capacitation, and so on). Although deleterious effects of RTV have been reported, it is not known whether RTV has male reproduction toxicity. Therefore, in this study, we aimed to investigate the effects of RTV on sperm function and male fertility. In the present study, sperm collected from the cauda epididymis of mice were incubated with various concentrations of RTV (0, 0.1, 1, 10, and 100 µM). The expression levels of AKT, phospho-AKT (Thr308 and Ser473), and phospho-tyrosine proteins, sperm motility, motion kinematics, capacitation status, and cell viability were assessed after capacitation. The results revealed that AKT phosphorylation at Thr308 and Ser473 was significantly increased, and the levels of tyrosine-phosphorylated proteins (at approximately 25 and 100 kDa) were significantly increased in a dose-dependent manner. In addition, RTV adversely affected sperm motility, motion kinematics, and cell viability. Taken together, RTV may have negative effects on sperm function through an abnormal increase in tyrosine phosphorylation and phospho-AKT levels. Therefore, individuals taking or prescribing RTV should be aware of its reproductive toxicity.

GRP78 plays a key role in sperm function via the PI3K/PDK1/AKT pathway.

Glucose-regulated protein 78 (GRP78), which is commonly found in the endoplasmic reticulum (ER), is involved in stabilizing ER proteins and inducing the unfolded protein response. Furthermore, GRP78 is expressed on the surface of most common cancer cells, such as cells of breast, lung, liver, and prostate cancers, and plays a role in apoptosis and cell proliferation via the PI3K/PDK1/AKT signaling pathway. Therefore, various trials have been performed for evaluating cancer treatment by inhibiting GRP78. Moreover, GRP78 is expressed on the surface of spermatozoa; however, its role in spermatozoa physiology remains unclear. Therefore, this study was designed to investigate the effects of GRP78 on sperm function during capacitation and elucidate the underlying mechanisms. Boar spermatozoa were exposed to various concentrations of HA15, a GRP78 antagonist, and sperm kinematic parameters, capacitation status, cell viability, levels of PI3K/PDK1/AKT-pathway related proteins, and tyrosine phosphorylation were evaluated. GRP78 inhibition significantly decreased sperm motility, kinematic parameters, capacitated and acrosome-reacted spermatozoa counts, and cell viability. Moreover, GRP78 expression was significantly decreased in HA15-treated spermatozoa compared to that in the control group, and levels of PI3K/PDK1/AKT-pathway related proteins changed significantly. Furthermore, tyrosine phosphorylation was significantly altered in the HA15-treated group. The results of this study suggest that GRP78 inhibition in cancer therapy may negatively affect sperm function. These results lay a strong foundation for future studies aiming to identify the molecular mechanisms related to GRP78 in spermatozoa.

Spatiotemporal evaluation of water quality and risk assessment of heavy metals in the northern Caspian Sea bounded by Kazakhstan.

The water quality of the northern Caspian Sea has not been well-known, and its contamination can adversely affect the health of swimmers and seashore residents. The study sought to determine the contamination state of the Caspian Sea in Kazakhstan and quantify human health risks coming from the existing heavy metals concentration. The Caspian Sea was found to be "fairly to marginally" contaminated (24 < CCME-WQI < 64), with Cd influencing the index significantly. Concentrations of Cd and Pb increase over time (seasonal Kendall test, p-values = 2-4 %) in sites near oil fields and ports, suggesting the significant role of anthropogenic sources in causing diverse pollution events. Pb demonstrated the highest variability and number of outliers (4.3 % of all samples with coefficients of variation reaching up to 175 %). The principal component analysis further revealed that various discharges from oilfields and upstream transport could contribute to the contamination by heavy metals and their concentrations. Contamination is associated with up to 6 % cancer risk for adults. The long exposure duration of swimmers in water increases risks by up to 18 %, indicating the local population is at a higher risk. In conclusion, statistical tests and analysis indicate the presence of anthropogenic sources, and risk assessment reveals swimming can contribute to cancer risk.

Disease progression and brain atrophy in NMDAR encephalitis: Associated factor & clinical implication.

OBJECTIVE: We investigated the longitudinal pattern, determining factors, and clinical implications of brain volume changes in N-methyl d-aspartate receptor-antibody (NMDAR) encephalitis. METHODS: Baseline clinical profiles, treatment profiles, and outcome measured using the Clinical Assessment Scale in Autoimmune Encephalitis (CASE) and modified Rankin scale (mRS) were obtained from a long-term clinical database documenting an NMDAR encephalitis cohort. In serial MRI, the change in the normalized volume of different brain regions from the baseline evaluation was measured. At each MRI evaluation time point, the cumulative disease burden (CASE score × months) and the cumulative duration of status epilepticus were also evaluated. RESULTS: Thirty-six patients were followed-up for 28.5 months (range 12-63 months). The volume ratio at last MRI to baseline was the lowest in the cerebellum (94.4 ± 5.7%, p < 0.001). Once developed, cerebellar volume reduction followed a progressive course until 2 years from disease onset. The degree of cerebellar volume reduction was positively correlated with mRS and total CASE scores (all, p < 0.001), and CASE scores in the domains of memory, language, and psychiatric problems, gait instability/ataxia, and weakness (all, p < 0.01). In linear mixed model analyses, the degree of cerebellar volume reduction was associated with cumulative disease burden up to 2 years (p < 0.001) and duration of status epilepticus (p < 0.001), and delayed removal of teratoma for ≥1 month (p = 0.006). INTERPRETATION: In NMDAR encephalitis, cerebellar volume reduction was progressive once developed. Cerebellar volume reduction might reflect disease burden and extent of progression and be associated with poor outcomes in multiple functional domains.

Aqueous monomethylmercury degradation using nanoscale zero-valent iron through oxidative demethylation and reductive isolation.

This paper proposes a Fenton-like reaction activated by nanoscale zero-valent iron (nZVI) for aqueous monomethylmercury (MMHg) decomposition. Reacting 10 µg L-1 MMHg with 280 mg L-1 nZVI removed 70% of the aqueous MMHg within 1 min, and its main product was aqueous Hg(II). Within 1 - 5 min, the aqueous Hg(II) decreased while the aqueous, solid, and gas-phase Hg(0) increased with 92% MMHg removal. Then, a secondary Hg(II) reduction to solid Hg(0) was prevalent within 30 - 60 min, with 98% MMHg removal. Diverse-shaped magnetite crystals were observed on the surface of nZVI in 2 h, suggesting that Fe(II) oxidation on magnetite can be a source of electrons for secondary Hg(II) reduction. When FeCl2 and H2O2 were added to the MMHg solution without nZVI, 99% of the MMHg changed to Hg(II) within 1 min. The reactive oxygen species (ROS) produced by the Fenton-like reaction accounted for the rapid demethylation but not for the further reduction of Hg(II) to Hg(0). The results suggest a three-step pathway of MMHg decomposition by nZVI: (1) rapid MMHg demethylation by ROS; (2) rapid Hg(II) reduction by Fe(0); and (3) slow Hg(II) reduction by magnetite on the nZVI surface.

Neuropsychiatric symptoms and seizure related with serum cytokine in epilepsy patients.

Neuroinflammation contributes to epileptogenesis and ictogenesis. Various signals of neuroinflammation lead to neuronal hyper-excitability. Since an interplay between epilepsy, psychiatric comorbidities and neuroinflammation has been suggested, we explored psychiatric symptoms in epilepsy patients, and the relationship with neuroinflammation. We screened epilepsy patients who were admitted for video-EEG monitoring between July 2019 and December 2020. Enrolled patients were asked to respond to neuropsychiatric questionnaires (Hospital Anxiety and Depression Scale (HADS) and Neuropsychiatric Inventory-Questionnaire (NPI-Q)) on admission. Serum cytokines (IL-1ß, IL-2, IL-6, IFN-γ, CCL2, and CCL5) were measured by ELISA on admission, and within 6 h after a seizure. We enrolled 134 patients, and 32 patients (23.9%) had seizures during monitoring. Cytokine levels did not change after seizures, but IL-2 and IL-6 increased in cases of generalized tonic-clonic seizures. The HADS-A score was lower in Q4 of CCL5 (p-value = 0.016) and anxiety was also less common in Q4 of CCL5 (p-value = 0.042). NPI-Q question 4 (depression) severity was higher in CCL2 (p-value = 0.024). This suggested that psychiatric symptoms may also be related to inflammatory processes in epilepsy patients. Further large, standardized studies are necessary to underpin the inflammatory mechanisms in epilepsy and psychiatric symptoms.