Secondary trigeminal neuralgia caused by lung adenocarcinoma metastasis on trigeminal nerve roots successfully relieved by opioids: A case report.

Secondary trigeminal neuralgia (TN) is caused by identifiable diseases or lesions of the trigeminal nerve root, Gasserian ganglion and/or pons. TN is a neuropathic pain disorder characterized by electric shock-like or stabbing pain in the facial region, which can lead to impaired health-related quality of life. The present case report describes a rare case of secondary TN caused by trigeminal nerve metastases from lung adenocarcinoma, in which opioids provided symptomatic relief. The patient was a 46-year-old man with stage IV lung adenocarcinoma. They were admitted to hospital for the introduction of fifth-line chemotherapy because of previous chemotherapy-refractory disease progression. Electric shock-like or stabbing pain in the left facial area and bilateral auditory disturbances coincided with intracranial peri-brainstem metastases. Facial pain was triggered by mastication, making it difficult for the patient to eat. A fentanyl transdermal patch (25 mcg/h) was initiated following a diagnosis of TN secondary to lung adenocarcinoma metastases on the trigeminal nerves by magnetic resonance imaging. Subsequently, the facial pain improved rapidly. In conclusion, unlike classic and idiopathic TN, which is usually treated with carbamazepine as a first-line drug, oncologic secondary TN can be treated with opioids.

Haploinsufficiency of Cnot3 Aggravates Acid-Induced Acute Lung Injury Likely Through Transcriptional and Post-Transcriptional Upregulation of Pro-Inflammatory Genes.

Background: Acute lung injury (ALI) is caused by a variety of illnesses, including aspiration pneumonia and sepsis. The CCR4-NOT complex is a large multimeric protein complex that degrades mRNA through poly(A) tail shortening, whereas it also contributes to regulation of transcription and translation. Cnot3 is a scaffold component of the CCR4-NOT complex and is essential for the integrity of the complex; loss of Cnot3 leads to depletion of whole complex. While the significance of cytokine mRNA degradation in limiting inflammation has been established, the roles of CCR4-NOT complex-mediated in ALI remain elusive. Methods: The effects of Cnot3 haploinsufficiency in the pathology and cytokine expression were analyzed in the mouse lungs of acid aspiration-induced acute lung injury. The decay rate and transcription activity of cytokine mRNAs under Cnot3 heterozygous deletion were analyzed in lipopolysaccharide (LPS) -stimulated mouse embryonic fibroblasts (MEFs). Results: Tamoxifen-induced heterozygous deletion of Cnot3 in adult mice (Cnot3 Hetz) did not show body weight loss or any apparent abnormality. Under acid aspiration-induced acute lung injury, Cnot3 Hetz mice exhibited increased pulmonary edema, worse lung pathologies and more severe inflammation compared with wild type mice. mRNA expression of pro-inflammatory genes Il1b and Nos2 were significantly upregulated in the lungs of Cnot3 Hetz mice. Consistently, mRNA expression of Il1b and Nos2 was upregulated in LPS-stimulated Cnot3 Hetz MEFs. Mechanistically, while heterozygous depletion of Cnot3 stabilized both Il1b and Nos2 mRNAs, the nascent pre-mRNA level of Il1b was upregulated in Cnot3 Hetz MEFs, implicating Cnot3-mediated transcriptional repression of Il1b expression in addition to destabilization of Il1b and Nos2 mRNAs. PU.1 (Spi1) was identified as a causative transcription factor to promote Il1b expression under Cnot3 haploinsufficient conditions. Conclusion: CNOT3 plays a protective role in ALI by suppressing expression of pro-inflammatory genes Il1b and Nos2 through both post-transcriptional and transcriptional mechanisms, including mRNA stability control of Spi1.

ACE2-like enzyme B38-CAP suppresses abdominal sepsis and severe acute lung injury.

Angiotensin-converting enzyme 2 (ACE2) is the carboxypeptidase to degrade angiotensin II (Ang II) to angiotensin 1-7 (Ang 1-7) and improves the pathologies of cardiovascular disease and acute respiratory distress syndrome (ARDS)/acute lung injury. B38-CAP is a bacteria-derived ACE2-like carboxypeptidase as potent as human ACE2 and ameliorates hypertension, heart failure and SARS-CoV-2-induced lung injury in mice. Recombinant B38-CAP is prepared with E. coli protein expression system more efficiently than recombinant soluble human ACE2. Here we show therapeutic effects of B38-CAP on abdominal sepsis- or acid aspiration-induced acute lung injury. ACE2 expression was downregulated in the lungs of mice with cecal ligation puncture (CLP)-induced sepsis or acid-induced lung injury thereby leading to upregulation of Ang II levels. Intraperitoneal injection of B38-CAP significantly decreased Ang II levels while upregulated angiotensin 1-7 levels. B38-CAP improved survival rate of the mice under sepsis. B38-CAP suppressed the pathologies of lung inflammation, improved lung dysfunction and downregulated elevated cytokine mRNA levels in the mice with acute lung injury. Thus, systemic treatment with an ACE2-like enzyme might be a potential therapeutic strategy for the patients with severe sepsis or ARDS.

ACE2-like carboxypeptidase B38-CAP protects from SARS-CoV-2-induced lung injury.

Angiotensin-converting enzyme 2 (ACE2) is a receptor for cell entry of SARS-CoV-2, and recombinant soluble ACE2 protein inhibits SARS-CoV-2 infection as a decoy. ACE2 is a carboxypeptidase that degrades angiotensin II, thereby improving the pathologies of cardiovascular disease or acute lung injury. Here we show that B38-CAP, an ACE2-like enzyme, is protective against SARS-CoV-2-induced lung injury. Endogenous ACE2 expression is downregulated in the lungs of SARS-CoV-2-infected hamsters, leading to elevation of angiotensin II levels. Recombinant Spike also downregulates ACE2 expression and worsens the symptoms of acid-induced lung injury. B38-CAP does not neutralize cell entry of SARS-CoV-2. However, B38-CAP treatment improves the pathologies of Spike-augmented acid-induced lung injury. In SARS-CoV-2-infected hamsters or human ACE2 transgenic mice, B38-CAP significantly improves lung edema and pathologies of lung injury. These results provide the first in vivo evidence that increasing ACE2-like enzymatic activity is a potential therapeutic strategy to alleviate lung pathologies in COVID-19 patients.

B38-CAP is a bacteria-derived ACE2-like enzyme that suppresses hypertension and cardiac dysfunction.

Angiotensin-converting enzyme 2 (ACE2) is critically involved in cardiovascular physiology and pathology, and is currently clinically evaluated to treat acute lung failure. Here we show that the B38-CAP, a carboxypeptidase derived from Paenibacillus sp. B38, is an ACE2-like enzyme to decrease angiotensin II levels in mice. In protein 3D structure analysis, B38-CAP homolog shares structural similarity to mammalian ACE2 with low sequence identity. In vitro, recombinant B38-CAP protein catalyzed the conversion of angiotensin II to angiotensin 1-7, as well as other known ACE2 target peptides. Treatment with B38-CAP suppressed angiotensin II-induced hypertension, cardiac hypertrophy, and fibrosis in mice. Moreover, B38-CAP inhibited pressure overload-induced pathological hypertrophy, myocardial fibrosis, and cardiac dysfunction in mice. Our data identify the bacterial B38-CAP as an ACE2-like carboxypeptidase, indicating that evolution has shaped a bacterial carboxypeptidase to a human ACE2-like enzyme. Bacterial engineering could be utilized to design improved protein drugs for hypertension and heart failure.

Maternal Undernutrition and Breast Milk Macronutrient Content Are Not Associated with Weight in Breastfed Infants at 1 and 3 Months after Delivery.

This study examined whether maternal nutritional intake and breast milk macronutrient content influence the weight of breastfed infants. We investigated 129 healthy mothers with singleton babies born from July 2016 to December 2017 in a university hospital in Tokyo, Japan. Information was obtained by a self-administered food frequency questionnaire at 1 (valid response n = 92; mean age, 34 years) and 3 (n = 57) months after delivery. Breast milk was sampled at 1 and 3 months and the macronutrient contents were analyzed. The average pre-pregnancy body mass index and weight gain during pregnancy were 20.7 ± 2.6 kg/m2 and 9.6 ± 3.7 kg, respectively. At 1 month, average maternal calorie intake was 1993 ± 417 kcal/day, which was lower than the intake recommended by Japanese Dietary Reference Intakes for breastfeeding mothers. There were no significant differences with regard to maternal calorie and protein intake, and breast milk macronutrient content between breastfed infants with weight above and below the 25th percentile of its distribution at both 1 and 3 months. This study suggests that suboptimal calorie intake by breastfeeding mothers and breast milk macronutrient content were not associated with weight of their infants at 1 and 3 months after delivery.