A number of human and animal studies have demonstrated that the hyperglycemia-lowering effects of metformin may result from modulation of the gut microbiota population. Metformin changes the Firmicutes/Bacteroidetes ratio and enhances the growth of some bacteria, such as Akkermansia muciniphila, Escherichia spp. or Lactobacillus and reduce the levels of others such as Intestinibacter. Moreover, in the intestine, metformin not only improves glucose absorption, but also promotes the production of short-chain fatty acids (SCFAs), regulates the secretion of the glucose-lowering hormone glucagon-like peptide 1 (GLP‑1) and other intestinal peptides, inhibits the Farnesoid-X-receptor (FXR) and resorption of the bile acid pool, and may reduce intestinal permeability barrier by increasing the expression of mucin and tight junction proteins, modulates the immune response, has an anti-inflammatory effect, etc. Thus, research results indicate that the intestinal microbiota is involved not only in the hypoglycemic effect of metformin in diabetes mellitus type 2, but also in the implementation of its numerous pleiotropic effects.

Введение. Желчнокаменная болезнь (ЖКБ) является одной из наиболее важных проблем общественного здравоохранения. Ее распространенность составляет 10–20 % в развитых странах мира, в целом ежегодные медицинские расходы на лечение ЖКБ превысили 6 млрд долларов в 2004 г. [1, 2].

Введение. желчнокаменная болезнь (ЖКБ) встречается у 10–20 % населения в экономически развитых странах. ЖКБ связана с несколькими кардиометаболическими факторами риска: ожирением, дислипидемиями, нездоровым питанием и малоподвижным образом жизни [1, 2]. Наличие ЖКБ значительно увеличивает риск сахарного диабета 2 типа (СД2), сердечно-сосудистых заболеваний, включая ИБС и артериальную гипертензию (АГ), что было доказано в нескольких эпидемиологических исследованиях [3–6]. СД приводит к увеличению индекса насыщения желчи и к гипомоторике желчного пузыря изза висцеральной невропатии, ожирения, гиперинсулинемии, резистентности к инсулину, что может способствовать образованию желчных камней [3]. Связь между АГ и ЖКБ основывается, в частности, на активизации эфферентных симпатических механизмов, ренин-ангиотензин-альдостероновой системы с нарушением моторики желудочно-кишечного тракта из-за импульсации от механорецепторов желчного пузыря при его растяжении, что приводит к повышению АД [5]. Однако при изучении связи ЖКБ и Аг показаны противоречивые результаты [3, 7]. Кроме того, мы не нашли исследований ассоциации АГ с ЖКБ в сочетании с СД2.

The last decade saw extensive studies of the human gut microbiome and its relationship to specific diseases, including gallstone disease (GSD). The information about the gut microbiome in GSD-afflicted Russian patients is scarce, despite the increasing GSD incidence worldwide. Although the gut microbiota was described in some GSD cohorts, little is known regarding the gut microbiome before and after cholecystectomy (CCE). By using Illumina MiSeq sequencing of 16S rRNA gene amplicons, we inventoried the fecal bacteriobiome composition and structure in GSD-afflicted females, seeking to reveal associations with age, BMI and some blood biochemistry. Overall, 11 bacterial phyla were identified, containing 916 operational taxonomic units (OTUs). The fecal bacteriobiome was dominated by Firmicutes (66% relative abundance), followed by Bacteroidetes (19%), Actinobacteria (8%) and Proteobacteria (4%) phyla. Most (97%) of the OTUs were minor or rare species with ≤1% relative abundance. Prevotella and Enterocossus were linked to blood bilirubin. Some taxa had differential pre- and post-CCE abundance, despite the very short time (1–3 days) elapsed after CCE. The detailed description of the bacteriobiome in pre-CCE female patients suggests bacterial foci for further research to elucidate the gut microbiota and GSD relationship and has potentially important biological and medical implications regarding gut bacteria involvement in the increased GSD incidence rate in females.

Gallstone disease (GSD) has, for many years, remained a high-cost, socially significant public health problem. Over the past decade, a number of studies have been carried out-both in humans and in animal models-confirming the role of the microbiota in various sections of the gastrointestinal tract as a new link in the etiopathogenesis of GSD. The microbiome of bile correlates with the bacterial composition of saliva, and the microbiome of the biliary tract has a high similarity with the microbiota of the duodenum. Pathogenic microflora of the oral cavity, through mechanisms of immunomodulation, can affect the motility of the gallbladder and the expression of mucin genes (MUC1, Muc3, MUC4), and represent one of the promoters of stone formation in the gallbladder. The presence of H. pylori infection contributes to the formation of gallstones and affects the occurrence of complications of GSD, including acute and chronic cholecystitis, cholangitis, pancreatitis. Intestinal bacteria (Clostridium, Bifidobacterium, Peptostreptococcus, Bacteroides, Eubacterium, and Escherichia coli) participating in the oxidation and epimerization of bile acids can disrupt enterohepatic circulation and lead to the formation of gallstones. At the same time, cholecystectomy due to GSD leads to the further transformation of the composition of the microbiota in various parts of the gastrointestinal tract, increasing the risk of developing stomach cancer and colorectal cancer. Further research is required to determine the possibility of using the evaluation of the composition of the microbiota of the gastrointestinal and biliary tracts as an early diagnostic marker of various gastroenterological diseases.

BACKGROUND: In the XXI century, the frequency of pancreas diseases increased 2–3 times. The expectation that causes a pandemic lead to the development of a number of diseases. The results of studies on the relationship of overweight, obesity with the risk of developing pancreas diseases (acute pancreatitis (AP), chronic pancreatitis (CP) and pancreas cancer (PC)) are very heterogeneous (for AP and PC) and not numerous (for CP). AIMS: to identify the frequency of obesity in AP patients (APр), CP patients (СPр) and PC patients (PCр) and compare these parameters. MATERIALS AND METHODS: at the observational multicenter clinical cross-sectional uncontrolled case-study 44 APp, 97 CPp and 45 PCp were examined; the groups were comparable by sex/age. Informed consent form for participate in the study was obtained from all patients. The main outcome of the study: the frequency of obesity in APp, CPp; PCp. RESULTS: The frequency of obesity in APp (13,6%), CPp (24,7%) and PCp (20,0%) did not differ significantly. Among the examined patients, the lowest average BMI (24,2±0,7 kg/m 2 ) was observed in APp (p=0,049). BMI ≥22,5 kg/m 2 was found to be associated with AP (OR=0,398; 95%CI 0,195–0,812; p=0,011). An inverse relationship was shown between the BMI and “definite” CP (Exp (B)=0,772; 95%CI 0,632–0,942; p=0,011). In men with CP and in CPp alcoholic etiology, weight deficit was observed significantly more often than in women with CP and in CPp biliary etiology, respectively. Earlier (a year before the present survey), obesity was more common in PCp (55,6%) than in APp (13,6%, χ 2 =3,3; p=0,000) and CPp (25,8%, χ 2 =12,0; p=0,001). A history of obesity (in our study one year before PC detection) and PC (OR=4,435; 95% CI 2,180–9,025; p=0,000) direct relationship was shown. CONCLUSIONS: the frequency of obesity in APp, CPp and PCp was similar. The average BMI was higher in APp, than in CPp and PCp. BMI≥22,5 kg/m2 was a protective factor for AP. BMI was inversely associated with “defined” CP. A history of obesity was directly associated with PC.

Study Objective: to determine blood lipids and incidence of dyslipidemia in patients with acute pancreatitis (AP), chronic pancreatitis (CP) and pancreas cancer (PC), and to compare them. Study Design: observational multicentral single-arm cross section clinical case series. Materials and Methods. The study enrolled 44 patients with AP, 97 patients with CP, 45 with PC; age and sex composition of groups was comparable. Blood lipids were measured using standard methods. Study Results. Hypercholesterolemia was more common in CP (58.8%), whereas in AP it was (40.9%, p = 0.049) or PC (15.6%, p = 0.000). The rate of hypertriglyceridemia was comparable. Hypoalphacholesterolemia was more common in PC (80.0%), whereas in AP it was (45.5%, p = 0.001) or CP (27.8%, p = 0.000). There is direct association between increased high density lipoprotein cholesterol (HDLP-C) per 1 mmol/L with CP risk (Exp (B) = 21.618; 95% CI: 4.741–98.582, p = 0.000) and invert association with PC risk (Exp (B) = 0.015; 95% CI: 0.002–0.092, p = 0.000). There is also a correlation between total cholesterol and pancreonecrosis and “specific” CP: increase of 1 mmol/L in total cholesterol results in pancreonecrosis risk reduction of 37.7% (Exp (B) = 0.623; 95% CI: 0.389–0.996, p = 0.048), “specific” CP — of 47.4% (Exp (B) = 0.526; 95% CI: 0.305–0.908, p = 0.021). Conclusion. Hypercholesterolemia was more often diagnosed in CP, hypoalphacholesterolemia — in PC; hypertriglyceridemia was comparable. There is a direct correlation between HDLP-C and PC and inverse correlation — with risk of pancreac cancer. Total cholesterol was reversely associated with the risk of pancreonecrosis and specific CP. The evidence determines the need in additional study of association between pancreatic diseases and blood lipids. Keywords: acute pancreatitis, chronic pancreatitis, pancreatic cancer, dyslipidemia, blood lipids.

Aim. To determine the prevalence of hypertension (HTN) in patients with acute pancreatitis (AP), chronic pancreatitis (CP), pancreatic cancer (PC) and establish associations of HTN with other risk factors (obesity, dyslipidemia (DLP), plasma glucose ≥7,0 mmol/l, smoking, alcohol consumption).Material and methods. This observational multicenter clinical cross-sectional uncontrolled study included 44 patients with AP, 97 patients with CP and 45 patients with PC. The groups were comparable by sex and age. The HTN was diagnosed according to the criteria of Russian Society of Cardiology (2020).Results. HTN was much more common in patients with PC (55,6%) than in patients with AP (25,0%) (χ 2 =8,6, p=0,003). In patients with CP, the prevalence of HTN (39,2%) did not differ from those with AP or PC. Among patients with AP and HTN, higher levels of triglycerides (TG) (U=88,0, p=0,010) and glucose (U=89,5, p=0,011) than in non-HTN patients with AP were determined. In HTN patients with CP, glucose ≥7,0 mmol/l was recorded 3 times more often than in non-HTN patients with CP (χ 2 =16,2, p=0,000). In patients with PC and HTN, a higher mean body mass index (BMI) (F=7,8, p=0,008) and less common normal body weight than in non-HTN patients with PC (28,0 and 65,0%, χ 2 =6,2, p=0,013) was revealed. In patients with CP, increased glucose levels by 1 mmol/l (Exp (B)=1,933, 95% confidence interval (CI) 1,350-2,767, p=0,000) or BMI by 1 kg/m2 (Exp (B)=1,224, 95% CI 1,085-1,380, p=0,001) raised the probability of HTN; in patients with PC, increased BMI by 1 kg/ m2 (Exp (B)=1,394, 95% CI 1,057-1,840, p=0,019) or age by 1 year (Exp (B)=1,251, 95% CI 1,052-1,489, p=0,011) raised the probability of HTN.Conclusion. HTN was more often observed in patients with PC than in those with AP. In patients with CP, the prevalence of HTN did not differ from those with AP or PC. HTN was a cofactor to other metabolic risk factors (glucose ≥7,0 mmol/l, obesity) in patients with AP or CP; behavioral risk factors, on the contrary, were less common in HTN patients with AP or CP. In patients with CP, there was a direct association of HTN with glucose levels or BMI, and in patients with PC — HTN with BMI or age.

The prevalence of metabolic syndrome (MS), non-alcoholic fatty liver disease (NAFLD) and non-alcoholic fatty pancreatic disease (NAFPD) is 1/4–1/3 of the planet population. It has been proven that the main links in their pathogenesis are disorders of lipid and carbohydrate metabolism. A high comorbidity of NAFLD and NAFPD was shown: in 67,9 % of patients with NAFPD, fatty liver was revealed, and in 96,8 % of patients with NAFLD, pancreatic steatosis was diagnosed. The prevalence of MC among NAFPD patients is 59,2–76,9 %. A meta-analysis revealed that NAFPD is associated with an increased risk of MS (relative risk (RR) = 2,25; 95 % CI 2,00–2,53; p < 0,0001), arterial hypertension (RR = 1,43; 95 % CI 1,08–1,90; p = 0,013), NAFLD (RR = 2,49; 95 % CI 2,06–3,02; p < 0,0001), diabetes mellitus 2 type (RR = 1,99; 95 % CI 1,18–3,35; p = 0,01), and obesity (RR = 1,91; 95 % CI 1,67–2,19; p < 0,0001). Concomitant MS negatively affects the clinical course of acute and chronic pancreatitis, for example, moderately severe acute pancreatitis is observed 3 times more often with MS than without MS, partly due to that I, IV and V types of hyperlipidemia are associated with acute pancreatitis. Dyslipidemia in NAFLD occurs in 60–70 % of cases and is characterized by hypertriglyceridemia, elevated level of free fatty acids and low density lipoprotein cholesterol, decreased content of high density lipoprotein cholesterol. Therefore, strategies aimed at the primary prevention of dyslipidemia can help reduce morbidity and mortality in liver and pancreatic pathology associated with MS.

The review presents current data on the Arterial Hypertension (AH) and Gallstone Disease (GSD) prevalence. The heterogeneity of the relationship between cardiovascular diseases, AH and GSD was shown. According to our data, in Novosibirsk, in the population sample of women 25-64 years with/without GSD (n=870) prevalence of AH (criteria blood pressure (BP) >160/95, WHO MONICA project, 1994-1995) was 41,6% and 31,3%, p<0,05. In this female population as a whole (n=1663) prevalence of AH was 30,8%. But with the criteria of BP >140/90, the corresponding indicators of prevalence of AH were similar: 55,4%, 47,1% and 49,0%. The evidence of the association between the GSD and the carotid arteries intima-media thickness, as atherosclerosis marker, is presented, and the main mechanisms of development of AH in GSD are highlighted. Gastroenterological symptoms, BP, blood lipids, quality of life were compared, which were worse in comorbid patients with GSD and AH than in GSD or AH. The expediency of an active approach to the detection of GSD and AH in terms of their contribution to cardiovascular prognosis is shown.

The aim of the study was to evaluate in the epidemiological study the possible association of coronary heart disease (CHD) and gallstone disease (GSD) in women aged 25–64 years and in men aged 35-54 years, and assess the possible impact on it of certain conventional risk factors (body mass index (BMI), dyslipoproteinemia (DLP), the presence of arterial hypertension (AH) and of diabetes mellitus (DM) type 2) in women. In the frame of the WHO “MONICA” programs it was shown, that among the unorganized urban men population (n = 399) there was no significant relationship between the presence of «definite» IHD and GSD: OR = 0.8 (95 % CI 0.1–6.4, p = 0.8). Among the unorganized urban women population (n = 870) a direct association of GSD with a «definite» coronary artery disease was established: OR = 2.0 (95 % CI 1.1–3.4; p < 0.05), which did not depend on the presence or absence of AH (OR = 1.8; 95 % CI 1.01–3.1; p < 0.05), DLP (OR = 1.9; 95 % CI 1.1–3.6; p < 0,05) or DM type 2 (OR = 1.8; 95 % CI 1.03–3.6; p < 0.05), but disappeared when age and BMI were included in the analysis (OR = 1.5; 95 % CI 0,9–2.7; p > 0.05 and OR = 1.6; 95 % CI 0.9–2.9; p > 0.05, respectively).

Elevated lipoprotein(a) plasma concentration - [Lp(a)] is considered a risk factor for cardiovascular disease (CVD). In African Americans (AA) have 2-3 times above [Lp(a)] than in Europeans and Asians, for example, in Chinese - 7.0 mg/dl, in black Sudanese - 46 mg/dl. Some authors believe that the apo(a) gene is the main determinant of the [Lp(a)] variation in AA, while others recognize the role of variant factors. The relationship between [Lp(a)] and the risk of CVD in AA is unclear: in meta-analysis under the Collaboration Emerging Risk Factors, at Europeans [Lp(a)] is associated with coronary artery disease, in AA - no. In Novosibirsk, from 96 men with confirmed surgically expressed coronary atherosclerosis [Lp(a)] is raised only in 16 %, and the high-atherogenous phenotype of apo(a) was detected in 20 %; but in the presence of unstable plaques (UP) in coronary arteries [Lp(a)] is 1.8 times higher than in persons without UP. Average [Lp(a)]+ ([Лп(а)]>0) at Chukchi male made 28,1 mg/dl, Chukchi female have 28,4 mg/dl, at Eskimos with [Lp(a)]+ the median of the [Lp(a)] - 22,4 mg/dl, and the mode - 15,5 mg/dl. In the aboriginals of Chukotka with AH, apo(a) S1, S2 occurred a little more frequently than among those without AH. Along with lipoprotein apheresis and niacin, apolipoprotein-(B-100)-antisense mipomersen, inhibitor of PCSK9 and apolipoprotein-(a)-antisense (oligonucleotide), showed promising results in reducing [Lp(a)]. In Russia, ehvolocumab and alirocoumab have been approved.

In pancreatic cancer (PC) proved the role of obesity not only as a PC risk factor, but also as a factor associated with reduced survival in PC in adulthood. In PC is marked by increased lipogenesis: an increased need of cancer cells in the fatty acid (FA) is implemented not only by increasing lipogenesis de novo, but also by the exogenous FA assimilation, although several meta-analyses have not confirmed the importance of dietary fat in increasing the PC risk. Metabolic reprogramming of cancer cells is aimed at ensuring the rapid proliferation of tumor cells: the transition to aerobic glycolysis, increased expression of enzymes involved in the FA formation (citrate-synthase, ATP-citrate lyase and FA synthase - FASN), due to a mutation of the gene TP53 . As therapeutic agents in PC offer to inhibit FASN, and also impact prenylation and post-prenylation of oncogenes, in particular, KRAS , known as drugs, given the pleiotropic effect of atorvastatin and newly synthesized inhibitor farnesyltransferase R115777.

In pancreatic cancer (PC) proved the role of obesity not only as a PC risk factor, but also as a factor associated with reduced survival in PC in adulthood. In PC is marked by increased lipogenesis: an increased need of cancer cells in the fatty acid (FA) is implemented not only by increasing lipogenesis de novo, but also by the exogenous FA assimilation, although several meta-analyses have not confirmed the importance of dietary fat in increasing the PC risk. Metabolic reprogramming of cancer cells is aimed at ensuring the rapid proliferation of tumor cells: the transition to aerobic glycolysis, increased expression of enzymes involved in the FA formation (citrate-synthase, ATP-citrate lyase and FA synthase - FASN), due to a mutation of the gene TP53 . As therapeutic agents in PC offer to inhibit FASN, and also impact prenylation and post-prenylation of oncogenes, in particular, KRAS , known as drugs, given the pleiotropic effect of atorvastatin and newly synthesized inhibitor farnesyltransferase R115777.

РПЖ (РПЖ) является одним из самых опасных и клинически сложных видов рака. Отсутствие эффективных методов скрининга, поздняя выявляемость являются основными причинами того, что РПЖ остается одним из заболеваний, при котором уровень смертности практически равен уровню заболеваемости. При этом хирургические и терапевтические методы лечения остаются малоэффективными. Использование различных видов химиотерапии увеличивает продолжительность жизни больных с 5–7 месяцев при лечении одним гемцитабином до 8,5–11 месяцев при комбинированной терапии. Поэтому поиск новых мишеней для терапии является ключевой задачей при данной патологии. В обзорной статье представлены результаты последних исследований в области генетики и молекулярной биологии РПЖ. Описаны мутации основных генов: KRAS, TP53, CDKN 2A, SMAD 4, ARID 1A и также часто выявляемые дефекты других генов: TGFBR 2, KDM6A, AXIN 1, ACVR 1B, PIK3CA, RNF43, GNAS, ATM, GLI3, ARID 1A и RBM10. Представлены результаты анализа связи мутаций этих генов с изменениями индуцируемых ими сигнальных путей и освещены возможности использования найденных особенностей в качестве мишеней для таргетной терапии РПЖ. В обзоре отражены проблемы изменения иммунного статуса, механизмы участия клеточного компонента стромы в процессах опухолевой прогрессии и метастазирования, возможности использования специфических антител в комбинированных схемах химиотерапии при РПЖ.

In this review we described the most frequently detected genomic alterations, defects in the genes TP53, KRAS, TGFBR 2, PIK3CA, CDKN2A, SMAD4, changes of the main signaling pathways those genes, certain immunological mechanisms of tumor progression and metastasis in pancreatic cancer (PC). The review reflects the possibility of using the identified molecular and genomic alterations to choose new targets for targeted therapy in order to increase the effectiveness of treatment of patients with PC and further development of personalized medicine.

Pancreatic ductal adenocarcinoma (PDA) is one of the most dangerous and clinically difficult cancers. PDA is one of the diseases for which the mortality rate is almost equal to the level of morbidity. The absence of effective methods of screening, late detection are the main reasons for that. At the same surgical and therapeutic treatments are ineffective. Using different types of chemotherapy increases the life expectancy of patients with 5-7 months of gemcitabine in the treatment of one to 8,5-11 months with combination therapy. Therefore, the search for new targets for therapy is a main task in this pathology. In a review article presents the results of recent research in the field of genetics and molecular biology of PDA. Described mutations in key genes: KRAS, TP53, CDKN 2A, SMAD 4, ARID 1A and also often identify other gene defects: TGFBR 2, KDM6A, AXIN 1, ACVR 1B, PIK3CA, RNF43, GNAS, ATM, GLI3, ARID 1A and RBM10. Presents the analysis of the relationship of gene mutations with changes of their signaling pathways and the possibility of using the features of targeted therapy of PDA. The review reflects the problems of changes in immune status, participation mechanisms stromal cell component in the processes of tumor progression and metastasis, the possibility of using specific antibodies in combination chemotherapy regimens in PDA.