Rejected

Inducible nitric oxide synthase (iNOS) produces NO from l-arginine and plays critical roles in inflammation and immune activation. Selective and potent iNOS inhibitors may be potentially used in many indications, such as rheumatoid arthritis, pain, and neurodegeration. In the current study, five new compounds, including a dibenzo-α- pyrone derivative ellagic acid B () and four αpyrones diaporpyrone A-D (), together with three known compounds (-), were isolated from the endophytic fungus sp. CB10100. The structures of these new natural products were unambiguously elucidated using NMR, HRESIMS or electronic circular dichroism calculations. Ellagic acid B () features a tetracyclic 6/6/6/6 ring system with a fused 2-chromene, which is different from ellagic acid () with a fused 2-chromen-2-one. Both 2-hydroxy-alternariol () and alternariol () reduced the expression of iNOS at protein levels in a dose-dependent manner, using a lipopolysaccharide (LPS)-induced RAW264.7 cell models. Also, they decreased the protein expression levels of pro-inflammatory cytokines, such as tumor necrosis factor-α, interleukin-6 and monocyte chemotactic protein 1. Importantly, and significantly reduced the production of NO as low as 10 μM in LPS-induced RAW264.7 cells. Molecular docking of and to iNOS further suggests that both of them may interact with iNOS. Our study suggests that and , as well as the alternariol scaffold may be further developed as potential iNOS inhibitors.

Intradural disc herniation (IDH) is a rare type of disc degeneration that infrequently affects the upper lumbar spine. Pre- and intraoperative diagnosis and surgical management of IDH are challenging. The present case study provides insight into these aspects of upper lumbar IDH and discusses possible mechanisms.

Thunderclap headache is frequently associated with serious intracranial vascular disorders and a usual reason for emergency department admissions. Association of thunderclap headaches with autoimmune disorders, such as steroid-responsive encephalopathy with autoimmune thyroiditis (SREAT), is highly unusual. Here, we report a patient who presented with high-intensity headache of abrupt onset. Cerebrospinal fluid (CSF) analysis revealed moderate lymphocytic pleocytosis without evidence of infectious, neoplastic, or metabolic causes. Brain magnetic resonance imaging showed no specific pathologies, and examinations for neuronal antibodies in serum and CSF were negative. The medical history revealed that seven years before, an episode of an aseptic meningoencephalitis with remarkable response to steroids was present. Finally, increased levels of serum anti-TPO antibodies were identified, and against the background of a previous steroid-responsive aseptic meningoencephalitis, diagnosis of SREAT was highly probable. Methylprednisolone therapy was initiated, and the patient recovered completely. In particular, because most SREAT patients respond very well to steroids, this case underlines the importance of taking SREAT into consideration during the assessment of a high-intensity headache of abrupt onset.

Management of neuropathic pain in people with diabetes has been widely investigated. However, little attention was paid to address ischemic-related pain in patients with diabetes mellitus who suffered from chronic limb-threatening ischemia (CLTI), the end stage of lower extremity arterial disease (LEAD). Pain management has a tremendous influence on patients' quality of life and prognosis. Poor management of this type of pain owing to the lack of full understanding undermines patients' physical and mental quality of life, which often results in a grim prognosis, such as depression, myocardial infarction, lower limb amputation, and even mortality. In the present article, we review the current strategy in the pain management of diabetes-related CLTI. The endovascular therapy, pharmacological therapies, and other optional methods could be selected following comprehensive assessments to mitigate ischemic-related pain, in line with our current clinical practice. It is very important for clinicians and patients to strengthen the understanding and build intervention strategy in ischemic pain management and possible adverse consequence.

Oral Chinese patent medicine (OCPM) combined with western medicine (WM) are believed to be effective for the therapy of chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) with sexual dysfunction (SD). These western medicines mainly involve antibiotics, phosphodiesterase type-5 inhibitor (PDE-5i), α-blockers. But there is no randomized controlled trial (RCT) that directly compares the efficacy of different OCPM. Hence, we operated a network meta-analysis (NMA) to contrast the efficacy of different OCPM for CP/CPPS with SD. Relevant studies were searched in PubMed, Cochrane Library, Web of Science, Embase, China National Knowledge Infrastructure (CNKI), Chinese Scientific Journal Database (VIP), and Wanfang database. All of the RCTs concentrated on the use of OCPM to cure CP/CPPS with SD from the inception of the databases to November 2020. We appraised the risk of bias under the Cochrane Handbook and CONSORT statement. The data were statistically analyzed STATA 13.0 and WinBUGS 1.4.3 instrument. Altogether, 30 pieces of literature with 2,996 participants containing 11 oral Chinese patent medicine and 11 interventions were included in the NMA. In terms of The National Institutes of Health chronic prostatitis symptom index (NIH-CPSI), Qianlie Shutong Capsules (QLSTC) + WM had the most possible of being the optimal treatment. In the light of the International Index of Erectile Function (IIEF-5), Congrong Yishen Granules (CRYSG) + WM had the most possible of being the optimal treatment. Shugan Yiyang Capsules (SGYYC) + WM performed the highest likelihood efficacy under cluster rank graph combined NIH-CPSI and IIEF-5. Liuwei Dihuang Pills/Yougui capsules (LWDHP/YGC) + WM had highly possible to be the optimal treatment not only for the clinical effective rate of CP/CPPS but also for the clinical effective rate of SD. Considering four outcomes, QLSTC, CRYSG, SGYYC, LWDHP/YGC, Qianlie Beixi Capsules (QLBXC) plus WM were the best therapy approach for CP/CPPS with SD, especially LWDHP/YGC + WM and QLBXC + WM. Based on the NMA, QLSTC, CRYSG, SGYYC, LWDHP/YGC, QLBXC plus WM demonstrated the maximum probability of being the optimal therapies. Owing to the limitations of this research, these results should be confirmed by elaborate RCTs. [https://www.crd.york.ac.uk/prospero/], identifier [CRD42021224060].

Electronic devices, laptops, tablets, ipad and smart phones are an integral part of one's life both in work and personal space. Excessive usage of these devices had led to health-related problems of which computer vision syndrome (CVS) is at risk of becoming a major public health issue.

[This corrects the article DOI: 10.1371/journal.pone.0249128.].

Spontaneous coronary artery dissection (SCAD) is increasingly recognized as an important cause of acute coronary syndrome (ACS) and myocardial infarction (MI) in individuals with few or no known atherosclerotic risk factors. While systemic autoimmune inflammatory disorders are associated with precipitating SCAD, the role of infection-induced systemic inflammation in SCAD is not well defined. We present the case of a 49-year-old Caucasian woman with ST-elevation myocardial infarction (STEMI) diagnosed as SCAD from a severe systemic inflammatory response related to disseminated blastomycosis. Punch biopsy of a skin lesion and synovial fluid culture confirmed . This case suggests the possibility of systemic infection-induced inflammation as a precipitating factor in SCAD pathogenesis similar to autoimmune inflammatory disorders.

Low back pain (LBP) has been a wide public health concern worldwide. Among the pathogenic factors, intervertebral disc degeneration (IDD) has been one of the primary contributors to LBP. IDD correlates closely with inflammatory response and oxidative stress, involving a variety of inflammation-related cytokines, such as interleukin 1 beta (IL-1), which could result in local inflammatory environment. Ulinastatin (UTI) is a kind of acidic protein extracted from human urine, which inhibits the release of tumor necrosis factor alpha (TNF-) and other inflammatory factors to protect organs from inflammatory damage. However, whether this protective effect of UTI on human nucleus pulposus (NP) exists, and how UTI affects the biological behaviors of human NP cells during IDD remain elusive. In this current study, we revealed that UTI could improve the viability of NP cells and promote the proliferation of NP cells. Additionally, UTI could protect human NP cells via ameliorating IL-1-induced apoptosis, inflammatory response, oxidative stress, and extracellular matrix (ECM) degradation. Molecular mechanism analysis suggested that the protective effect from UTI on IL-1-treated NP cells were through activating nuclear factor- (erythroid-derived 2-) like 2 (Nrf2)/heme oxygenase-1 (HO-1) signaling pathway and the suppression of NF-B signaling pathway. Therefore, UTI may be a promising therapeutic medicine to ameliorate IDD.

The intrathecal (i.t.) injection of substance P (SP) and N-methyl-D-aspartate (NMDA) induce transient nociceptive response by activating neurokinin (NK) 1 and NMDA receptors, respectively. We have recently reported that angiotensin (Ang) (1-7), an N-terminal fragment of Ang II, could alleviate several types of pain including neuropathic and inflammatory pain by activating spinal MAS1. Here, we investigated whether Ang (1-7) can inhibit the SP- and NMDA-induced nociceptive response. The nociceptive response induced by an i.t. injection of SP or NMDA was assessed by measuring the duration of hindlimb scratching directed toward the flank, biting and/or licking of the hindpaw or the tail for 5 min. Localization of MAS1 and either NK1 or NMDA receptors in the lumbar superficial dorsal horn was determined by immunohistochemical observation. The nociceptive response induced by SP and NMDA was attenuated by the i.t. co-administration of Ang (1-7) (0.03-3 pmol) in a dose-dependent manner. The inhibitory effects of Ang (1-7) (3 pmol) were attenuated by A779 (100 pmol), a MAS1 antagonist. Moreover, immunohistochemical analysis showed that spinal MAS1 co-localized with NK1 receptors and NMDA receptors on cells in the dorsal horn. Taken together, the i.t. injection of Ang (1-7) attenuated the nociceptive response induced by SP and NMDA via spinal MAS1, which co-localized with NK1 and NMDA receptors. Thus, the spinal Ang (1-7)/MAS1 pathway could represent a therapeutic target to effectively attenuate spinal pain transmission caused by the activation of NK1 or NMDA receptors.