The lipid mediator protectin D1 inhibits influenza virus replication and improves severe influenza.

Influenza A viruses are a major cause of mortality. Given the potential for future lethal pandemics, effective drugs are needed for the treatment of severe influenza such as that caused by H5N1 viruses. Using mediator lipidomics and bioactive lipid screen, we report that the omega-3 polyunsaturated fatty acid (PUFA)-derived lipid mediator protectin D1 (PD1) markedly attenuated influenza virus replication via RNA export machinery. Production of PD1 was suppressed during severe influenza and PD1 levels inversely correlated with the pathogenicity of H5N1 viruses. Suppression of PD1 was genetically mapped to 12/15-lipoxygenase activity. Importantly, PD1 treatment improved the survival and pathology of severe influenza in mice, even under conditions where known antiviral drugs fail to protect from death. These results identify the endogenous lipid mediator PD1 as an innate suppressor of influenza virus replication that protects against lethal influenza virus infection.

LPCAT3/LPLAT12 deficiency in the liver ameliorates acetaminophen-induced acute liver injury.

Acetaminophen (APAP) is a double-edged sword, mainly depending on the dosage. A moderate dose of APAP is effective for fever and pain relief; however, an overdose induces acute liver injury. The mechanism underlying APAP-induced acute liver failure is unclear, and its treatment is limited. A recent report has shown that several oxidized phospholipids are associated with APAP-induced acute liver failure. Lysophosphatidylcholine acyltransferase 3 (Lpcat3, Lplat12), which is highly expressed in the liver, preferentially catalyzes the incorporation of arachidonate into lysophospholipids (PLs). In the present study, we investigated the roles of Lpcat3 on APAP-induced acute liver injury using liver-specific Lpcat3-knockout mice. Hepatic Lpcat3 deficiency reduced the degree of APAP-induced necrosis of hepatocytes around Zone 3 and ameliorated the elevation of hepatic injury serum marker levels, and prolonged survival. Lipidomic analysis showed that the accumulation of oxidized and hydroperoxidized phospholipids was suppressed in Lpcat3-knockout mice. The amelioration of APAP-induced acute liver injury was due not only to the reduction in the lipid synthesis of arachidonic acid PLs because of Lpcat3 deficiency, but also to the promotion of the APAP detoxification pathway by facilitating the conjugation of glutathione and N-acetyl-p-benzoquinone imine. Our findings suggest that Lpcat3 is a potential therapeutic target for treating APAP-induced acute liver injury.

Overexpression of lysophospholipid acyltransferase, LPLAT10/LPCAT4/LPEAT2, in the mouse liver increases glucose-stimulated insulin secretion.

Postprandial hyperglycemia is an early indicator of impaired glucose tolerance that leads to type 2 diabetes mellitus (T2DM). Alterations in the fatty acid composition of phospholipids have been implicated in diseases such as T2DM and nonalcoholic fatty liver disease. Lysophospholipid acyltransferase 10 (LPLAT10, also called LPCAT4 and LPEAT2) plays a role in remodeling fatty acyl chains of phospholipids; however, its relationship with metabolic diseases has not been fully elucidated. LPLAT10 expression is low in the liver, the main organ that regulates metabolism, under normal conditions. Here, we investigated whether overexpression of LPLAT10 in the liver leads to improved glucose metabolism. For overexpression, we generated an LPLAT10-expressing adenovirus (Ad) vector (Ad-LPLAT10) using an improved Ad vector. Postprandial hyperglycemia was suppressed by the induction of glucose-stimulated insulin secretion in Ad-LPLAT10-treated mice compared with that in control Ad vector-treated mice. Hepatic and serum levels of phosphatidylcholine 40:7, containing C18:1 and C22:6, were increased in Ad-LPLAT10-treated mice. Serum from Ad-LPLAT10-treated mice showed increased glucose-stimulated insulin secretion in mouse insulinoma MIN6 cells. These results indicate that changes in hepatic phosphatidylcholine species due to liver-specific LPLAT10 overexpression affect the pancreas and increase glucose-stimulated insulin secretion. Our findings highlight LPLAT10 as a potential novel therapeutic target for T2DM.

PTEN Regulates PI(3,4)P2 Signaling Downstream of Class I PI3K.

The PI3K signaling pathway regulates cell growth and movement and is heavily mutated in cancer. Class I PI3Ks synthesize the lipid messenger PI(3,4,5)P3. PI(3,4,5)P3 can be dephosphorylated by 3- or 5-phosphatases, the latter producing PI(3,4)P2. The PTEN tumor suppressor is thought to function primarily as a PI(3,4,5)P3 3-phosphatase, limiting activation of this pathway. Here we show that PTEN also functions as a PI(3,4)P2 3-phosphatase, both in vitro and in vivo. PTEN is a major PI(3,4)P2 phosphatase in Mcf10a cytosol, and loss of PTEN and INPP4B, a known PI(3,4)P2 4-phosphatase, leads to synergistic accumulation of PI(3,4)P2, which correlated with increased invadopodia in epidermal growth factor (EGF)-stimulated cells. PTEN deletion increased PI(3,4)P2 levels in a mouse model of prostate cancer, and it inversely correlated with PI(3,4)P2 levels across several EGF-stimulated prostate and breast cancer lines. These results point to a role for PI(3,4)P2 in the phenotype caused by loss-of-function mutations or deletions in PTEN.

Phosphatidylinositol-3,4,5-trisphosphate interacts with alpha-synuclein and initiates its aggregation and formation of Parkinson's disease-related fibril polymorphism.

Lipid interaction with α-synuclein (αSyn) has been long implicated in the pathogenesis of Parkinson's disease (PD). However, it has not been fully determined which lipids are involved in the initiation of αSyn aggregation in PD. Here exploiting genetic understanding associating the loss-of-function mutation in Synaptojanin 1 (SYNJ1), a phosphoinositide phosphatase, with familial PD and analysis of postmortem PD brains, we identified a novel lipid molecule involved in the toxic conversion of αSyn and its relation to PD. We first established a SYNJ1 knockout cell model and found SYNJ1 depletion increases the accumulation of pathological αSyn. Lipidomic analysis revealed SYNJ1 depletion elevates the level of its substrate phosphatidylinositol-3,4,5-trisphosphate (PIP3). We then employed Caenorhabditis elegans model to examine the effect of SYNJ1 defect on the neurotoxicity of αSyn. Mutations in SYNJ1 accelerated the accumulation of αSyn aggregation and induced locomotory defects in the nematodes. These results indicate that functional loss of SYNJ1 promotes the pathological aggregation of αSyn via the dysregulation of its substrate PIP3, leading to the aggravation of αSyn-mediated neurodegeneration. Treatment of cultured cell line and primary neurons with PIP3 itself or with PIP3 phosphatase inhibitor resulted in intracellular formation of αSyn inclusions. Indeed, in vitro protein-lipid overlay assay validated that phosphoinositides, especially PIP3, strongly interact with αSyn. Furthermore, the aggregation assay revealed that PIP3 not only accelerates the fibrillation of αSyn, but also induces the formation of fibrils sharing conformational and biochemical characteristics similar to the fibrils amplified from the brains of PD patients. Notably, the immunohistochemical and lipidomic analyses on postmortem brain of patients with sporadic PD showed increased PIP3 level and its colocalization with αSyn. Taken together, PIP3 dysregulation promotes the pathological aggregation of αSyn and increases the risk of developing PD, and PIP3 represents a potent target for intervention in PD.

A Complex of Type I Platelet-Activating Factor Acetylhydrolase (PAF-AH) Catalytic Subunits Switches from α1/α2 Heterodimer to α2/α2 Homodimer during Adipocyte Differentiation of 3T3-L1 Cells.

Platelet-activating factor acetylhydrolase (PAF-AH) hydrolyzes an acetyl ester at the sn-2 position of platelet-activating factor (PAF), thereby mediating a variety of biological functions. PAF-AH is found in three isoforms: Type I PAF-AH (PAF-AH I) and Type II PAF-AH (PAF-AH II) are intracellular enzymes whereas plasma PAF-AH is characterized by association with lipoprotein in plasma. PAF-AH I forms a tetramer constituted by two catalytic subunits (α1 and α2) with ß regulatory subunits. We recently showed that a deficiency of PAF-AH I catalytic subunits in male mice caused an increase of body weight, food intake, and white adipose tissue (WAT) weight. In this study, we examined whether the expression of this enzyme was altered in the differentiation of 3T3-L1 preadipocytes into adipocytes. The amount of PAF-AH I α1 subunit protein was significantly reduced in 3T3-L1 differentiation, while the amount of the PAF-AH I α2 subunit was not changed. Immunoprecipitation analysis of 3T3-L1 differentiation showed that the complex of PAF-AH I catalytic subunits was changed from α1/α2 heterodimer to α2/α2 homodimer. Our findings suggest that changes in PAF-AH I catalytic subunits are involved in adipocyte differentiation of 3T3-L1 and obesity in mice.

Intraneural fibrosis within ilioinguinal nerve in inguinal hernia patients with preoperative pain: it's the sign of irreversible nerve injury, isn't it?

PURPOSE: Preoperative pain is known as one of the most powerful risk factors for chronic postoperative inguinal pain (CPIP), while its pathogenesis has not been fully elucidated. The aim of the present study was to evaluate patients with preoperative pain from the pathological perspective and discuss the potential pathogenesis of CPIP in those patients. METHODS: This was a single-institutional retrospective study. The study population was inguinal hernia patients with preoperative pain who underwent open anterior hernia repair for primary inguinal hernia with pragmatic ilioinguinal neurectomy during surgery between March 2021 and March 2023. The primary and secondary outcomes were proportion of collagen deposition and mucus accumulation within ilioinguinal nerve in those patients, respectively, which were evaluated histologically using Image J software. RESULTS: Forty patients were evaluated. Median value of proportion of intraneural collagen deposition was 38.3% (27.7-95.9). These values were positively correlated with the duration of pain (r2=0.468, P<0.001). Median value of proportion of mucus accumulation in ilioinguinal nerve was 50.1% (0-82.0). These values had no correlation with any clinicopathological variables. CONCLUSIONS: In the present study population, all patients with preoperative pain had intraneural fibrosis within ilioinguinal nerve, and its degree had a positive correlation with the pain duration.

Mid-term outcomes of intracorporeal versus extracorporeal anastomosis after laparoscopic colectomy: a propensity score-matched cohort study from a single institution.

PURPOSE: There is still insufficient discussion of the mid- to long-term safety of the intracorporeal anastomosis (IA) method of reconstruction after laparoscopic colectomy (LAC) for colon cancer. The present study clarified the postoperative mid-term results of IA based on recurrence and the incidence of incision hernia. METHODS: This single-institution observational retrospective study included 268 patients with colon cancer who underwent IA or extracorporeal anastomosis (EA) after LAC at our institution between 2018 and 2021. The mid-term results of the IA group were compared with those of the EA group using a propensity score matching method. RESULTS: The median follow-up periods were 36 and 25 months in the EA and IA groups, respectively (p < 0.0001). In this matched cohort study, the recurrence-free survival (RFS) rates were comparable between the IA and EA groups (each group, n = 72; 3-year RFS: IA, 92.1%; EA, 88.2%; hazard ratio, 0.78; 95% confidence interval, 0.25-2.40; p = 0.66). The cumulative incisional hernia rates were 9.8% and 9.9% (p = 0.99) for the IA and EA groups, respectively. CONCLUSION: The safety of IA after LAC was demonstrated in this study, as IA after LAC showed good mid-term results, including with regard to the rates of recurrence and incisional hernia.

Usefulness of Carcinoembryonic Antigen Doubling Time in Prognosis Prediction after Curative Resection of Locally Recurrent Rectal Cancer: A Retrospective Study.

INTRODUCTION: Given that doubling time is an indicator of tumor growth, we assessed the usefulness of carcinoembryonic antigen doubling time (CEA-DT) in prognosis prediction after curative resection for locally recurrent rectal cancer. METHODS: During January 1986-December 2016, 33 patients with locally recurrent rectal cancer who underwent curative resection at our hospital were retrospectively reviewed. The primary endpoint was the 3-year recurrence-free survival (RFS) rate. The Kaplan-Meier method was used to compare RFS rates and evaluate univariate and multivariate analyses for factors associated with oncologic outcomes, including CEA-DT. CEA-DT was classified into 2 groups: the short and long CEA-DT groups. RESULTS: The 3-year overall survival and RFS rates were 62.6% and 42.4%, respectively. In multivariate analyses, CEA-DT was an independent risk factor for poor RFS. The 3-year RFS rate was significantly better in the long CEA-DT group than in the short CEA-DT group (58.8% vs. 25.0%, p = 0.0063). CONCLUSION: CEA-DT is a useful prognostic factor that can be assessed before surgery for locally recurrent rectal cancer. Long CEA-DT may indicate a favorable prognosis. Contrarily, short CEA-DT is associated with poor prognosis; therefore, further treatment intervention is necessary for patients with short CEA-DT.

Polarized PtdIns(4,5)P2 distribution mediated by a voltage-sensing phosphatase (VSP) regulates sperm motility.

The voltage-sensing phosphatase (VSP) is a unique protein that shows voltage-dependent phosphoinositide phosphatase activity. Here we report that VSP is activated in mice sperm flagellum and generates a unique subcellular distribution pattern of PtdIns(4,5)P2 Sperm from VSP-/- mice show more Ca2+ influx upon capacitation than VSP+/- mice and abnormal circular motion. VSP-deficient sperm showed enhanced activity of Slo3, a PtdIns(4,5)P2-sensitive K+ channel, which selectively localizes to the principal piece of the flagellum and indirectly enhances Ca2+ influx. Most interestingly, freeze-fracture electron microscopy analysis indicates that normal sperm have much less PtdIns(4,5)P2 in the principal piece than in the midpiece of the flagellum, and this polarized PtdIns(4,5)P2 distribution disappeared in VSP-deficient sperm. Thus, VSP appears to optimize PtdIns(4,5)P2 distribution of the principal piece. These results imply that flagellar PtdIns(4,5)P2 distribution plays important roles in ion channel regulation as well as sperm motility.

Short-term outcomes of intracorporeal versus extracorporeal anastomosis after laparoscopic colectomy: a propensity score-matched cohort study from a single institution.

PURPOSE: To compare the postoperative short-term results of intracorporeal anastomosis (IA) using overlap anastomosis (OLA), with those of extracorporeal anastomosis (EA) using functional end-to-end anastomosis (FEEA) or hand-sewn anastomosis (HSA), after laparoscopic colectomy (LAC). METHODS: The subjects of this retrospective study were 208 patients with colon cancer who underwent OLA, FEEA, or HSA after LAC at our institution, between 2018 and 2021. The short-term results of the OLA group were compared with those of the FEEA and HSA groups, respectively, using a propensity score-matching method. RESULTS: The mean operative time for anastomosis was longer in the OLA group than in the FEEA and HSA groups (p < 0.0001). The mean blood loss volume was less in the OLA group than in the FEEA and HSA groups (p = 0.0344 and p = 0.0002, respectively). The mean skin incision size was smaller in the OLA group than in the FEEA and HSA groups (p < 0.0001 and p = 0.0031, respectively). None of the patients in the OLA group had surgical site infections. Three to five patients were required for the surgeon to plateau on the learning curve. CONCLUSION: Although IA required more time than EA, the skills appeared to improve with experience and the short-term results were superior to those of EA.

[Retrospective Analysis of Adjuvant Chemotherapy for Elderly Patients with Stage â ¢ Colorectal Cancer].

OBJECTIVE: To investigate the efficacy and toxicity of adjuvant chemotherapy(AC)in elderly patients with Stage Ⅲ colorectal cancer(CRC). METHODS: We performed a single-institutional retrospective analysis of 84 patients aged≥75 years with Stage Ⅲ CRC who underwent curative resection from August 2009 to February 2018. RESULTS: Thirty-seven(44.0%) patients received AC. Eleven(29.7%)patients required dose reduction at the start of AC. Twenty-three(62.2%)patients accomplished AC, and 13(35.1%)needed dose reduction during AC. Although toxicities of Grade 3 or higher occurred in 56.8% of patients, they were controllable. The 3-year recurrence-free survival rate was significantly better in the AC group than in the non-AC group(70.3% versus 50.5%, respectively; p=0.011). The prognosis tended to be worse in the group that started AC with dose reduction than in the group with the normal dose. CONCLUSION: AC is effective and well tolerated in elderly patients with Stage Ⅲ CRC. When reducing the initial dose, the need for dose reduction should be carefully considered.

[Usefulness of Nutritional Evaluation in Adjuvant Chemotherapy for Colorectal Cancer in Older Patients].

OBJECTIVE: To clarify the usefulness of Onodera's prognostic nutritional index(OPNI)in adjuvant chemotherapy(AC)for older patients with colorectal cancer. MATERIALS AND METHODS: This study included 39 patients aged over 70 years who underwent AC for colorectal cancer from August 2009 to February 2018. We evaluated the association of OPNI with AC toxicities and prognosis. RESULTS: OPNI was an independent predictor of toxicities of Grade 3 or higher(OR: 0.18, 95%CI: 0.043-0.75, p=0.019). The 3-year recurrence-free survival rate was significantly better in the higher OPNI group than in the lower OPNI group(89.9% and 66.7%, respectively; HR: 0.19, 95%CI: 0.04-0.92, p=0.038). There was a positive correlation with Spearman's rank correlation coefficient of 0.66 in OPNI before and after AC(p<0.001). CONCLUSION: OPNI could be one of the valuable predictors of AC toxicities and the prognosis. There was a high correlation between OPNI before and after AC. These findings suggest the importance of early nutritional support for patients with lower OPNI.

TMEM55a localizes to macrophage phagosomes to downregulate phagocytosis.

TMEM55a (also known as PIP4P2) is an enzyme that dephosphorylates the phosphatidylinositol (PtdIns) PtdIns(4,5)P2 to form PtdIns(5)P in vitro However, the in vivo conversion of the polyphosphoinositide into PtdIns(5)P by the phosphatase has not yet been demonstrated, and the role of TMEM55a remains poorly understood. Here, we found that mouse macrophages (Raw264.7) deficient in TMEM55a showed an increased engulfment of large particles without affecting the phagocytosis of Escherichia coli Transfection of a bacterial phosphatase with similar substrate specificity to TMEM55a, namely IpgD, into Raw264.7 cells inhibited the engulfment of IgG-erythrocytes in a manner dependent on its phosphatase activity. In contrast, cells transfected with PIP4K2a, which catalyzes PtdIns(4,5)P2 production from PtdIns(5)P, increased phagocytosis. Fluorescent TMEM55a transfected into Raw264.7 cells was found to mostly localize to the phagosome. The accumulation of PtdIns(4,5)P2, PtdIns(3,4,5)P3 and F-actin on the phagocytic cup was increased in TMEM55a-deficient cells, as monitored by live-cell imaging. Phagosomal PtdIns(5)P was decreased in the knockdown cells, but the augmentation of phagocytosis in these cells was unaffected by the exogenous addition of PtdIns(5)P. Taken together, these results suggest that TMEM55a negatively regulates the phagocytosis of large particles by reducing phagosomal PtdIns(4,5)P2 accumulation during cup formation.

Lysophosphatidylinositol-acyltransferase-1 is involved in cytosolic Ca2+ oscillations in macrophages.

Lysophosphatidylinositol-acyltransferase-1 (LPIAT1) specifically catalyzes the transfer of arachidonoyl-CoA to lysophosphoinositides. LPIAT-/- mice have been shown to have severe defects in the brain and liver; however, the exact molecular mechanisms behind these conditions are not well understood. As immune cells have been implicated in liver inflammation based on disfunction of LPIAT1, we generated Raw264.7 macrophages deficient in LPIAT1, using shRNA and CRISPR/Cas9. The amount of C38:4 species in phosphoinositides, especially in PtdInsP2 , was remarkably decreased in these cells. Unlike in wild-type cells, LPIAT1-deficient cells showed prolonged oscillations of intracellular Ca2+ upon UDP stimulation, which is known to activate phospholipase Cß through the Gq-coupled P2Y6 receptor, even in the absence of extracellular Ca2+ . It is speculated that the prolonged Ca2+ response may be relevant to the increased risk of liver inflammation induced by LPIAT1 disfunction.

Clinical impact of non-predominant histopathological subtypes on the long-term prognosis of colorectal cancer patients in Japan.

PURPOSE: We performed a retrospective study to clarify the long-term prognosis of patients with histopathological high-grade colorectal cancer (CRC). METHODS: We reviewed data from 24 institutions for 18,360 patients with pStage I to III CRC who had undergone curative surgery between 2004 and 2012. The patients were classified into seven groups according to the proportion of the histopathological component: classical adenocarcinoma (CAC) group, M-l and M-h groups (< 50% and ≥ 50% mucinous adenocarcinoma, respectively), P-l and P-h groups (< 50% and ≥ 50% poorly differentiated adenocarcinoma, respectively), and S-l and S-h groups (< 50% and ≥ 50% signet-ring cell carcinoma (SRCC), respectively). RESULTS: The 5-year recurrence-free survival (RFS) rates of the M-l, P-l, and S-l groups were 75.5%, 68.4%, and 52.4%, respectively, and were significantly lower than those of the CAC group (83.5%, hazard ratio [HR] 1.22, 95% confidence interval [CI] 1.01-1.48, p = 0.0365; HR 1.60, 95% CI 1.32-1.91, p < 0.0001; HR 2.61, 95% CI 1.30-4.57, p = 0.0090, respectively). The 5-year RFS of the P-l and S-l groups was as poor as that of the P-h and S-h groups, respectively (HR 0.87, 95% CI 0.68-1.10, p = 0.25; HR 0.90, 95% CI 0.37-2.13, p = 0.81, respectively). The histopathological component of the S-l group was an independent factor affecting overall survival in multivariate analysis. CONCLUSION: The long-term prognoses of the non-predominant poorly differentiated adenocarcinoma (PAC) groups were as poor as those of the predominant group. In particular, the histopathological component of the P-l and S-l groups could be classified into predominant PAC and SRCC subtypes for appropriate prognostic predictions.

Prognostic impact of the number of lateral pelvic lymph node metastases on rectal cancer.

BACKGROUND: This study aimed to clarify the number of lateral pelvic lymph node metastases of colorectal cancer for which prognosis could be improved by dissection. METHODS: We analysed the data of 30 patients with lateral pelvic lymph node metastases of rectal cancer that underwent a total mesorectal excision with lateral pelvic lymph node dissection at our institute from 1986 to 2016. We performed survival analysis on the number of lateral pelvic lymph node metastases in each of these patients and identified an optimal cut-off point of the number of lateral pelvic lymph node metastases that would predict recurrence-free survival using the receiver operating characteristic curves and an Akaike information criterion value. RESULTS: The 5-year recurrence-free survival and overall survival of patients with one or two lateral pelvic lymph node metastases were significantly better than that of those with three or more (5-year recurrence-free survival, 63.3 vs. 0.0%, respectively; hazard ratio, 0.23; 95% CI, 0.07-0.72; P = 0.0124) (5-year overall survival, 68.2 vs. 15.6%, respectively; hazard ratio, 0.29; 95% CI, 0.09-0.92; P = 0.0300). All of the metastatic lateral pelvic lymph nodes in the group with one or two lateral pelvic lymph node metastases were restricted to the internal iliac artery or obturator nerve regions. CONCLUSIONS: The cut-off number of lateral pelvic lymph node metastases in the internal iliac artery or obturator nerve regions of colorectal cancer cases in whom prognosis was improved by lateral pelvic lymph node dissection was 2; patients who had <3 lateral pelvic lymph node metastases had better prognoses than those with ≥3 lateral pelvic lymph node metastases.

Differential Diagnosis of COVID-19: Importance of Measuring Blood Lymphocytes, Serum Electrolytes, and Olfactory and Taste Functions.

Coronavirus disease 2019 (COVID-19) is associated with various symptoms and changes in hematological and biochemical variables. However, clinical features, which can differentiate COVID-19 from non-COVID-19, are not clear. We therefore examined the key clinical features of COVID-19 and non-COVID-19 patients. This study included 60 COVID-19 patients and 100 non-COVID-19 patients, diagnosed by PCR, and no significant differences in the age and sex were seen between the two groups. The frequencies of fatigue, loose stool, diarrhea, nasal obstruction, olfactory dysfunction, taste dysfunction, underlying hyperlipidemia, and the prescription of angiotensin II receptor blocker (ARB) were significantly higher in COVID-19 patients than those in non-COVID-19 patients. The counts of leucocytes, neutrophils, lymphocytes, eosinophils, monocytes, and basophils and the levels of chloride and calcium in blood of COVID-19 patients were significantly lower than those of non-COVID-19 patients. The frequencies of atypical lymphocytes and the levels of lactate dehydrogenase (LDH) and potassium were significantly higher in COVID-19 than those in non-COVID-19. The C-reactive protein (CRP) level in COVID-19 patients was significantly lower than that in non-COVID-19 patients, when we compared CRP levels among patients with elevated CRP. This study is the first to indicate that electrolyte levels and the frequency of atypical lymphocytes in COVID-19 are significantly different from those in non-COVID-19. Fatigue, loose stool, diarrhea, nasal obstruction, olfactory dysfunction, and taste dysfunction were the key symptoms of COVID-19. Furthermore, hyperlipidemia and ARB may be risk factors of COVID-19. In conclusion, leucocytes, leucocyte fractions, CRP, LDH, and electrolytes are useful indicators for COVID-19 diagnosis.

Sirt1 counteracts decrease in membrane phospholipid unsaturation and diastolic dysfunction during saturated fatty acid overload.

BACKGROUND: The fatty acid (FA) composition of membrane phospholipid reflects at least in part dietary fat composition. Saturated FA (SFA) suppress Sirt1 activity, while monounsaturated FA (MUFA) counteract this effect. OBJECTIVE: We explored a role of Sirt1 in homeostatic control of the fatty acid composition of membrane phospholipid in the presence of SFA overload. METHODS AND RESULTS: Sirt1 deficiency in cardiomyocytes decreased the expression levels of liver X receptor (LXR)-target genes, particularly stearoyl-CoA desaturase-1 (Scd1), a rate-limiting enzyme in the cellular synthesis of MUFA from SFA, increased membrane SFA/MUFA ratio, and worsened left ventricular (LV) diastolic function in mice fed an SFA-rich high fat diet. In cultured cardiomyocytes, Sirt1 knockdown (KD) exacerbated the palmitate overload-induced increase in membrane SFA/MUFA ratio, which was associated with decrease in the expression of LXR-target genes, including Scd1. Forced overexpression of Scd1 in palmitate-overloaded Sirt1KD cardiomyocytes lowered the SFA/MUFA ratio. Nicotinamide mononucleotide (NMN) increased Sirt1 activity and Scd1 expression, thereby lowering membrane SFA/MUFA ratio in palmitate-overloaded cardiomyocytes. These effects of NMN were not observed for Scd1KD cardiomyocytes. LXRα/ßKD exacerbated palmitate overload-induced increase in membrane SFA/MUFA ratio, while LXR agonist T0901317 alleviated it. NMN failed to rescue Scd1 protein expression and membrane SFA/MUFA ratio in palmitate-overloaded LXRα/ßKD cardiomyocytes. The administration of NMN or T0901317 showed a dramatic reversal in membrane SFA/MUFA ratio and LV diastolic function in SFA-rich HFD-fed mice. CONCLUSION: Cardiac Sirt1 counteracted SFA overload-induced decrease in membrane phospholipid unsaturation and diastolic dysfunction via regulating LXR-mediated transcription of the Scd1 gene.

Lysophosphatidic acid acyltransferase 3 tunes the membrane status of germ cells by incorporating docosahexaenoic acid during spermatogenesis.

Docosahexaenoic acid (DHA) is one of the essential ω-3 polyunsaturated fatty acids with a wide range of physiological roles important for human health. For example, DHA renders cell membranes more flexible and is therefore important for cellular function, but information on the mechanisms that control DHA levels in membranes is limited. Specifically, it is unclear which factors determine DHA incorporation into cell membranes and how DHA exerts biological effects. We found that lysophosphatidic acid acyltransferase 3 (LPAAT3) is required for producing DHA-containing phospholipids in various tissues, such as the testes and retina. In this study, we report that LPAAT3-KO mice display severe male infertility with abnormal sperm morphology. During germ cell differentiation, the expression of LPAAT3 was induced, and germ cells obtained more DHA-containing phospholipids. Loss of LPAAT3 caused drastic reduction of DHA-containing phospholipids in spermatids that led to excess cytoplasm around its head, which is normally removed by surrounding Sertoli cells via endocytosis at the final stage of spermatogenesis. In vitro liposome filtration assay raised the possibility that DHA in phospholipids promotes membrane deformation that is required for the rapid endocytosis. These data suggest that decreased membrane flexibility in LPAAT3-KO sperm impaired the efficient removal of sperm content through endocytosis. We conclude that LPAAT3-mediated enrichment of cell membranes with DHA-containing phospholipids endows these membranes with physicochemical properties needed for normal cellular processes, as exemplified by spermatogenesis.