Rejected

Magnoliae Flos is a traditional herbal medicine used to treat nasal congestion associated with headache, empyema, and allergic rhinitis. In our preliminary screening of crude drugs used in Japanese Kampo formulas for melanin synthesis, the methanol extract of Magnoliae Flos was found to exhibit strong melanin synthesis activity. However, there have been no studies evaluating the effects of Magnoliae Flos or its constituents on melanogenesis. The present study aimed to isolate the active compounds from Magnoliae Flos that activate melanin synthesis in melanoma cells and three-dimensional human skin equivalent, and to investigate the molecular mechanism underlying melanin induction. The methanol extract of Magnoliae Flos induced an increase of melanin content in both B16-F1 and HMV-II cells. A comparison of melanin induction by three fractions prepared from the extract showed that the ethyl acetate fraction markedly induced melanin synthesis. Bioassay-guided separation of the ethyl acetate fraction resulted in the isolation of seven lignans (1:  - 7: ). Among them, (+)-magnolin (5: ) strongly induced melanin synthesis and intracellular tyrosinase activity. Furthermore, the ethyl acetate fraction and 5: clearly induced melanin content in a three-dimensional human skin equivalent. Molecular analysis revealed that 5: triggered the protein expression of tyrosinase, tyrosinase-related protein-1, and tyrosinase-related protein-2. Further analysis of transcriptional factors and signaling pathways demonstrated that 5: induces the protein expression of tyrosinase, tyrosinase-related protein-1, and tyrosinase-related protein-2 activated by the protein kinase A- and p38 mitogen-activated protein kinase-dependent pathways, leading to cAMP-responsive element-binding protein phosphorylation and microphthalmia-associated transcription factor expression. These findings demonstrate the potential of 5: as a potent therapeutic agent for hypopigmentation.

Synthetic cannabinoid receptor agonists (SCRAs) are a large group of abused psychoactive compounds that elicit numerous toxic effects not observed with cannabis, including death. Abuse of third-generation SCRA 5F-MDMB-PINACA (also known as 5F-ADB) has been associated with over 40 fatalities. This SCRA is metabolized to several active phase I metabolites, including excessively high post-mortem serum concentrations of an ester hydrolysis metabolite, 5F-MDMB-PINACA-M7 (M7). Although high serum concentrations of M7 (and other active metabolites) have been suggested to contribute to 5F-MDMB-PINACA toxicity, the affinity of M7 for CB1 receptors is unknown and more complete pharmacodynamic characterization of 5F-MDMB-PINACA and its active metabolites is needed. Competition binding and G-protein modulation studies presented here confirm reports that 5F-MDMB-PINACA and a second N-5-hydroxypentyl metabolite (M2) exhibit nanomolar affinity and act as high efficacy agonists at CB1 receptors. Also as previously published, M7 exhibits high efficacy at CB1 receptors; however, demonstrated here for the first time, M7 retains only low μM affinity. Empirically derived Kb values indicate rimonabant differentially antagonizes G-protein activation produced by 5F-MDMB-PINACA, relative to Δ9-THC (THC) or its metabolites. Chronic administration of 5F-MDMB-PINACA and metabolites results in CB1 down-regulation, but only 5F-MDMB-PINACA produces desensitization. Although low CB1 affinity/potency of M7 precluded in vivo studies, both M2 and THC produce locomotor suppression and CB1-mediated dose-dependent hypothermia and analgesia in mice. Collectively, these data confirm and extend previous studies suggesting that 5F-MDMB-PINACA is metabolized to active compounds exhibiting atypical pharmacodynamic properties at CB1 receptors, that may accumulate with parent drug to produce severe toxicity.

An elderly male presented with complaint of dull aching pain in left upper abdomen of 2 months' duration. He was well built, and on abdominal examination, a large lump was palpable in left lumbar region. His biochemical, hematological parameters and tumor markers including CA 19.9 were within prescribed normal limits. Contrast enhanced computed tomography (CT) of the abdomen revealed large, well-defined, mixed solid, and cystic lesion arising from distal body-tail of the pancreas extending up to splenic hilum. Chronic thrombosis involving retro pancreatic splenic vein with multiple perisplenic, peripancreatic, and perigastric collaterals were noted. Based on characteristic CT abdomen findings, a diagnosis of solid pseudopapillary tumor (SPT) of the pancreas with sinistral portal hypertension (SPH) was made. The patient was planned for open distal pancreatectomy with splenectomy. At surgery, splenic flexure of colon was densely adhered to the tumor, and hence en bloc resection of colon was also performed. Postoperative period was uneventful, and he was discharged from the hospital on postoperative day 6. Histopathology reported solid pseudopapillary tumor of the pancreas, 22 cm in the largest dimension. SPT of the pancreas rarely present with SPH. At 22-cm size, this may be one of the largest SPTs reported in the English literature to date.

Metastases to the sellar region and pituitary gland are rare and usually occur in advanced cancers, commonly breast and lung adenocarcinomas. Metastases from sarcomas to the pituitary gland are extremely rare. Here, we report the case of a 52-year-old man who had undergone surgery and radiotherapy for a clear cell sarcoma (CCS) of the knee at age of 42. The patient underwent resection of 2 distinct metastatic lung nodules 9 years later. During follow-up, he developed a persistent headache and diabetes insipidus. MRI revealed a sellar and suprasellar lesion, which was removed with an endoscopic trans-sphenoidal approach. Histopathology was consistent with CSS metastasis. At 2-year follow-up, there was no evidence of local recurrence in the sella, while a single brain metastasis was documented, together with other deposits in the paravertebral and pelvic muscles. CCS is a rare, aggressive neoplasm usually involving the deep soft tissue of the extremities, including trunk or limb girdles, and extensive surgical removal, along with adjuvant chemo- and radiotherapy, significantly prolongs survival. Nevertheless, prognosis remains poor, mainly due to frequent local recurrences and eventually distant metastases, usually within regional lymph nodes, lung, and bone. To the best of our knowledge, this is the first description of a sellar metastasis from CCS.

Spinal cord injury (SCI) can cause secondary brain changes, leading to hypomyelination in the dorsolateral prefrontal cortex (dlPFC). Some studies have shown that notch signaling pathway activation can regulate oligodendrocyte maturation and myelination. The aim of this study was to investigate whether inhibition of the Notch signaling pathway can alleviate hypomyelination in the dlPFC caused by SCI. Moreover, we further investigated whether the changes in myelination in the dlPFC are associated with neuropathic pain following SCI. We established a mouse model of SCI and observed the changes in mechanical and thermal hyperalgesia. Western blotting and immunofluorescence were used to analyze the changes in myelination in the dlPFC. The results indicated the existence of a relationship between activation of the Notch signaling pathway and hypomyelination in the dlPFC and confirmed the existence of a relationship between hypomyelination in the dlPFC and decreases in mechanical and thermal hyperalgesia thresholds. In conclusion, these results suggested that the Notch signaling pathway is activated after SCI, leading to hypomyelination in the dlPFC, and that DAPT can inhibit the Notch signaling pathway and improve mechanical and thermal hyperalgesia thresholds. Our findings provide a new target for the treatment of neuropathic pain caused by SCI.

Recent advancements in analytical techniques have greatly contributed to the analysis of latent fingermarks' (LFMs) "touch chemistry" and identification of materials that a suspect might have come into contact with. This type of information about the FM donor is valuable for criminal investigations because it narrows the pool of suspects. It is estimated that at least 30 million people around the world take over-the-counter and prescription nonsteroidal anti-inflammatory drugs (NSAIDs) for pain relief, headaches and arthritis every day. The daily use of such drugs can lead to an increased risk of their abuse. In the present study, Raman spectroscopy combined with multivariate statistical analysis was used for the detection and identification of drug traces in LFMs when NSAID tablets of aspirin, ibuprofen, diclofenac, ketoprofen and naproxen have been touched. Partial least squares discriminant analysis of Raman spectra showed an excellent separation between natural FMs and all NSAID-contaminated FMs. The developed classification model was externally validated using FMs deposited by a new donor and showed 100% accuracy on a FM level. This proof-of-concept study demonstrated the great potential of Raman spectroscopy in the chemical analysis of LFMs and the detection and identification of drug traces in particular.

To date, there is still partial data on the effects of COVID-19 on pregnant women. The constant collection of information results in a continuous updating of the knowledge about the best management of pregnant patients affected by COVID-19. This work aims to summarize the state of the art on prevention and management of SARSCoV-2 infection in obstetric patients. This was enabled by a comprehensive literature search for the most recent and relevant publications on the subject, including guidelines and recommendations. Management of these women by a multidisciplinary team is of crucial importance, given the extreme clinical complexity of this condition. Every health worker involved must put in place all possible procedures to protect themselves from contagion. Neuraxial anesthesia should be favored in the management of labor and caesarean section over other modalities, unless there are contraindications based on the patient's status. There is still no standardized drug treatment in pregnant women with COVID-19 due to their exclusion from studies conducted to evaluate pharmacological therapies. Nevertheless, various drugs have been used to treat this disease in pregnancy, although the data at our disposal are still few. As regards mRNA vaccines, it seems that their immunogenicity, safety and tolerability in pregnant women are comparable to those of non-pregnant women of the same age. More studies are certainly needed in infected pregnant women to establish treatment and prevention protocols for this special category of patients.

In most population-based studies of low back pain (LBP), women have a higher risk than men, possibly reflecting hormonal influences. The aim of this study was to explore associations between age at menarche and menopause and risk of chronic LBP.

Optimal control of acute postoperative pain and prevention of chronic persistent pain in total knee arthroplasty (TKA) remain a challenge.