Thalamocortical Dysconnectivity In Lifelong Premature Ejaculation: A Functional MRI Study.

OBJECTIVES: To detect seed-based functional connectivity (FC) between various cortical sub-regions and the thalamus in lifelong premature ejaculation (LPE) patients and explore whether specific thalamocortical networks are significantly altered in PE patients compared to healthy controls (HCs) METHODS: Fifty non-medicated LPE patients and 40 age-matched HCs underwent a resting-state functional MRI. FC was adopted to identify specific thalamocortical connectivity between the thalamus and 6 cortical regions of interest (i.e., the motor cortex/supplementary motor, the prefrontal cortex, the temporal lobe, the posterior parietal cortex, the somatosensory cortex and the occipital lobe). In LPE patients, regression analysis was subsequently conducted to assess relationships of thalamocortical connectivity with the Premature Ejaculation Diagnostic Tool (PEDT) score and the Intravaginal Ejaculatory Latency Time (IELT). RESULTS: LPE patients had significantly decreased FC between the motor cortex and bilateral ventral thalamus, between the prefrontal cortex and left dorsomedial thalamus, as well as between the temporal cortex and bilateral ventromedial thalamus. In LPE patients, PEDT score was significantly positively associated with the thalamus-posterior parietal cortex FC, and negatively associated with the thalamus-temporal cortex FC, while IELT was positively associated with the thalamus-temporal cortex and thalamus-motor cortex FC. CONCLUSION: These results enrich the imaging evidence for the understanding of the neurobiological mechanisms and/or consequences of LPE.

Electroacupuncture effects on the P2X4R pathway in microglia regulating the excitability of neurons in the substantia gelatinosa region of rats with spinal nerve ligation.

Electroacupuncture (EA) has been used to treat neuropathic pain induced by peripheral nerve injury (PNI) by applying an electrical current to acupoints with acupuncture needles. However, the mechanisms by which EA treats pain remain indistinct. High P2X4 receptor (P2X4R) expression levels demonstrate a notable increase in hyperactive microglia in the ipsilateral spinal dorsal horn following PNI. In order to demonstrate the possibility that EA analgesia is mediated in part by P2X4R in hyperactive microglia, the present study performed mechanical withdrawal threshold (MWT) and thermal withdrawal latency (TWL) tests in male Sprague­Dawley rats that had undergone spinal nerve ligation (SNL). The expression levels of spinal P2X4R were determined using reverse transcription­quantitative PCR, western blotting analysis and immunofluorescence staining. Furthermore, spontaneous excitatory postsynaptic currents (sEPSCs) were recorded using whole­cell patch clamp to demonstrate the effect of EA on synaptic transmission in rat spinal substantia gelatinosa (SG) neurons. The results of the present study demonstrated that EA increased the MWT and TWL and decreased overexpression of P2X4R in hyperactive microglia in SNL rats. Moreover, EA attenuated the frequency of sEPSCs in SG neurons in SNL rats. The results of the present study indicate that EA may mediate P2X4R in hyperactive spinal microglia to inhibit nociceptive transmission of SG neurons, thus relieving pain in SNL rats.

Altered Functional Connectivity of Hypothalamus in Lifelong Premature Ejaculation Patients.

BACKGROUND: As one of the most prevalent sexual dysfunctions in men, lifelong premature ejaculation (PE) often leads to patient distress. The hypothalamus is implicated in the ejaculatory control of healthy males. However, we do not know whether the hypothalamus-related intrinsic connectivity is altered in lifelong PE patients. PURPOSE: To investigate abnormal intrinsic connectivity of the hypothalamus in lifelong PE patients compared with healthy controls (HCs). STUDY TYPE: Prospective pilot study using cross-sectional data of patients and HCs. SUBJECTS: Forty-seven lifelong PE patients and 30 HCs were included in this study. FIELD STRENGTH/SEQUENCE: 3.0T MRI scanner for T1 -weighted imaging using spoiled gradient recalled echo sequence and functional imaging using a single-shot gradient recalled echo sequence. ASSESSMENT: Preprocessing of MRI data and hypothalamus-seeded functional connectivity (FC) computation were performed using DPABI4.1. STATISTICAL TESTS: The two-sample t-test within SPM12 was adopted to examine possible alterations of intrinsic connectivity of hypothalamus in lifelong PE patients compared with HCs including anxiety and depression scores as covariates (false discovery rate-corrected, P < 0.05). The correlation analysis was then used to assess possible associations between the imaging findings and clinical features in the patient group (Bonferroni-corrected, P < 0.05). RESULTS: Compared with HCs, lifelong PE patients had decreased hypothalamus-seeded FC in the left orbitofrontal cortex, bilateral insula, superior temporal cortex, superior temporal pole, middle temporal cortex, left fusiform, right parahippocampal gyrus, and right cerebellum. The intravaginal ejaculatory latency time positively correlated with the mean z-score from the hypothalamus-insula (r = 0.45) and hypothalamus-cerebellum (r = 0.48) intrinsic connectivity, separately. DATA CONCLUSION: We have shown that hypothalamus-seeded FC alterations and the correlations between the aforementioned abnormal FC alterations and intravaginal ejaculatory latency time. The current findings may promote the understanding of the hypothalamus-related neural mechanisms involved in the abnormal ejaculatory information processing in lifelong PE patients. LEVEL OF EVIDENCE: 1 TECHNICAL EFFICACY STAGE: 3 J. Magn. Reson. Imaging 2020;52:778-784.

Moderate osteoporosis itself is beneficial for bones.

There have been increasing numbers of reports that anti-osteoporosis drugs cause osteonecrosis. A typical example is medication-related osteonecrosis of the jaws (MRONJ) which can cause massive necrosis and defects of the jaws. Thus, the dosage and effects of anti-osteoporosis drugs should be re-examined. Our hypothesis is that primary moderate osteoporosis itself is beneficial for bones and should not be excessively treated other than vitamin D, calcium supplementation and functional exercises. The self-repair and anti-infection abilities of bone depend on its organic tissues including stem cells, blood vessels, osteoclastic and osteogenic factors in bone, which jointly fight against invading pathogens and repair bone damage. Recent evidence supports age-related changes in mesenchymal stem cell including loss of self-renewal and increases in senescent cell numbers. Thus, the number of MSCs and vessels need to be increased to achieve functions similar to those in young people. This requires dissolving a portion of inorganic materials and providing extra space to hold more cells and blood vessels. In contrast, anti-osteoporosis drugs prevent bone destruction, and increase mineralization that occupies the space of organic materials, reduces bone immunity and self-repair. Moreover, long term use of anti-osteoporosis drugs also have negative effects on long bones and cartilages. Therefore, moderate age-related osteoporosis is natural in humans to protect bones. Excessive treatment of osteoporosis weakens immunity and self-repair.

Parthenolide, an NF-κB inhibitor, alleviates peritoneal fibrosis by suppressing the TGF-ß/Smad pathway.

Transforming growth factor (TGF)-ß/Smad signalling plays a central role in the pathogenesis of peritoneal fibrosis related to peritoneal dialysis (PD). Parthenolide (PTL), a naturally occurring phytochemical, is isolated from the shoots of feverfew (Tanacetum parthenium) and displays analgesia, anti-inflammation and anticancer activities. In this study, we examined the therapeutic potential of PTL on PD-related peritoneal fibrosis induced by daily intraperitoneal injection of 4.25% dextrose-containing PD fluid (PDF) in vivo and TGF-ß1-induced epithelial-mesenchymal transition (EMT) in vitro. PTL was administered daily before PDF injection or after 14 days of PDF injection. Both PTL treatments showed a protective effect on peritoneal fibrosis and prevented peritoneal dysfunction. Similarly, PTL suppressed the expression of fibrotic markers (fibronectin and collagen I) and restored the expression of the epithelial marker (E-cadherin) in TGF-ß1-treated HMrSV5 cells. Furthermore, PTL inhibited TGF-ß1-induced Smad2 and Smad3 phosphorylation and nuclear translocation but did not influence Smad1/5/9 phosphorylation or activate other downstream signalling pathways of TGF-ß1, including AKT, extracellular signal-regulated kinase (ERK) or p38. In conclusion, PTL treatment may represent an effective and novel therapy for PD-associated peritoneal fibrosis by suppressing the TGF-ß/Smad pathway.

AMPK as a potential pharmacological target for alleviating LPS-induced acute lung injury partly via NLRC4 inflammasome pathway inhibition.

Old people are spectacularly susceptible to acute lung injury (ALI) and the accompanying complications. An acute aggravated inflammatory response is a characteristic feature of ALI, and inflammasomes play a critical role in the inflammatory response. Metformin has been shown to be an effective anti-inflammatory agent in ALI. However, the mechanism of this regulation still remains poorly understood. In this study, 18- to 19-month-old male mice were treated by intratracheal instillation of lipopolysaccharide (LPS) or PBS with or without metformin pretreatment. We found that the metformin pretreatment alleviated the lung injury and decreased the levels of TNF-a, IL-1ß and IL-6 in the bronchoalveolar lavage fluid (BALF) and in lung tissues, as well as the levels of NLRP3, NLRC4 and cleaved caspase-1 associated with LPS-induced ALI in old mice. Furthermore, the in vitro study showed metformin dose-dependently suppressed NLRC4 inflammasome expression. Metformin activated AMPK by phosphorylation; thus, we investigated the role of AMPK in NLRC4 activation. The results demonstrated that the efficacy of metformin was reduced when using the AMPK pharmacological inhibitor compound C or AMPKα1 expression was knocked down in RAW 264.7 cells. In conclusion, our data indicated that metformin may inhibit NLRC4 inflammasome activation in LPS-induced ALI in old mice through AMPK signaling, and further understanding of the AMPK/NLRC4 axis may provide a novel therapeutic strategy for LPS-induced ALI in the future.

Atractylenolide III ameliorates cerebral ischemic injury and neuroinflammation associated with inhibiting JAK2/STAT3/Drp1-dependent mitochondrial fission in microglia.

BACKGROUND: Inflammation is a major contributor to stroke pathology, making it a promising strategy for intervention. Microglia, the resident macrophages in the brain, play essential roles in both the generation and resolution of neuroinflammation. In particular, mitochondrial homeostasis is critical for microglial function and its dysregulation is involved in the pathogenesis of ischemic stroke. Atractylenolide III (A III), a sesquiterpene lactone found in Atractylodes macrocephala Koidz, has been shown to have an inhibitory effect on inflammation. However, its effect specifically on neuroinflammation and microglial mitochondrial homeostasis following stroke remains elusive. HYPOTHESIS: We hypothesized that A III protects against brain ischemia through inhibition of neuroinflammation mediated by JAK2/STAT3/Drp1-dependent mitochondrial fission. METHODS: The neuroprotective and anti-neuroinflammatory effects of A III were investigated in vivo in mice with transient occlusion to the middle cerebral artery (MCAO) and in vitro in oxygen glucose deprivation-reoxygenation (OGDR)-stimulated primary microglia from mice. RESULTS: A III and AG490, an inhibitor of JAK2, treatment reduced brain infarct size, restored cerebral blood flow (CBF), ameliorated brain edema and improved neurological deficits in MCAO mice. Furthermore, A III and AG490 inhibited mRNA and protein expressions of proinflammatory (IL-1ß, TNF-α, and IL-6) and anti-inflammatory cytokines in both MCAO mice and OGDR-stimulated primary microglia. The JAK2/STAT3 pathway was effectively suppressed by A III, similar to the effect of AG490 treatment. In addition, A III and AG490 treatments significantly decreased Drp1 phosphorylation, translocation and mitochondrial fission in primary microglia stimulated with OGDR for 24 h. CONCLUSION: Our study demonstrated that A III was able to reduce complications associated with ischemia through inhibiting neuroinflammation, which was mediated in part by JAK2/STAT3-dependent mitochondrial fission in microglia.

Dimethylaminomicheliolide ameliorates peritoneal fibrosis through the activation of autophagy.

Peritoneal fibrosis (PF) is a major cause of ultrafiltration failure in patients receiving long-term peritoneal dialysis (PD), and effective prevention and treatment strategies are urgently needed. The dimethylamino Michael adduct of a natural product-derived micheliolide (MCL), dimethylaminomicheliolide (DMAMCL), is a new lead compound with the advantages of high stability, low toxicity, and sustainable release of MCL. This study aimed to investigate the protective effect of DMAMCL against PD-related PF and the mechanisms involved. In this study, we found that DMAMCL significantly decreased PD-induced extracellular matrix (ECM) deposition in a mouse model of PD, and that delayed DMAMCL administration halted the progression of PF in an established PD model. In addition, rapamycin administration induced autophagy and significantly ameliorated PF. The protective effect of DMAMCL against PF was weakened when co-administered with DMAMCL and 3-methyladenine. Inducing autophagy by rapamycin decreased transforming growth factor-ß1-induced ECM accumulation in vitro. MCL promoted autophagy and inhibited ECM deposition. The anti-fibrotic effect of MCL was eliminated when knocking down ATG7 by siRNA. Taken together, DMAMCL might prevent against PF through activating autophagy. The anti-fibrotic effect of DMAMCL may be a new candidate for the treatment in patients with PD-related PF. KEY MESSAGES: Dimethylaminomicheliolide, the pro-drug of micheliolide, protects against peritoneal fibrosis in a mouse peritoneal dialysis model. Micheliolide inhibits TGF-ß1-induced extracellular matrix accumulation in vitro. Autophagy plays a protective role against peritoneal fibrosis. The antifibrogenic effect of dimethylaminomicheliolide may be due to the activation of autophagy.

Enhanced lead and cadmium removal using biochar-supported hydrated manganese oxide (HMO) nanoparticles: Behavior and mechanism.

Hydrated manganese oxide (HMO) nanoparticles were impregnated into a peanut shell-derived biochar (BC) to obtain a remarkable nanocomposite adsorbent, HMO-BC, which overcomes the technical barriers of singly applying either HMO or BC in practical heavy metal-containing wastewater treatment. HMO-BC can effectively sequestrate Pb(II) and Cd(II) in a wide pH range of 3-7 and exhibited more preferable sorption than bare BC in the presence of high-level competing cations. BC also significantly lowered the Mn leaching at acidic pH. Fixed-bed column adsorption tests showed that the effective treatment volume of HMO-BC for a simulated Pb(II)- or Cd(II)-laden wastewater is about 4-6 times higher than that of the BC host. In addition, HMO-BC was effective in removing Pb(II) from a real Pb-containing electroplating wastewater to discharge limit (0.2mgL-1) with treatable volume of 525BV, much higher than that of the bare BC (60BV). More importantly, the saturated HMO-BC can be thoroughly regenerated for repeated uses without any observable capacity loss. Such attractive results of HMO-BC were attributed to the complementary effect of its two components. The embedded HMO nanoparticles provide preferable capture of target cations through specific inner-sphere complexation, as illustrated by XPS spectra of Pb 4f7/2 and O1s, while the non-diffusive negatively charged oxygen-containing groups bound to BC facilitate the pre-enrichment and permeation of Pb(II) and Cd(II) cations into the pore channels prior to their preferable sorption through the Donnan membrane effect.

Monoclonal antibody-based serological assays for detection of Potato virus S in potato plants.

Potato virus S (PVS) often causes significant losses in potato production in potato-growing countries. In this study, the ordinary strain of PVS (PVSO) was purified from PVS-infected potato plants and used as the immunogen to produce hybridomas secreting monoclonal antibodies (MAbs). Five highly specific and sensitive murine MAbs (1A3, 16C10, 18A9, 20B12, and 22H4) against PVS were prepared using conventional hybridoma technology. Using these MAbs, tissue print-enzyme-linked immunosorbent assay (ELISA), dot-ELISA, and double-antibody sandwich (DAS)-ELISA were developed for sensitive and specific detection of PVS infection in potato plants. The results of sensitivity assays revealed that PVS could be reliably detected in PVS-infected leaf crude extracts diluted at 1:10 240 and 1:163 840 (w/v, g/ml) in phosphate buffer saline (PBS) by dot-ELISA and DAS-ELISA, respectively. Twenty-two samples collected from potato fields in Yunnan Province, China were tested for PVS infection using the serological assays we had developed, and 14 of them were found to be positive. This indicates that PVS is now prevalent in potato fields in Yunnan Province.

Correlations between serum intact parathyroid hormone (PTH) and N-terminal-probrain natriuretic peptide levels in elderly patients with chronic heart failure (CHF).

OBJECTIVES: The aim of this study was to investigate the association between PTH and Nt-proBNP in elderly patients with CHF in an attempt to gain insights into the role of PTH in a community-based cohort of elderly patients with CHF. METHODS: A total of 182 consecutive CHF patients with follow-up for mortality after 3 years were prospectively studied. Serum levels of intact PTH, Nt-proBNP and biochemical parameters were examined. The enrolled patients were divided into groups by the levels of PTH and New York Heart Association (NYHA) functional classes. RESULTS: A total of 66 (36%) patients had PTH values above the upper limit of the normal range. Serum creatinine (p=0.001), estimated glomerular filtration rate (eGFR) (p=0.001), Nt-proBNP (p<0.001), serum calcium (p=0.030), heart rate (p=0.002) showed statistical significance in different stages of PTH. The mean PTH and Nt-proBNP levels increased as the NYHA functional class increased. The optimal cut-off value of PTH to predict CHF-related death was 48.98 pg/ml, with 57.14% sensitivity and 86.24% specificity. The best cut-off point of Nt-proBNP was 480 ng/ml with 76.47% sensitivity and 80.48% specificity. Over a mean follow-up of 3 years, Kaplan-Meier survival curves demonstrate that patients with higher levels of intact PTH had lower survival time, with a hazard ratio of 2.5 (95% CI 1.5-3.9). CONCLUSIONS: The study has shown that serum intact PTH level obtained in the elderly patients with CHF is a novel biomarker associated with Nt-proBNP and could provide supplementary information for the diagnosis and prognostic prediction of CHF, especially when it is used in combination with Nt-proBNP.