An hMAO-B-activatable mitochondrial binding fluorescent probe in live-cell via enzyme-anchored and charge-driven dual targeting.

Indole-incorporated-benzoeindolium as a novel mitochondrial and ratiometric fluorescent probe for real-time tracking of SO2 derivatives in vivo and herb samples

MAFLD and Cardiovascular Events: What Does the Evidence Show?

A mitochondrial-targetable fluorescent probe based on high-quality InP quantum dots for the imaging of living cells

A new NIR emission mitochondrial targetable fluorescent probe and its application in detecting viscosity changes in mouse liver and kidney injury

MAP4K4 is a serine/threonine protein kinase belonging to the germinal center kinase subgroup of sterile 20 protein family of kinases. MAP4K4 has been involved in regulating multiple biologic processes and a plethora of pathologies, including systemic inflammation, cardiovascular diseases, cancers, and metabolic and hepatic diseases. Recently, multiple reports have indicated the upregulation of MAP4K4 expression and signaling in hyperglycemia and liver diseases. This review provides an overview of our current knowledge of MAP4K4 structure and expression, as well as its regulation and signaling, specifically in metabolic and hepatic diseases. Reviewing these promising studies will enrich our understanding of MAP4K4 signaling pathways and, in the future, will help us design innovative therapeutic interventions against metabolic and liver diseases using MAP4K4 as a target. SIGNIFICANCE STATEMENT: Although most studies on the involvement of MAP4K4 in human pathologies are related to cancers, only recently its role in liver and other metabolic diseases is beginning to unravel. This mini review discusses recent advancements in MAP4K4 biology within the context of metabolic dysfunction and comprehensively characterizes MAP4K4 as a clinically relevant therapeutic target against liver and metabolic diseases.

As a vital index of the mitochondrial micro-environment, mitochondrial micro-viscosity plays a fundamental role in cell life activities. Normal mitochondrial viscosity is a necessary condition for the maintenance of normal life activities of mitochondria. Abnormal mitochondrial viscosity can lead to a series of mitochondria-related diseases. Therefore, it is essential to observe mitochondrial viscosity for physiological and pathological processes. Given the conventional viscosity measurement methods (viscometer, etc.) cannot monitor the changes in mitochondrial viscosity, the fluorescence method supplemented with the fluorescent probe is widely used to observe the changes in mitochondrial viscosity. In view of the booming development in this area, this review describes the applications of viscosity-responsive mitochondrial fluorescent probes in biological samples from the cellular and tissue levels. We hope that this review will deepen our understanding of mitochondrial viscosity and related fields, and promote the development of viscosity-sensitive mitochondrial probes and other organelle fluorescence probes.

Metabolic liver disease is the underlying diagnosis in only a small proportion of patients who undergo liver transplantation (LT), but for these patients, LT is lifesaving. Patients with metabolic liver disease often do not present with typical findings of end-stage liver disease and require special consideration and scrutiny concerning the appropriateness and timing of LT. Liverbased metabolic disease is classified into 3 types: (1) disease that causes structural liver damage with liver failure or cirrhosis, (2) metabolic disease without structural liver damage that affects other organs (especially the central nervous system), and (3) metabolic disease with systemic deficiencies that are partially represented in the liver. There may be overlap in presentation, with some disease forms presenting either with or without structural liver disease. General considerations that affect review board decisions may include the relative contraindication of the use of living-related donor organs and the unpredictable metabolic course that may cause severe central nervous system complications in several of these disease states. Also, although many of these diseases present mostly in children, adolescents and adults previously managed medically are increasingly presenting for LT consideration when medical management becomes more difficult or complex as they mature.

Using colorimetric and fluorescent probes has garnered significant interest in detecting NAD(P)H within practical systems and biological organisms. Herein, we synthesized a mitochondrial targetable fluorescent probe (ISQM) for fast NAD(P)H detection in <1 min. The ISQM is positively impacted because of the quinolinium reduction facilitated by NAD(P)H. It consequently liberates the push-pull fluorophore ISQM-H with a large Stokes shift (110 nm). This release leads to a turn-on response of red-emitting fluorescence, accompanied by a meager detection limit of 59 nM. To compare the differences in the NAD(P)H levels of tumor cells and normal cells, we used ISQM to measure the fluorescent signal intensities of HeLa cells (tumor cells) and RAW 264.7 cells (normal cells), respectively. Surprisingly, the experiment, including the measurement of colocalization over time, indicated that the probe exhibits a reaction with mitochondrial NAD(P)H and trace NAD(P)H in hypoxia conditions in cancer cells. Moreover, we effectively used the probe ISQM to identify the NAD(P)H in tumor mice.

Elucidating the intrinsic relationship between disease and mitochondrial viscosity is crucial for early diagnosis. However, current mitochondrial viscosity fluorescent probes are highly dependent on mitochondrial membrane potential (MMP) and are sensitive to other mitochondrial microenvironment parameters. To address these issues, a mitochondria-targeting MMP-independent and viscosity exclusive near-infrared (NIR) fluorescent probe, ACR-DMA, was developed. ACR-DMA consists of thiophene acetonitrile as the skeleton and viscosity-sensitive unit, a pyridinium cation for the mitochondria-targeting group, and a benzyl bromide subunit for mitochondrial immobilization. It is very sensitive to viscosity and shows significant "turn-on" fluorescence behavior at 710 nm with a more than 150-fold fluorescence intensity increase. Furthermore, ACR-DMA can be firmly immobilized in mitochondria and can monitor viscosity changes induced by nystain, monensin, and lipopolysaccharide. Additionally, it was successfully used to visualize mitochondrial viscosity changes resulting from tumors, inflammation, and drug-induced acute kidney injury, revealing the relationship between viscosity and disease both in vitro and in vivo. ACR-DMA is expected to be a promising candidate for diagnosing mitochondrial viscosity-related diseases.

After completing this article, readers should be able to:Hepatomegaly can represent intrinsic liver disease or may be the presenting physical finding of a generalized disorder. Early diagnosis and treatment of children who have liver disease is important because specific treatments are available for some diseases that can prevent disease progression or hepatic failure.The presence of a palpable liver does not always indicate hepatomegaly. Normal liver size is based on normative values of liver span by percussion, degree of extension below the right costal margin, or length of the vertical axis estimated from imaging techniques. In general,a liver edge greater than 3.5 cm in newborns and greater than 2 cm in children below the right costal margin suggests enlargement. Liver span is determined by measuring the distance between the upper edge,determined by percussion, and the lower edge, determined by palpation, in the midclavicular line. The lower border also may be determined by auscultation. With the stethoscope placed below the xiphoid, the examiner should gently scratch superiorly,starting in from the right lower quadrant, and listen for sound enhancement as the finger passes over the liver edge. Liver span increases linearly with body weight and age in both genders and correlates more with weight than with height. The normal range for liver span by percussion at 1 week of age is 4.5 to 5 cm. At 12 years, the normal value for boys is 7 to 8 cm and for girls is 6 to 6.5 cm.The liver can be displaced inferiorly by the diaphragm or thoracic organs, giving the impression of hepatomegaly. Accumulation of fluid or air in the thorax (eg,pneumothorax) also may displace the liver inferiorly. A retroperitoneal mass, choledochal cyst, or perihepatic abscess also may be mistaken for hepatomegaly. Children who have orthopedic abnormalities such as narrow chest walls or pectus excavatum can erroneously appear to have hepatomegaly. A normal variant of the right lobe of the liver,called a Riedel lobe, may extend far below the right costal margin and be confused as pathologic hepatic enlargement. However, patients who have a Riedel lobe will have no signs, symptoms, or laboratory evidence of liver disease.Hepatomegaly generally occurs via five mechanisms: inflammation,excessive storage, infiltration,congestion, and obstruction (Table 1). Infections from viruses, bacteria,fungi, and parasites promote inflammation-induced hepatomegaly. Toxins, radiation, autoimmune disease, and Kupffer cell hyperplasia also may cause hepatomegaly by this mechanism.Storage products that accumulate in the enlarged liver include glycogen, fats, metals, and abnormal proteins. Glycogen storage occurs in glycogen storage disease and diabetes mellitus and in some patients receiving parenteral nutrition. Steatosis, the accumulation of fat in the liver, occurs most commonly in overweight children and less commonly in the presence of certain metabolic diseases and diabetes. Metals and abnormal proteins can be stored inappropriately in the liver. For example, hepatomegaly is caused by the accumulation of copper in Wilson disease and the accumulation of abnormal protein in alpha-1-antitrypsin deficiency.Cellular infiltration can occur from primary tumors of the liver or metastatic disease. Primary tumors can be malignant or benign. Malignant tumors include hepatoblastoma or hepatocellular carcinoma. Benign tumors include hemangiomas,teratomas, and focal nodular hyperplasia. Metastatic infiltration occurs in leukemia, lymphoma, neuroblastoma,and histiocytosis. Parasitic cysts,although uncommon in North America, are a common cause of liver enlargement worldwide. Extramedullary hematopoiesis and hemophagocytic syndrome cause hepatomegaly due to infiltration by blood cells.Congestive blood flow in the liver causes hepatomegaly. Suprahepatic obstruction from congestive heart failure, restrictive pericardial disease, hepatic vein thrombosis(Budd-Chiari), or suprahepatic vascular webs are examples. Veno-occlusive disease causes hepatomegaly by obstructing intrahepatic blood flow. This problem occurs mainly in bone marrow transplant patients. Lastly, obstruction of biliary flow causes hepatic enlargement. This may be due to tumors outside the liver or congenital and acquired problems of the biliary system. Biliary atresia, choledochal cysts, and cholelithiasis are examples of diseases in which bile flow is obstructed.A thorough evaluation of hepatomegaly should begin with a complete history. In the neonate, a history of hyperbilirubinemia after 2 weeks of age requires rapid assessment of the underlying disorder to rule out extrahepatic biliary atresia. A family history of early infant death or hepatic,neurodegenerative, or psychiatric disease suggests a metabolic etiology. Eliciting a careful birth history may uncover risk factors for perinatally acquired infections, such as maternal intravenous drug use, maternal infections,or previous blood transfusions. Prenatal history of Rh or ABO incompatibility suggests isoimmunization and hemolysis as the cause of hepatomegaly. Maternal infections that can be transmitted to the fetus or neonate include hepatitis B,toxoplasmosis, syphilis, cytomegalovirus,rubella, herpes simplex, enterovirus,rubella, and human immunodeficiency virus. A history of an umbilical catheter increases the risk for hepatic abscess. A history of prolonged hyperbilirubinemia in infancy may point to cystic fibrosis or alpha-1-antitrypsin deficiency. Delayed passage of meconium also suggests cystic fibrosis.In the child and adolescent,careful questioning about foreign travel,ingestion of shellfish or drugs, and environmental toxins may reveal risk factors for acute hepatitis or parasitic disease. A history of poor weight gain, vomiting, diarrhea,distinctive odors, loss of developmental milestones, complex seizure disorder, or hypotonia suggests a metabolic disease. A history of hyperbilirubinemia with or without acholic stools and dark urine indicates hepatic dysfunction. Acholic stool usually suggests obstruction of the biliary tract, but it also can be seen in severe hepatocellular injury. Acute onset of hepatomegaly associated with hyperbilirubinemia in an older child raises the suspicion of infection with hepatitis A. Exposure to blood products, having a tattoo,and illicit intravenous drug use are risk factors for hepatitis C and B infection. Commonly used medications that may cause hepatic enlargement include nonsteroidal anti-inflammatory agents, isoniazid,propylthiouracil, and sulfonamides. Systemic symptoms related to chronic inflammatory diseases should be sought in the older child who has hepatomegaly. A history of inflammatory bowel disease or immunodeficiency increases the likelihood for primary sclerosing cholangitis.A careful physical examination often can narrow the diagnostic considerations (Table 2). In addition to size,liver nodularity and firmness should be assessed. Auscultation over the liver may detect bruits or increased flow to the liver. The stigmata of generalized disease processes should be sought. Jaundice (yellowing of the skin and sclera) usually becomes apparent when the serum bilirubin concentration reaches 34.2 to 51.3 mcmol/L (2 to 3 mg/dL). Other nonspecific signs and symptoms of hepatic disease include fatigue,anorexia, weight loss, blood in the stool, and abdominal distention. Signs of chronic liver disease, such as spider angiomas, xanthomas, and palmar erythema, are more common among adults. Fever suggests a systemic illness or infection. A neonatal history of intrauterine growth retardation, microcephaly, chorioretinitis,and purpura accompanied by hepatomegaly strongly suggests congenital infection, which will allow the clinician to tailor the diagnostic evaluation accordingly.Portal hypertension, hepatic infiltration by malignant cells, or storage disease cause splenomegaly as well as hepatomegaly. Other signs of portal hypertension include ascites or a prominent abdominal venous pattern. Massive splenomegaly is more common with storage diseases and malignancies than with portal hypertension. An altered sensorium may be due to a metabolic disease. Failure to thrive and hepatomegaly in infancy result from a metabolic disease such as glycogen storage,hereditary fructose intolerance,galactosemia, or cystic fibrosis. If the patient has a distinctive breath or urine odor, consider organic acidemias. Cutaneous hemangiomas or a hepatic bruit suggests hemangiomatosis. Patients who exhibit progressive neurologic deterioration may have glycogen or lipid storage disease or Wilson disease. The constellation of mongoloid facies,hypotonia, and neurologic deterioration suggests Zellweger syndrome, a disorder of peroxisomal function. Coarse facial features are seen with the mucopolysaccharidoses. Ocular findings of Kayser-Fleischer rings or cataracts occur in Wilson disease. Papular acrodermatitis (or Gianotti-Crosti syndrome) is a self-limiting dermatosis that may be seen in patients who have viral hepatitis.Useful laboratory tests for patients who have hepatomegaly are listed in Table 3. Routine evaluations include a complete blood count with differential count and smear, serum chemistry with hepatic profile, and urinalysis and urine culture. Results of the history and physical examination should tailor the laboratory evaluation and suggest the need for further diagnostic testing. Laboratory studies must be interpreted in the context of age-related changes because many hepatic enzyme levels fluctuate substantially with age. Two true"liver function tests" are measurement of serum albumin and prothrombin time, which assess the synthetic function of the liver directly and may be helpful in monitoring responses to therapy and suggesting a prognosis. The presence of hyperbilirubinemia in a patient who has hepatomegaly suggests cholestasis or hemolytic disease. Cholestatic disease causes predominantly elevations in congugated bilirubin,alkaline phosphatase, and gamma glutamyl transpeptidase. Bilirubin can be fractionated to distinguish between hepatic dysfunction(conjugated/direct bilirubin) and hemolytic disease or congenital disorders of bilirubin metabolism(unconjugated/indirect bilirubin).Hepatocellular injury results in a predominant rise in hepatic aminotransferases, which suggests a viral or toxic insult. Alanine aminotransferase is more liver-specific than aspartate aminotransferase, which also is found in other tissues such as muscle. Because cholestasis results in some hepatocyte injury, the pattern of laboratory abnormalities may not be distinct. However, the rise in aminotransferases will be higher than the rises in alkaline phosphatase and gamma-glutamyl transferase levels. The degree of aminotransferase elevation does not correlate well with clinical prognosis; declining aminotransferase levels may indicate a decrease in functioning hepatocytes from ongoing necrosis.Hepatic synthetic function is assessed by serum albumin and prothrombin time. Prothrombin time rapidly reflects changes in hepatic synthetic function because of the short half-life of some clotting factors. Prolonged prothrombin time may be the result of malabsorption of vitamin K. A decrease in albumin indicates a more chronic problem, but it also may indicate another process, such as protein-losing enteropathy and chronic infection.Measurement of serum glucose,ketones, lactic acid, pyruvic acid,amino acids, and uric acid along with urine organic acids is helpful when a metabolic defect is suspected.Imaging studies can help define the problem and direct further diagnostic evaluations. Plain films generally are not useful diagnostically, except in certain cases. The liver may appear denser with iron storage or less dense with fatty infiltration. Calcifications in the liver, the vasculature, or the biliary tree may suggest malignancy or parasites, portal vein thrombosis, or gallstones,respectively.Ultrasonography with Doppler flow imaging of hepatic vessels usually is the most helpful initial study.It can determine the size and consistency of the liver and visualize mass lesions as small as 1 cm. Ultrasonography is the imaging modality of choice for the biliary tree. It can identify stones, biliary sludge, and biliary anatomy. Hepatic and portal vein blood flow and collateral circulation also are assessed by Doppler ultrasonography.Computed tomography (CT) or magnetic resonance imaging (MRI)may be superior to ultrasonography in detecting small focal lesions, such as tumors, cysts, or abscesses. When a tumor is suspected, CT is useful to define its extent. CT may be superior for detecting subtle differences in liver density. CT or MRI may differentiate obstructive from nonobstructive causes of cholestasis.Radionuclide scanning is most helpful in the young infant to distinguish biliary atresia from neonatal hepatitis. In biliary atresia,hepatic uptake of the radionuclide is normal, but excretion into the intestine is absent. In neonatal hepatitis, uptake by the diseased liver parenchyma is impaired, but there is excretion into the intestines. Biliary atresia is diagnosed definitively by cholangiography.Cholangiography directly visualizes the intra- and extrahepatic biliary tree, which is useful to define cause, extent, and level of obstruction. Intraoperative cholangiography is the method of choice in neonates for ruling out atresia;endoscopic cholangiography is an alternate and less invasive method for older children. Magnetic resonance cholangiopancreatography is a newer noninvasive modality for visualizing the biliary tree.Percutaneous liver biopsy can be performed in infants as young as 1 week of age. This procedure provides adequate tissue for both histologic and biochemical analyses. Clinical history, laboratory studies,and liver histology provide the diagnosis in the majority of cases of hepatomegaly. The histology demonstrates diseases of the parenchyma,provides tissue for enzyme quantitation, and identifies stored material.The most frequent causes of hepatomegaly in a neonate are listed in Table 4A. A diagnostic approach to the neonate who has hepatomegaly is outlined in Figure 1. This algorithm is designed to discriminate among the most common diagnostic possibilities. The evaluation of hepatomegaly without splenomegaly in the neonate who has conjugated hyperbilirubinemia should proceed rapidly to exclude biliary atresia because diagnosis and surgical correction are most likely to be successful in establishing bile flow if performed by 8 to 10 weeks of life. A small or absent gallbladder also suggests biliary atresia. A radionuclide excretion study that shows no excretion into the duodenum is suspicious for biliary atresia. These patients should undergo liver biopsy. If the pathology is consistent with the diagnosis of biliary atresia,intraoperative cholangiography should be used to confirm the diagnosis before undertaking a Kasai hepatoportoenterostomy. Further evaluation for a specific cause of liver dysfunction is pursued if liver biopsy is not consistent with biliary atresia. Ultrasonography can identify choledochal cysts or other obstructing mass lesions. Idiopathic neonatal hepatitis is diagnosed after known causes of neonatal hepatitis are excluded. Conjugated hyperbilirubinemia associated with splenomegaly, failure to thrive, or vomiting suggests congenital infection, sepsis, or metabolic disease.Unconjugated or mixed hyperbilirubinemia associated with splenomegaly suggests congenital infections, increased portal pressures, or extramedullary hematopoiesis. Findings on the physical examination will guide further diagnostic studies to identify the disorders, such as abdominal ultrasonography with Doppler flow, cardiac ultrasonography,or a bone marrow biopsy. Hepatosplenomegaly in an infant who has no hyperbilirubinemia suggests an obstructive or infiltrative cause. Abdominal ultrasonography is indicated to evaluate liver consistency, patency of venous flow, and mass lesions. Liver biopsy is diagnostic for infiltrative diseases.Hepatomegaly without hyperbilirubinemia or splenomegaly and ultrasonographic findings that are nondiagnostic usually lead to liver biopsy. Primary and metastatic tumors and storage diseases are diagnosed definitively by analysis of liver tissue.The most common causes of hepatomegaly in children older than 1 year of age are listed in Table 4B. A diagnostic approach for the older child is outlined in Figure 2. A complete history and physical examination often lead to the diagnosis, with only confirmatory testing necessary. For example, a history of known cystic fibrosis makes an extensive evaluation for hepatomegaly unnecessary. The presence of hyperbilirubinemia with associated elevated conjugated bilirubin and elevated aminotransferases prompts an evaluation for viral hepatitis. Other less common disorders that present similarly are drug or toxin exposures, autoimmune hepatitis,and Wilson disease. In the absence of positive serologies for viral hepatitis, testing for these diseases is warranted. Liver biopsy may be necessary to establish, direct,stage, or confirm the diagnosis.Patients who have conjugated hyperbilirubinemia with a cholestatic pattern of liver test abnormalities usually have an obstructive process and benefit from ultrasonography and possibly cholangiography.Patients who have an elevated unconjugated bilirubin level and an elevated reticulocyte count should be evaluated for hemolytic disease. Congestive heart failure, restrictive pericardial disease, and infections should be considered when there is no evidence of hemolysis.In the absence of hyperbilirubinemia, a child who has hepatosplenomegaly should have a complete blood count with a smear and bone marrow biopsy to determine the presence of malignancy. Hepatosplenomegaly also can be caused by storage disorders, and a careful search for other organ involvement may provide clues to the diagnosis. If indicated by history or physical examination, ultrasonography to search for parasitic cysts is warranted. Finally, a child who does not have hyperbilirubinemia or splenomegaly should undergo ultrasonography and serology to rule out cystic or mass lesions and viral or autoimmune hepatitis.The evaluation of the child who has hepatomegaly should proceed in a logical and stepwise fashion. A thorough history and physical examination often point to the most likely diagnoses. Further evaluation should be tailored to the more likely diagnoses.

The global incidence and mortality rates associated with cancer are increasing annually, presenting significant challenges in oncology, particularly regarding the efficacy and toxicity of antineoplastic agents. Additionally, mitochondria are recognized for their multifaceted roles in the progression of malignant tumors. Mitochondrial-targeting drugs offer promising avenues for cancer therapy. This study focuses on the synthesis of a mitochondrial fluorescent probe, designated Mitochondrial Probe Molecule-1 (MPM-1), and evaluates its anti-tumor effects on colon cancer (CRC) and lung cancer (LUNG) both in vitro and in vivo. Mito Tracker Green FM staining was performed to investigate the subcellular location of MPM-1. Cell cycle assay, colony formation, EdU, assay of cell apoptosis, wound healing assay, and trans-well migration assay were utilized to confirm anticancer properties of MPM-1 in vitro. Using a xenograft mouse model, the effects of MPM-1 in tumor treatment were also identified. RNA-seq and Western blot were performed to examine the underlying mechanism of MPM-1. The findings indicate that MPM-1 selectively targets mitochondria and exerts inhibitory effects on CRC and LUNG cells. Specifically, MPM-1 significantly reduced the proliferation and migration of lung cancer cell lines A549 and H1299, as well as colon cancer cell lines SW480 and LOVO, with IC50 values of 4.900, 7.376, 8.677, and 7.720µM, respectively, while also promoting apoptosis. RNA-seq analysis revealed that MPM-1 exerts its broad-spectrum anticancer effects through interactions with multiple signaling pathways, including mTOR, Wnt, Hippo, PI3K/Akt, and MAPK pathways. Additionally, in vivo studies demonstrated that MPM-1 effectively inhibited tumor progression. In summary, MPM-1 demonstrates the ability to inhibit the growth of CRC and LUNG by targeting mitochondria and modulating several signaling pathways that attenuate tumor cell migration and proliferation while promoting apoptosis. This research underscores the potential of MPM-1 as a tumor suppressor and lays a robust foundation for the future development of innovative anticancer therapies that target mitochondrial functions.

Hemoporfin is a novel second-generation porphyrin-related photosensitizer for ovarian cancer photodynamic treatment (PDT). The purpose of this study was to investigate the molecular mechanisms of Hemoporfin-mediated photocytotoxicity. Human epithelial ovarian cancer cell line 3AO was incubated with different concentrations of Hemoporfin, and phototoxic effects of Hemoporfin on cells were determined using a Cell Viability Analyzer. Apoptosis or necrosis was determined by flow cytometry analysis using the Annexin V-FITC apoptosis kit. Cellular caspase activation was determined using the fluorescent assay kit for caspase-3 and caspase-9. Rhodamine123 was used as a mitochondrial probe and Lucifer Yellow as a lysosomal probe to investigate the intracellular localization of Hemoporfin in 3AO cancer cells. We demonstrated that both high-dose (30 microg mL(-1)) and low-dose (3 microg mL(-1)) Hemoporfin significantly reduced the viability of ovarian cancer cell 3AO with light illumination, and the photocytotoxicity was dose-dependent (P < 0.01). Using a mitochondrial fluorescence probe, we demonstrated a distinct mitochondrial aggregation in 3AO cells with a low concentration of Hemoporfin. Loss of mitochondrial membrane potential was detected as early as 1 h after Hemoporfin-mediated PDT. PDT with low-dose Hemoporfin predominantly induced apoptosis but not necrosis, and both caspase-3 and caspase-9 were activated. Based on our results, mitochondria play an important role in the Hemoporfin-induced apoptosis, and mitochondria membrane potential loss initiated apoptosis via the activation of caspases. Understanding the mechanisms involved in PDT-mediated apoptosis may improve its therapeutic efficacy and facilitate its transition into the clinic.

Calcium homeostasis is correlated closely with the occurrence and development of various cancers. The role of calcium homeostasis in prostate cancer has remained unclear. The present study aimed to investigate the relationship between transmembrane and crimp-crimp domain 1 (TMCO1) and calreticulin (CALR) in the pathological characteristics of prostate cancer and the mechanism of action on prostate cancer metastasis. Effects of CALR recombinant protein and TMCO1 knockdown on prostate cancer cells were investigated using following methods: cell cloning, Transwell, wound scratch assay, JC-1 assay, Fluo-4 Assay, endoplasmic reticulum (ER) fluorescent probe, mitochondrial fluorescence probe, Western blot and Immunofluorescence. TMCO1 and CALR are overexpressed in prostate cancer and knockdown of TMCO1 significantly inhibited the invasion, migration and cell proliferation. Furthermore, knocking down TMCO1 modulated the intensity of ER probes and mitochondrial fluorescence probes, and affected the levels of intracellular calcium ion and mitochondrial membrane potential. In addition, CALR recombinant protein upregulated the expression of epithelial-mesenchymal transition marker, Vimentin, Conversely, knockout of TMCO1 significantly reduced the expression of CALR and Vimentin. Knockout of TMCO1 can reverse the effect of CALR recombinant protein, elucidating the pivotal roles of TMCO1 and CALR in the regulation of prostate cancer metastasis through modulation of calcium homeostasis.

The relationship between the Charlson comorbidity index (CCI) and short-term readmission is as yet unknown. Therefore, we aimed to investigate whether the CCI was independently related to short-term readmission in patients with heart failure (HF) after adjusting for other covariates. From December 2016 to June 2019, 2008 patients who underwent HF were enrolled in the study to determine the relationship between CCI and short-term readmission. Patients with HF were divided into 2 categories based on the predefined CCI (low < 3 and high > =3). The relationships between CCI and short-term readmission were analyzed in multivariable logistic regression models and a 2-piece linear regression model. In the high CCI group, the risk of short-term readmission was higher than that in the low CCI group. A curvilinear association was found between CCI and short-term readmission, with a saturation effect predicted at 2.97. In patients with HF who had CCI scores above 2.97, the risk of short-term readmission increased significantly (OR, 2.66; 95% confidence interval, 1.566-4.537). A high CCI was associated with increased short-term readmission in patients with HF, indicating that the CCI could be useful in estimating the readmission rate and has significant predictive value for clinical outcomes in patients with HF.

Expanding the liver exposome: Should hepatologists care about air pollution?