An oncogenic enhancer promotes melanoma progression via regulating ETV4 expression.

BACKGROUND: Enhancers are important gene regulatory elements that promote the expression of critical genes in development and disease. Aberrant enhancer can modulate cancer risk and activate oncogenes that lead to the occurrence of various cancers. However, the underlying mechanism of most enhancers in cancer remains unclear. Here, we aim to explore the function and mechanism of a crucial enhancer in melanoma. METHODS: Multi-omics data were applied to identify an enhancer (enh17) involved in melanoma progression. To evaluate the function of enh17, CRISPR/Cas9 technology were applied to knockout enh17 in melanoma cell line A375. RNA-seq, ChIP-seq and Hi-C data analysis integrated with luciferase reporter assay were performed to identify the potential target gene of enh17. Functional experiments were conducted to further validate the function of the target gene ETV4. Multi-omics data integrated with CUT&Tag sequencing were performed to validate the binding profile of the inferred transcription factor STAT3. RESULTS: An enhancer, named enh17 here, was found to be aberrantly activated and involved in melanoma progression. CRISPR/Cas9-mediated deletion of enh17 inhibited cell proliferation, migration, and tumor growth of melanoma both in vitro and in vivo. Mechanistically, we identified ETV4 as a target gene regulated by enh17, and functional experiments further support ETV4 as a target gene that is involved in cancer-associated phenotypes. In addition, STAT3 acts as a transcription factor binding with enh17 to regulate the transcription of ETV4. CONCLUSIONS: Our findings revealed that enh17 plays an oncogenic role and promotes tumor progression in melanoma, and its transcriptional regulatory mechanisms were fully elucidated, which may open a promising window for melanoma prevention and treatment.

Genome-wide analysis of bZIP transcription factors and their expression patterns in response to methyl jasmonate and low-temperature stresses in Platycodon grandiflorus.

Background: Platycodon grandiflorus belongs to the genus Platycodon and has many pharmacological effects, such as expectorant, antitussive, and anti-tumor properties. Among transcription factor families peculiar to eukaryotes, the basic leucine zipper (bZIP) family is one of the most important, which exists widely in plants and participates in many biological processes, such as plant growth, development, and stress responses. However, genomic analysis of the bZIP gene family and related stress response genes has not yet been reported in P. grandiflorus. Methods: P. grandiflorus bZIP (PgbZIP) genes were first identified here, and the phylogenetic relationships and conserved motifs in the PgbZIPs were also performed. Meanwhile, gene structures, conserved domains, and the possible protein subcellular localizations of these PgbZIPs were characterized. Most importantly, the cis-regulatory elements and expression patterns of selected genes exposed to two different stresses were analyzed to provide further information on PgbZIPs potential biological roles in P. grandiflorus upon exposure to environmental stresses. Conclusions: Forty-six PgbZIPs were identified in P. grandiflorus and divided into nine groups, as displayed in the phylogenetic tree. The results of the chromosomal location and the collinearity analysis showed that forty-six PgbZIP genes were distributed on eight chromosomes, with one tandem duplication event and eleven segmental duplication events identified. Most PgbZIPs in the same phylogenetic group have similar conserved motifs, domains, and gene structures. There are cis-regulatory elements related to the methyl jasmonate (MeJA) response, low-temperature response, abscisic acid response, auxin response, and gibberellin response. Ten PgbZIP genes were selected to study their expression patterns upon exposure to low-temperature and MeJA treatments, and all ten genes responded to these stresses. The real-time quantitative polymerase chain reaction (RT-qPCR) results suggest that the expression levels of most PgbZIPs decreased significantly within 6 h and then gradually increased to normal or above normal levels over the 90 h following MeJA treatment. The expression levels of all PgbZIPs were significantly reduced after 3 h of the low-temperature treatment. These results reveal the characteristics of the PgbZIP family genes and provide valuable information for improving P. grandiflorus's ability to cope with environmental stresses during growth and development.

Spatial diversity processing mechanism based on the distributed underwater acoustic communication system.

To address the problem of unreliable single-link underwater acoustic communication caused by large signal delays and strong multipath effects in shallow water environments, this paper proposes a distributed underwater acoustic diversity communication system (DUA-DCS). DUA-DCS employs a maneuverable distributed cross-medium buoy network to form multiple distributed, non-coherent, and parallel communication links. In the uplink, a receiving diversity processing mechanism of joint decision feedback equalizer embedded phase-locked loop and maximum signal-to-interference ratio combining (DFE-PLL-MSIRC) is proposed to achieve waveform-level diversity combining of underwater signals. A phase-locked loop module is embedded in each branch of the decision feedback equalizer to eliminate the residual frequency and phase errors after Doppler compensation. Meanwhile, the combining coefficients are determined based on the maximum signal-to-interference ratio criterion, taking into account the residual inter-symbol interference after equalization, resulting in efficient and accurate computation. Additionally, the combined decision values are fed back to the feedback filters in each branch to ensure more accurate feedback output. Simulation and lake experiment results demonstrate that, compared to the single-link communication system, DFE-PLL-MSIRC can achieve a diversity gain of more than 5.2 dB and obtain about 3 dB more diversity gain than the comparison algorithm. And the BER of DFE-PLL-MSIRC can be reduced by at least one order of magnitude, which is lower by at least 0.6 order of magnitude compared to the comparison algorithm. In the downlink, a transmitting diversity processing mechanism of complex orthogonal space-time block coding (COSTBC) is proposed. By utilizing a newly designed generalized complex orthogonal transmission matrix, complete transmission diversity can be achieved at the coding rate of 3/4. Compared to the single-link communication system, the system can achieve a diversity gain of more than 6 dB.

The pleiotropic enhancer enh9 promotes cell proliferation and migration in non-small cell lung cancer via ERMP1 and PD-L1.

Enhancers, cis-acting DNA elements for transcriptional regulation, are important regulators of cell identity and disease. However, of the hundreds of thousands of enhancers annotated in the human genome, only a few have been studied for their regulatory mechanisms and functions in cancer progression and therapeutic resistance. Here, we report the pleiotropy of one enhancer (named enh9) in both cell proliferation and migration in non-small cell lung cancer (NSCLC) cells. By integrating multi-genomic data, ERMP1 and PD-L1 were screened out as potential targets of enh9. CUT&Tag sequencing demonstrated that enh9 was involved in the genomic interactions between the transcription factor RELA and the promoters of ERMP1 and PD-L1. In addition, ERMP1 and PD-L1 were validated to be involved in cell proliferation and migration, respectively. Our study fully elucidated the function and transcriptional regulation mechanisms of enh9 in NSCLC. The exploration on enhancers is promising to provide new insights for cancer diagnosis and therapy.

Integrative approaches based on genomic techniques in the functional studies on enhancers.

With the development of sequencing technology and the dramatic drop in sequencing cost, the functions of noncoding genes are being characterized in a wide variety of fields (e.g. biomedicine). Enhancers are noncoding DNA elements with vital transcription regulation functions. Tens of thousands of enhancers have been identified in the human genome; however, the location, function, target genes and regulatory mechanisms of most enhancers have not been elucidated thus far. As high-throughput sequencing techniques have leapt forwards, omics approaches have been extensively employed in enhancer research. Multidimensional genomic data integration enables the full exploration of the data and provides novel perspectives for screening, identification and characterization of the function and regulatory mechanisms of unknown enhancers. However, multidimensional genomic data are still difficult to integrate genome wide due to complex varieties, massive amounts, high rarity, etc. To facilitate the appropriate methods for studying enhancers with high efficacy, we delineate the principles, data processing modes and progress of various omics approaches to study enhancers and summarize the applications of traditional machine learning and deep learning in multi-omics integration in the enhancer field. In addition, the challenges encountered during the integration of multiple omics data are addressed. Overall, this review provides a comprehensive foundation for enhancer analysis.

Chiral mesostructured NiFe2O4 films with chirality induced spin selectivity.

Chiral mesostructured NiFe2O4 films (CMNFFs) were synthesized using L-/D-tyrosine as symmetry-breaking and structure-directing agents through a hydrothermal method. For the first time, chirality induced spin selectivity was directly observed in these ferrimagnetic materials using chirality-dependent magnetic-tip conducting atomic force microscopy (mc-AFM).

The Mechanotransduction Signaling Pathways in the Regulation of Osteogenesis.

Bones are constantly exposed to mechanical forces from both muscles and Earth's gravity to maintain bone homeostasis by stimulating bone formation. Mechanotransduction transforms external mechanical signals such as force, fluid flow shear, and gravity into intracellular responses to achieve force adaptation. However, the underlying molecular mechanisms on the conversion from mechanical signals into bone formation has not been completely defined yet. In the present review, we provide a comprehensive and systematic description of the mechanotransduction signaling pathways induced by mechanical stimuli during osteogenesis and address the different layers of interconnections between different signaling pathways. Further exploration of mechanotransduction would benefit patients with osteoporosis, including the aging population and postmenopausal women.

N6-methyladenosine (m6A) methylation in kidney diseases: Mechanisms and therapeutic potential.

The N6-methyladenosine (m6A) modification is regulated by methylases, commonly referred to as "writers," and demethylases, known as "erasers," leading to a dynamic and reversible process. Changes in m6A levels have been implicated in a wide range of cellular processes, including nuclear RNA export, mRNA metabolism, protein translation, and RNA splicing, establishing a strong correlation with various diseases. Both physiologically and pathologically, m6A methylation plays a critical role in the initiation and progression of kidney disease. The methylation of m6A may also facilitate the early diagnosis and treatment of kidney diseases, according to accumulating research. This review aims to provide a comprehensive overview of the potential role and mechanism of m6A methylation in kidney diseases, as well as its potential application in the treatment of such diseases. There will be a thorough examination of m6A methylation mechanisms, paying particular attention to the interplay between m6A writers, m6A erasers, and m6A readers. Furthermore, this paper will elucidate the interplay between various kidney diseases and m6A methylation, summarize the expression patterns of m6A in pathological kidney tissues, and discuss the potential therapeutic benefits of targeting m6A in the context of kidney diseases.

Jinlida granules combined with metformin improved the standard-reaching rate of blood glucose and clinical symptoms of patients with type 2 diabetes: secondary analysis of a randomized controlled trial.

Background: Previous studies found that Jinlida granules could significantly reduce blood glucose levels and enhance the low-glucose action of metformin. However, the role of Jinlida in the standard-reaching rate of blood glucose and improving clinical symptoms has yet to be studied. We aimed to elaborate on the efficacy of Jinlida in type 2 diabetes (T2D) patients who experience clinical symptoms based on secondary analysis of a randomized controlled trial. Methods: Data were analyzed from a 12-week, randomized, placebo-controlled study of Jinlida. The standard-reaching rate of blood glucose, the symptom disappearance rate, the symptom improvement rate, the efficacy of single symptoms, and the total symptom score were evaluated. The correlation between HbA1c and the improvement of clinical symptoms was analyzed. Results: For 12 weeks straight, 192 T2D patients were randomly assigned to receive either Jinlida or a placebo. The treatment group showed statistically significant differences in the standard-reaching rate of HbA1c < 6.5% (p = 0.046) and 2hPG (< 10 mmol/L, 11.1 mmol/L) (p < 0.001), compared with the control group. The standard-reaching rate of HbA1c < 7% (p = 0.06) and FBG < 7.0 mmol/L (p = 0.079) were not significantly different between the treatment and control groups. Five symptoms exhibited a statistical difference in symptom disappearance rate (p < 0.05). All the symptoms exhibited a significant difference in symptom improvement rate (p < 0.05). The mean change in total symptom score from baseline to week 12 was -5.45 ± 3.98 in the treatment group and -2.38 ± 3.11 in the control group, with statistically significant differences (p < 0.001). No significant correlations were noted between symptom improvement and HbA1c after 12 weeks of continuous intervention with Jinlida granules or placebo. Conclusion: Jinlida granules can effectively improve the standard-reaching rate of blood glucose and clinical symptoms of T2D patients, including thirst, fatigue, increased eating with rapid hungering, polyuria, dry mouth, spontaneous sweating, night sweat, vexing heat in the chest, palms, and soles, and constipation. Jinlida granules can be used as an effective adjuvant treatment for T2D patients who experience those symptoms.

Isoorientin reverses lung cancer drug resistance by promoting ferroptosis via the SIRT6/Nrf2/GPX4 signaling pathway.

Cisplatin, or DDP, is a highly successful and well-known chemotherapy drug used to treat cancer. Acquired resistance to chemotherapy is a major clinical concern, yet the mechanisms of this resistance are still unknown. Ferroptosis is a type of cell death distinct from other forms, fueled by a buildup of iron-associated lipid reactive oxygen species (ROS). Gaining insight into the process of ferroptosis could lead to novel treatments for overcoming cancer resistance. In this study, the combination of isoorientin (IO) and DDP treatment resulted in a significant decrease in the viability of drug-resistant cells, a substantial increase in intracellular iron, malondialdehyde (MDA) and ROS concentrations, a notable decrease in glutathione concentration, and the occurrence of ferroptosis in cells, as revealed by in vitro and in vivo experiments. Additionally, there was a decrease in the expression of nuclear factor-erythroid factor 2-related factor 2 (Nrf2), glutathione peroxidase 4 (GPX4), and sirtuin 6 (SIRT6) proteins, and an increase in cellular ferroptosis. Isoorientin acts as a mediator to regulate cellular ferroptosis and reverse drug resistance in lung cancer cells by controlling the SIRT6/Nrf2/GPX4 signaling pathway. The findings of this study suggest that IO can promote ferroptosis and reverse drug resistance in lung cancer through the SIRT6/Nrf2/GPX4 signaling pathway, thus offering a theoretical basis for its potential clinical application.

Axonal transport deficits in the pathogenesis of diabetic peripheral neuropathy.

Diabetic peripheral neuropathy (DPN) is a chronic and prevalent metabolic disease that gravely endangers human health and seriously affects the quality of life of hyperglycemic patients. More seriously, it can lead to amputation and neuropathic pain, imposing a severe financial burden on patients and the healthcare system. Even with strict glycemic control or pancreas transplantation, peripheral nerve damage is difficult to reverse. Most current treatment options for DPN can only treat the symptoms but not the underlying mechanism. Patients with long-term diabetes mellitus (DM) develop axonal transport dysfunction, which could be an important factor in causing or exacerbating DPN. This review explores the underlying mechanisms that may be related to axonal transport impairment and cytoskeletal changes caused by DM, and the relevance of the latter with the occurrence and progression of DPN, including nerve fiber loss, diminished nerve conduction velocity, and impaired nerve regeneration, and also predicts possible therapeutic strategies. Understanding the mechanisms of diabetic neuronal injury is essential to prevent the deterioration of DPN and to develop new therapeutic strategies. Timely and effective improvement of axonal transport impairment is particularly critical for the treatment of peripheral neuropathies.

A novel hybrid PSO based on levy flight and wavelet mutation for global optimization.

The concise concept and good optimization performance are the advantages of particle swarm optimization algorithm (PSO), which makes it widely used in many fields. However, when solving complex multimodal optimization problems, it is easy to fall into early convergence. The rapid loss of population diversity is one of the important reasons why the PSO algorithm falls into early convergence. For this reason, this paper attempts to combine the PSO algorithm with wavelet theory and levy flight theory to propose a new hybrid algorithm called PSOLFWM. It applies the random wandering of levy flight and the mutation operation of wavelet theory to enhance the population diversity and seeking performance of the PSO to make it search more efficiently in the solution space to obtain higher quality solutions. A series of classical test functions and 19 optimization algorithms proposed in recent years are used to evaluate the optimization performance accuracy of the proposed method. The experimental results show that the proposed algorithm is superior to the comparison method in terms of convergence speed and convergence accuracy. The success of the high-dimensional function test and dynamic shift performance test further verifies that the proposed algorithm has higher search stability and anti-interference performance than the comparison algorithm. More importantly, both t-Test and Wilcoxon's rank sum test statistical analyses were carried out. The results show that there are significant differences between the proposed algorithm and other comparison algorithms at the significance level α = 0.05, and the performance is better than other comparison algorithms.

Evaluation of the coagulation properties of magnesium hydroxide for removal combined contamination of reactive dyes and microfibers.

Microfibers are a new type of pollutants that are widely distributed in water bodies. And the simultaneous removal of pollutants in water is popular research in the field of water treatment. In this study, magnesium hydroxide was used as coagulant to investigate the performance and mechanism of coagulation and removal of dyes (reactive orange) and microfibers (MFs). The presence of dyestuff in the composite system promoted the removal of microfibers, and the maximum removal efficiency of both could reach 95.55% and 95.35%. The coagulation mechanism was explored by scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FTIR), and zeta potential. The removal of reactive orange and microfibers relied on electrical neutralization, sweep flocculation, and adsorption mechanisms. Turbidity can enhance the removal efficiency of both. Boosting the rotational speed can increase the removal efficiency of microfibers. This study provides an important theoretical support for an in-depth understanding of the characteristics and mechanisms of coagulation for the removal of complex pollutants from printing and dyeing wastewater.

Model exploration for discovering COVID-19 targeted traditional Chinese medicine.

In terms of treatment, a particularly targeted drug is needed to combat the COVID-19 pandemic. Although there are currently no specific drugs for COVID-19, traditional Chinese medicine(TCM) is clearly effective. It is recommended that through data analysis and mining of TCM cases (expert experience) and population evidence (RCT and cohort studies), core prescriptions for various efficacy can be obtained. Starting from a multidimensional model of regulating immunity, improving inflammation, and protecting multiple organs, this paper constructs a multidimensional model of targeted drug discovery, integrating molecular, cellular, and animal efficacy evaluation. Through functional activity testing, biophysical detection of compound binding to target proteins, multidimensional pharmacodynamic evaluation systems of cells (Vero E6, Vero, Vero81, Huh7, and caca2) and animals (mice infected with the new coronavirus, rhesus macaques, and hamsters), the effectiveness of effective preparations was evaluated, and various efficacy effects including lung moisturizing, dehumidification and detoxification were obtained. Using modern technology, it is now possible to understand how the immune system is controlled, how inflammation is reduced, and how various organs are protected. Complete early drug characterization and finally obtain effective targeted TCM. This article provides a demonstration resource for the development of new drugs specifically for TCM.

Effective prediction of potential ferroptosis critical genes in clinical colorectal cancer.

Background: Colon cancer is common worldwide, with high morbidity and poor prognosis. Ferroptosis is a novel form of cell death driven by the accumulation of iron-dependent lipid peroxides, which differs from other programmed cell death mechanisms. Programmed cell death is a cancer hallmark, and ferroptosis is known to participate in various cancers, including colon cancer. Novel ferroptosis markers and targeted colon cancer therapies are urgently needed. To this end, we performed a preliminary exploration of ferroptosis-related genes in colon cancer to enable new treatment strategies. Methods: Ferroptosis-related genes in colon cancer were obtained by data mining and screening for differentially expressed genes (DEGs) using bioinformatics analysis tools. We normalized the data across four independent datasets and a ferroptosis-specific database. Identified genes were validated by immunohistochemical analysis of pathological and healthy clinical samples. Results: We identified DEGs in colon cancer that are involved in ferroptosis. Among these, five core genes were found: ELAVL1, GPX2, EPAS1, SLC7A5, and HMGB1. Bioinformatics analyses revealed that the expression of all five genes, except for EPAS1, was higher in tumor tissues than in healthy tissues. Conclusions: The preliminary exploration of the five core genes revealed that they are differentially expressed in colon cancer, playing an essential role in ferroptosis. This study provides a foundation for subsequent research on ferroptosis in colon cancer.

Naoxintong capsule delay the progression of diabetic kidney disease: A real-world cohort study.

Introduction: Diabetic kidney disease (DKD) is a severe and growing health problem, associated with a worse prognosis and higher overall mortality rates than non-diabetic renal disease. Chinese herbs possess promising clinical benefits in alleviating the progression of DKD due to their multi-target effect. This real-world retrospective cohort trial aimed to investigate the efficacy and safety of Naoxintong (NXT) capsules in the treatment of DKD. Our study is the first real-world study (RWS) of NXT in the treatment of DKD based on a large database, providing a basis for clinical application and promotion. Methods: The data was collected from Tianjin Healthcare and Medical Big Data Platform. Patients with DKD were enrolled from January 1, 2011, to March 31, 2021. NXT administration was defined as the exposure. The primary outcome was the change in estimated glomerular filtration rate (eGFR). We employed the propensity score matching (PSM) method to deal with confounding factors. Results: A total of 1,798 patients were enrolled after PSM, including 899 NXT users (exposed group) and 899 non-users (control group). The eGFR changes from baseline to the end of the study were significantly different in the exposed group compared to the control group (-1.46 ± 21.94 vs -5.82 ± 19.8 mL/(min·1.73m2), P< 0.01). Patients in the NXT group had a lower risk of composite renal outcome event (HR, 0.71; 95%CI, 0.55 to 0.92; P = 0.009) and deterioration of renal function (HR, 0.74; 95% CI, 0.56 to 0.99; P = 0.039). Conclusion: NXT can significantly slow the decline of eGFR and reduce the risk of renal outcomes. However, large cohort studies and RCTs are needed to further confirm our results.

Chiral Mesostructured Inorganic Materials with Optical Chiral Response.

Fabricating chiral inorganic materials and revealing their unique quantum confinement-determined optical chiral responses are crucial tasks in the multidisciplinary fields of chemistry, physics, and biology. The field of chiral mesostructured inorganic materials started from the synthesis of individual nanocrystals and evolved to include their assembly from metals, semiconductors, ceramics, and inorganic salts endowed with various chiral structures ranging from atomic to micron scales. This tutorial review highlights the recent research on chiral mesostructured inorganic materials, especially the novel expression of mesostructured chirality and endowed optical chiral response, and it may inspire us with new strategies for the design of chiral inorganic materials and new opportunities beyond the traditional applications of chirality. Fabrication methods for chiral mesostructured inorganic materials are classified according to chirality type, scale, and symmetry-breaking mechanism. Special attention is given to highlight systems with original discoveries, exceptional phenomena, or unique mechanisms of optical chiral response for left- and right-handedness.

Synchronous quantitative analysis of chiral mesostructured inorganic crystals by 3D electron diffraction tomography.

Chiral mesostructures exhibit distinctive twisting and helical hierarchical stacking ranging from atomic to micrometre scales with fascinating structural-chiral anisotropy properties. However, the detailed determination of their multilevel chirality remains challenging due to the limited information from spectroscopy, diffraction techniques, scanning electron microscopy and the two-dimensional projections in transmission electron microscopy. Herein, we report a general approach to determine chiral hierarchical mesostructures based on three-dimensional electron diffraction tomography (3D EDT), by which the structure can be solved synchronously according to the quantitative measurement of diffraction spot deformations and their arrangement in reciprocal space. This method was verified on two samples-chiral mesostructured nickel molybdate and chiral mesostructured tin dioxide-revealing hierarchical chiral structures that cannot be determined by conventional techniques. This approach provides more precise and comprehensive identification of the hierarchical mesostructures, which is expected to advance our understanding of structural-chiral anisotropy at the fundamental level.

Effect of Chinese Patent Medicines on Ocular Fundus Signs and Vision in Calcium Dobesilate-Treated Persons With Non-Proliferative Diabetic Retinopathy: A Systematic Review and Meta-Analysis.

Background: Diabetic retinopathy (DR), one of the commonest microvascular complications in diabetic patients, is featured by a series of fundus lesions. Conventional Western medicine therapies for DR are always with modest treatment outcome. This paper is to assess the ocular fundus signs, vision and safety of Chinese patent medicines (CPMs) as an add-on treatment for DR. Method: 7 electronic databases were searched to determine eligible trials. Randomized controlled trials (RCTs) of non-proliferative diabetic retinopathy (NPDR) in which the intervention group received CPMs combined with calcium dobesilate (CD), and the control group received only CD were included for analysis. Two reviewers extracted the data independently. Results expressing as mean differences (MD) and relative risks (RR) were analyzed with a fixed-effects or random-effects models. Results: 19 RCTs involved 1568 participants with 1622 eyes met our inclusion criteria. The results suggested that compared with CD alone, CPMs plus CD for NPDR was superior at reducing the microaneurysm volume (MD -3.37; 95% confidence interval [CI], -3.59 to -3.14), microaneurysm counts (MD -2.29; 95%CI -2.97 to -1.61), hemorrhage area (MD -0.79; 95%CI -0.83 to -0.75), and macular thickness (MD -59.72; 95%CI -63.24 to -56.20). Participants in CPMs plus CD group also achieved a better vision. No obvious adverse events occurred. Conclusion: CPMs as an add-on therapy for NPDR have additional benefits and be generally safe. This meta-analysis demonstrated that CPMs combined with CD could improve retinal microaneurysm, hemorrhage, macular thickness, visual acuity, fasting blood glucose (FBG), and glycosylated hemoglobin (HbAlc) compared with CD alone. Further studies are needed to provide more conclusive evidence. Systematic Review Registration: PROSPERO https://www.crd.york.ac.uk/prospero/, identifier CRD42021257999.

The Long-Term Effects of Non-Pharmacological Interventions on Diabetes and Chronic Complication Outcomes in Patients With Hyperglycemia: A Systematic Review and Meta-Analysis.

Objective: This study aimed at examining the long-term effects of non-pharmacological interventions on reducing the diabetes incidence among patients with prediabetes and chronic complications events among patients with hyperglycemia (pre-diabetes and diabetes) by performing a systematic review and meta-analysis of randomized controlled trials (RCTs). Methods: PubMed, MEDLINE, EMBASE, the Cochrane Library, and the Web of Science Core Collection were searched for studies published between January 1990 and November 2021, looking for RCTs to evaluate the effects of non-pharmacological interventions on preventing the incidence of diabetes and chronic complications in comparison with medical therapy, placebo, or usual diabetes care. Two independent reviews extracted relevant data and quality assessment. Any discrepancies were resolved by a third reviewer. Results: In total, 20 articles involved 16 RCTs (follow-up ranged from 2 to 30 years) were included. Pooled analysis of intervention studies demonstrated clearly that non-pharmacological interventions have a significant effect on reducing the diabetes events in patients with prediabetes (RR 0.62; 95% CI 0.54, 0.71). Pooled analysis of extended follow-up studies showed that non-pharmacological interventions could effectively reduce the diabetes incidence in patients with prediabetes (RR 0.78; 95% CI 0.63, 0.96). Meta-regression and subgroup analysis indicates that the diabetes incidence of the long-term group (duration > 3 years) was clearly reduced by 0.05% compared with the relatively short-term group (duration ≤ 3 years). The incidence of microvascular complications in patients with hyperglycemia was effectively lowered by non-pharmacological interventions (RR 0.60; 95% CI 0.43, 0.83). Conclusion: Non-pharmacological interventions have a long-term effect on reducing the diabetes incidence among prediabetic patients and effectively preventing microvascular complications on hyperglycemia. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/.