Acetic acid enhances the effect of photodynamic therapy in gastric cancer cells via the production of reactive oxygen species.

Acetic acid is a major component of vinegar and is reported to have beneficial health effects. Notably, it causes oxidative stress and enhances the production of reactive oxygen species (ROS) in gastric cancer cells. ROS play important roles in cellular signal transduction, resulting in the regulation of protein expression and apoptosis. We previously reported that ROS upregulate heme carrier protein 1 (HCP1). Moreover, ROS increase the cellular uptake of porphyrins, which are precursors of heme and substrates for uptake by HCP1. Therefore, we hypothesized that photodynamic therapy (PDT) for cancer treatment using laser irradiation and photosensitizers, such as porphyrin, is enhanced via ROS produced by acetic acid. Herein, we used the rat gastric mucosal cells, RGM1, its cancer-like mutated cells, RGK1, and a manganese superoxide dismutase (MnSOD)-overexpressing RGK cell line, RGK-MnSOD. We confirmed that cancer-specific cellular uptake of porphyrin is increased upon acetic acid treatment and enhances the PDT cytotoxicity in RGK-1, not in RGM-1 and RGK-MnSOD. We believe that this occurs because of the overproduction of ROS and subsequent upregulation of HCP1 in cancerous cells. In conclusion, acetic acid can elevate the effect of PDT by inducing cancer-specific HCP1 expression via ROS production.

Autoimmune hepatitis with history of HCV treatment triggered by COVID-19 vaccination: case report and literature review.

Although vaccines have been effective against the worldwide pandemic of Coronavirus Disease 19 (COVID-19), some case reports have described autoimmune hepatitis triggered by COVID-19 vaccination. Meanwhile, hepatitis C virus (HCV) is known to be related to autoimmune diseases. Here, we report a case of autoimmune hepatitis with history of HCV treatment triggered by COVID-19 vaccination. An 82-year-old woman was referred to our hospital for severe liver injury. She had received a COVID-19 vaccination 7 days prior. She had a history of HCV treatment with direct-acting antivirals 7 years previously. In her blood data, despite HCV antibody positivity, she was negative for HCV RNA by real-time RT-PCR. Anti-nuclear antibody was positive and IgG was elevated. Interface hepatitis and plasma cell infiltration were confirmed pathologically. She was diagnosed as autoimmune hepatitis and her liver injury quickly improved after initiation of steroid administration. This is a first case report of autoimmune hepatitis with history of HCV treatment triggered by COVID-19 vaccination.

Usefulness of argon plasma coagulation for bleeding around hepaticojejunal anastomosis.

Ectopic varices due to extrahepatic portal vein obstruction (EHO) after hepaticojejunostomy have been previously reported. However, few case reports have described angiodysplasia-like lesions due to EHO around the hepaticojejunal anastomosis because they comprise small vessels in the mucosal surface and cannot be detected by contrast-enhanced computed tomography. Physicians need to insert the endoscope into the long afferent limb to diagnose angiodysplasia-like lesions around the hepaticojejunal anastomosis. Some reports have described that endoscopy stops bleeding from angiodysplasia-like lesions around the hepaticojejunal anastomosis; however, a standard methodology remains to be established. We present three cases of bleeding from an angiodysplasia-like lesion around the hepaticojejunal anastomosis that were successfully treated using argon plasma coagulation (APC) with balloon-assisted enteroscopy. Although one patient died owing to cancer progression 3 months after APC hemostasis, the hemostatic effect persisted for >2 years in the remaining two patients. These results suggest that APC is a good treatment option to stop bleeding from angiodysplasia-like lesions at hepaticojejunal anastomosis.

Percutaneous transhepatic obliteration-related procedures for isolated gastric varices: experience of three cases.

Percutaneous transhepatic obliteration (PTO) can facilitate antegrade embolization of variceal veins. We herein report three patients who underwent percutaneous transhepatic sclerotherapy (PTS) or percutaneous transportal outflow-vessel-occluded sclerotherapy (PTOS) for isolated gastric varices. PTS was performed in Cases 1 and 2, and PTOS was performed in Case 3. Technical success was achieved in all patients without a decline in liver function; however, lack of a therapeutic benefit with rupture of esophageal varices occurred in Case 3. Case 3 had a history of pylorus gastrectomy plus Billroth-I reconstruction for gastric cancer and multiple feeding veins existed. PTO-related procedures are good treatment options for isolated gastric varices, but clinicians should be aware of the risk of treatment failure, especially the cases which have multiple feeding veins.

Elevated Production of Mitochondrial Reactive Oxygen Species via Hyperthermia Enhanced Cytotoxic Effect of Doxorubicin in Human Breast Cancer Cell Lines MDA-MB-453 and MCF-7.

Hyperthermia (HT) treatment is a noninvasive cancer therapy, often used with radiation therapy and chemotherapy. Compared with 37 °C, 42 °C is mild heat stress for cells and produces reactive oxygen species (ROS) from mitochondria. To involve subsequent intracellular accumulation of DOX, we have previously reported that the expression of ATP-binding cassette sub-family G member 2 (ABCG2), an exporter of doxorubicin (DOX), was suppressed by a larger amount of intracellular mitochondrial ROS. We then hypothesized that the additive effect of HT and chemotherapy would be induced by the downregulation of ABCG2 expression via intracellular ROS increase. We used human breast cancer cell lines, MCF-7 and MDA-MB-453, incubated at 37 °C or 42 °C for 1 h to clarify this hypothesis. Intracellular ROS production after HT was detected via electron spin resonance (ESR), and DOX cytotoxicity was calculated. Additionally, ABCG2 expression in whole cells was analyzed using Western blotting. We confirmed that the ESR signal peak with HT became higher than that without HT, indicating that the intracellular ROS level was increased by HT. ABCG2 expression was downregulated by HT, and cells were injured after DOX treatment. DOX cytotoxicity enhancement with HT was considered a result of ABCG2 expression downregulation via the increase of ROS production. HT increased intracellular ROS production and downregulated ABCG2 protein expression, leading to cell damage enhancement via DOX.

Nitric oxide regulates the expression of heme carrier protein-1 via hypoxia inducible factor-1α stabilization.

Photodynamic therapy (PDT) is a cancer therapy that capitalizes on cancer-specific porphyrin accumulation. We have investigated this phenomenon to propose the following three conclusions: 1) the mechanism underlying this phenomenon is closely related to both nitric oxide (NO) and heme carrier protein-1 (HCP-1), 2) NO inactivates ferrochelatase, and thus, the intracellular porphyrin levels in the cells are increased by the administration of an NO donor after 5-aminolevulinic acid treatment, 3) HCP-1 transports not only heme but also other porphyrins. Since NO stabilizes hypoxia-inducible factor (HIF)-1α, resulting in the upregulation of heme biosynthesis, HCP-1 expression can be increased by HIF-1α stabilization. In this study, we determined whether NO regulates HCP-1 expression by stabilizing HIF-1α expression. For this purpose, rat gastric cancer cell line RGK36 was treated with L-arginine or N6-(1-iminoethyl)-L-lysine (L-NIL). L-arginine treatment increased the intracellular NO concentration, and both HCP-1 and HIF-1α expression, while L-NIL treatment decreased them. Cytotoxicity of PDT was enhanced by L-arginine, following intracellular hemato-porphyrin dihydrochloride (HpD) accumulation. Both Cytotoxicity of PDT and HpD accumulation were decreased by L-NIL. The HCP-1 and HIF-1α expression, intracellular HpD accumulation and PDT cytotoxicity were decreased by 2-methoxyestradiol, which is a HIF-1α inhibitor. Moreover, these phenomena were not increased by a combination of both L-arginine and 2-Me. Thus, HCP-1 can be a downstream target of HIF-1α. These effects were also induced in the human gastric cancer cell line MKN45. Taken together, we conclude that HCP-1 expression is regulated by NO via HIF-1α stabilization.

Hyperthermia enhances photodynamic therapy by regulation of HCP1 and ABCG2 expressions via high level ROS generation.

Photodynamic therapy (PDT) is a cancer treatment that make use of the cancer-specific accumulation of porphyrins. We have reported that mitochondrial reactive oxygen species (mitROS) upregulate uptake transporter of porphyrins, heme carrier protein-1 (HCP-1). The accumulation of cancer-specific porphyrins was increased by mitROS production, thereby the cancer-specific PDT cytotoxicity was enhanced. Thus we investigated whether mitROS production by hyperthermia can enhanced the cytotoxicity of PDT or not. In this study, 1 h of hyperthermia at 42 °C increased the mitROS production, and both the accumulation of cancer-specific porphyrins and the PDT cytotoxicity increased. Moreover, the authors treated cells with N-acetyl-L-cysteine (NAC) to examine the effect of mitROS. NAC inhibited the increasing ROS production after hyperthermia to restrain the post-treatment increase of cancer-specific porphyrins accumulation. Moreover, the increase of ROS production in cancer cells after hyperthermia upregulated HCP-1 expression and downregulated ABCG2 expression. These regulation were inhibited by NAC. These results suggest that hyperthermia treatment increased mitROS production, which involved HpD accumulation and enhanced PDT effects in cancer cells. The mechanism of this phenomenon was most likely to be due to both the upregulation of HCP-1 and the downregulation of ABCG2 by mitROS.

The preventive effect of Qing Dai on bisphosphonate-induced gastric cellular injuries.

The Chinese herbal medicine Qing Dai has been traditionally used for the treatment of various inflammatory diseases. We previously reported that reactive oxygen species play an important role in bisphosphonate-induced gastrointestinal injuries and that Qing Dai improved ulcerative colitis by scavenging reactive oxygen species. In this study, we investigated whether Qing Dai prevented bisphosphonate-induced gastric cellular injuries. Risedronate (a bisphosphonate) was added to rat gastric mucosal cells. Risedronate-induced cellular injury, cellular lipid peroxidation, mitochondrial membrane potential, and reactive oxygen species production in rat gastric mucosal cells were examined via viable cell counting, specific fluorescent indicators, and electron spin resonance. Pretreatment with Qing Dai attenuated the fluorescence intensity of diphenyl-1-pyrenylphosphine and MitoSox as well as the signal intensities of electron spin resonance. Cell viability improved from 20% to 80% by pretreatment with Qing Dai. Thus, Qing Dai prevented this injury by suppressing mitochondrial reactive oxygen species production, which is the main cause of cellular lipid peroxidation. Qing Dai also maintained mitochondrial potential, reducing reactive oxygen species production. We conclude that Qing Dai has protective effects on bisphosphonate-induced gastrointestinal injury and thus has the potential for clinical application.

Acetic acid is an oxidative stressor in gastric cancer cells.

Acetic acid can cause cellular injury. We previously reported that acetic acid induces cancer cell-selective death in rat gastric cells. However, the mechanism is unclear. Generally, cancer cells are more sensitive to reactive oxygen species than normal cells. Accordingly, in this study, we investigated the involvement of oxidative stress in cancer cell-selective death by acetic acid using normal gastric mucosal cells and cancerous gastric mucosal cells. The cancer cell-selective death was induced at the concentration of 2-5 µM acetic acid. Cancerous gastric mucosal cells had increased expression of monocarboxylic transporter 1 and high uptake of acetic acid, compared to normal gastric mucosal cells. The exposure of cancerous gastric mucosal cells to acetic acid enhanced production of reactive oxygen species and expression of monocarboxylic transporter 1, and induced apoptosis. In contrast, acetic acid showed minor effects in normal gastric mucosal cells. These results indicate that acetic acid induced cancer cell-selective death in gastric cells through a mechanism involving oxidative stress.

Waterjet submucosal dissection of porcine esophagus with the HybridKnife and ERBEJET 2 system: a pilot study.

Background and study aims Esophageal endoscopic submucosal dissection (ESD) is technically difficult because of narrow working spaces and ease of perforation due to the lack of serosa. HybridKnife is a recently developed ESD device that is combined with the high pressure waterjet ERBEJET 2 system to lift mucosa. We hypothesized that this waterjet could make submucosal dissection safer and studied this in porcine esophagus. Materials and methods Water pressures of 30 - 70 bar were tested to determine the appropriate pressure for waterjet ESD with HybridKnife (WJ-ESD) in one pig. WJ-ESD safety and completion were compared with those of conventional ESD using DualKnife (C-ESD) as a reference. Each of three virtual esophageal lesions in two pigs were resected alternatively using both methods from the lower to upper esophagus. For WJ-ESD, the submucosa, apart from hard fibrous tissues, was dissected using water pressure alone. Results Using 50 bar of water pressure resulted in the best balance between proper dissection and view-disturbing water backflow. The dissection speeds for the lower, middle, and upper esophagus were 0.2, 0.9, and 0.2 cm2/min in 50 bar WJ-ESD and 1.1, 0.5, and 1.0 cm2/min in C-ESD, respectively. Minor bleeding was frequent in WJ-ESD, but was easily stopped by electrocoagulation with the same needle. No perforation was observed in either procedure. Thermal damage to dissected tissues appeared mild, and the extent of muscle injury was lower for WJ-ESD (4, 6, and 8 %) compared with C-ESD (14, 16, and 7 %). Conclusions WJ-ESD could be completed safely for porcine esophagus with less damage to the muscle layer compared with C-ESD.

A Rare Case of Colonic Leiomyosarcoma in Association with Ulcerative Colitis.

Ulcerative colitis (UC) is known to be associated with an increased risk of colorectal cancer. However, the occurrence of non-epithelial malignancies is uncommon. An elevated lesion in the descending colon was found in a 51-year-old woman with a 30-year history of UC. Despite tumor progression, repeated biopsies showed no cancerous findings. Because the lesion was highly suspected to be a malignant tumor, a partial colectomy was performed. The pathological diagnosis was leiomyosarcoma. Leiomyosarcoma of the gastrointestinal tract is rare, and this is only the third known case reported in patients with UC.

Endoscopic detachable snare ligation: a new treatment method for colonic diverticular hemorrhage.

BACKGROUND AND STUDY AIMS: Colonic diverticular hemorrhage is the most common cause of lower intestinal bleeding. We tried to develop a convenient and reliable hemostatic method, endoscopic detachable snare ligation (EDSL), to treat diverticular hemorrhage and retrospectively explored its safety and efficacy. PATIENTS AND METHODS: The definitive bleeding diverticulum was ligated with a detachable snare, instead of a rubber band, in a procedure similar to endoscopic band ligation. Removal of the scope to attach a ligation device and reinsertion for treatment are not needed in this method. RESULTS: From November 2013 to September 2014, EDSL was used to treat 8 patients with colonic diverticular hemorrhage. The mean procedure time required for hemostasis after identification of the bleeding diverticulum was 5 ±â€Š2 minutes. Sustained hemostasis was achieved in 7 patients (88 %), and early rebleeding occurred in 1 patient, in whom the applied suction seemed inadequate. No complications occurred in any patient. CONCLUSIONS: EDSL may be a safe and effective treatment for colonic diverticular hemorrhage. However, additional studies are warranted to confirm these initial exploratory data.