Molecules Of Interest Research Articles

CRISPR-Enabled Graphene-Based Bio-Cyber Interface Model for In Vivo Monitoring of Non-Invasive Therapeutic Processes.

In this paper, we present a model of the bio-cyber interface for the Internet of Bio-Nano Things application. The proposed model is inspired by the gains of integrating the Clustered Regularly Interspace Short Palindromic Repeats (CRISPR) technology with the Graphene-Field effect transistor (GFET). The capabilities of the integrated system are harnessed to detect nucleic acids transcribed by another component of the bio-cyber interface, a bioreporter, on being exposed to the signalling molecule of interest. The proposed model offers a label-free real-time signal transduction with multi-symbol signalling capability. We model the entire operation of the interface as a set of simultaneous differential equations representing the process's kinetics. The solution to the model is obtained using a numerical method. Numerical results show that the performance of the interface is influenced by parameters such as the concentrations of the input signalling molecules, the surface receptor on the bioreporter, and the CRISPR complex. The interface's performance also depends considerably on the elimination rate of the signalling molecules from the body. For multi-symbol molecular signalling, the rate of degradation of the transcribed RNAs influences the system's susceptibility to inter-symbol interference.

In vivo injection of exogenous molecules into octocorals: Application to the study of calcification

AbstractIn vivo studies of the effects of molecules of interest, such as hormones or xenobiotics on corals, are essential to uncover their effects on coral biological processes. However, exposure to such molecules is very challenging in aquarium systems due to the duration of exposure, the high cost of the compounds, their quantity, and their diffusion in seawater. In this study, we provide a durable alternative method by in vivo injection. The aim of this study was to evaluate slow release and local injection as a novel method of delivering compounds to corals. In this method, coconut oil, which solidifies upon injection and has a melting point of about 24°C, is used as the vehicle for injection. Local diffusion of the injected products in the organism was followed using visual tracers. Specifically, two classes of fluorescent markers were used, one of which examined internalization into cells (rhodamine), while the others were used as an application to monitor the calcification process (alizarin, calcein). In parallel, we developed an analytical method to quantify the calcein and alizarin labeling of sclerites, which allowed us to determine calcification rates in different parts of the coral. Two octocorals were used to optimize these methods, with Sarcophyton sp. being the preferred organism to develop and validate the injection procedures and characterize the diffusion of the markers. Once the method was perfected, injections were performed on the precious coral Corallium rubrum to prove the transferability of the method.

Synthesis, NMR, electronic properties using DFT study and anticancer activity of 3-methyl-6-(m-tolylamine) quinazolin-4(3H)-one

3-methyl-6-(m-tolylamine) quinazolin-4(3H)-one (MTAQ) was synthesized. Its formation was ascertained with the help ESI mass spectroscopy in conjunction with 1HNMR spectroscopy. Anticancer activity of MTAQ was measured experimentally, for human carcinoma cell line pertaining to cervix (HeLa). Optimized structure parameters, Frontier molecular orbital (FMO) behavior, non linear optical (NLO) profile, molecular electrostatic potential surface (MESP), Fukui functions (FF) and thermodynamic parameters were evaluated for the molecule of interest employing DFT/B3LYP/6–311++G(d,p) formalism. TD-DFT was made use of to calculate absorption maxima (λmax) of electronic transitions for the molecule in CDCl3 solvent. Frontier molecular orbitals revealed the origin of UV–Vis spectrum and to comprehend chemical reactivity of the molecule. Good coincidence was noticed between measured and computed structure parameters, UV–Vis spectra, and 1HNMR signals. Fukui functions helped in identifying electrophilic and nucleophilic centers of MTAQ. The calculations showed that MTAQ exhibits significant NLO activity in addition to predicting existence of intramolecular hydrogen bond.

Natural products might just be our best weapon against antibiotic resistance

Nature has always been an interesting source of chemical diversity for the search of molecules of therapeutic interest. Here we showed how large plant extract libraries can be transformed into a chemical library. This library could then be efficiently used to isolate molecules of unreported bioactivity to advance our knowledge on disease treatments.

Carbosilane Dendritic Amphiphiles from Cholesterol or Vitamin E for Micelle Formation.

Cationic dendritic amphiphiles were prepared through the linkage of interesting hydrophobic molecules such as cholesterol or vitamin E to the focal point of carbosilane dendrons. These new dendritic systems self-assembled in saline, producing micellar aggregates with hydrodynamic diameters ranging from 6.5 to 9.2 nm, and critical micelle concentrations of approximately 5 and 10 μM for second- and third-generation systems, respectively. The assemblies were able to encapsulate drugs of different charges (anionic, neutral, and cationic). Surprisingly, a 92% encapsulation efficiency for diclofenac was achieved in micelles prepared from second-generation dendrons. Toxicity measurements on peripheral blood mononuclear cells indicated different behavior depending on the generation, corresponding to the micellar regime. In contrast to the third-generation system, the second-generation system was non-toxic up to 20 μM, opening a window for its use in a micellar regimen, thereby operating as a drug delivery system for different biomedical applications.

Niclosamide: A career builder

My contribution to honoring Professor Kinam Park celebrates and resonates with his scholarly career in drug delivery, his commitment to encouraging the next generation(s), and his efforts to keep us focused on clinically effective formulations. To do this I take as my example, niclosamide, a small molecule protonophore that, uniquely, can “target” all cell membranes, both plasma and organelle. As such, it acts upstream of many cell pathways and so has the potential to affect many of the essential events that a cell, and particularly a diseased cell or other entities like a virus, use to stay alive and prosper. Literature shows that it has so far been discovered to positively influence (at least): cancer, bacterial and viral infection, metabolic diseases such as Type II diabetes, NASH and NAFLD, artery constriction, endometriosis, neuropathic pain, rheumatoid arthritis, sclerodermatous graft-versus-host disease, systemic sclerosis, Parkinson's, and COPD. With such a fundamental action and broad-spectrum activity, I believe that studying niclosamide in all its manifestations, discovering if and to what extent it can contribute positively to disease control (and also where it can't), formulating it as effective therapeutics, and testing them in preclinical and clinical trials is a career builder for our next generation(s).The article is divided into two parts: Part I introduces niclosamide and other proton shunts mainly in cancer and viral infections and reviews an exponentially growing literature with some concepts and physicochemical properties that lead to its proton shunt mechanism. Part II focuses on repurposing by reformulation of niclosamide. I give two examples of “carrier-free formulations”, — one for cancer (as a prodrug therapeutic of niclosamide stearate for i.v. and other administration routes, exemplified by our recent work on Osteosarcoma in mice and canine patients), and the other as a niclosamide solution formulation (that could provide the basis for a preventative nasal spray and early treatment option for COVID19 and other respiratory virus infections).My goal is to excite and enthuse, encourage, and motivate all involved in the drug development and testing process in academia, institutes, and industry, to learn more about this interesting molecule and others like it. To enable such endeavors, I give many proposed ideas throughout the document, that have been stimulated and inspired by gaps in the literature, urgent needs in disease, and new studies arising from our own work. The hope is that, by reading through this document and studying the suggested topics and references, the drug delivery and development community will continue our lineage and benefit from our legacy to achieve niclosamide's potential as an effective contributor to the treatment and control of many diseases and conditions.

A biogenic organic molecule involved in the formation of secondary organic aerosols: Microwave and millimeter-wave spectroscopy of 3-methylcatechol backed by quantum chemistry

3-methylcatechol (3MC) is a molecule of environmental interest due to its presence in the atmosphere during biomass burning events, leading to the formation of secondary organic aerosols. This paper goes one step further than the paper from A.S. Hazrah et al. (2022) [10]. A three-dimensional torsional potential energy surface was determined, confirming the existence of three rotamers for 3MC. One dimensional potential energy curves along the rotation of the methyl group were computed and fitted to estimate the barrier height in each conformer. Experiments were performed at low temperature in the microwave domain (2−20GHz range) and, for the first time, in the millimeter-wave domain (70−110GHz range) at T=323K with a specially designed heated absorption cell. The rotational linelist was fitted to provide updated spectroscopic parameters for the two 3MC conformers of lowest energies. In particular, the A−E splitting is observed in the microwave region for both conformers while in the millimeter-wave region, it is only seen for the conformer of the lowest energy.

Electrospun photothermally active graphene-based nanofibers with a Retro-Diels-Alder reaction to initiate drug release

Externally controlled local drug release systems have garnered significant interest, with stimuli-responsive electrospun nanofibers emerging as a prominent platform for local drug delivery. Their advantages, such as a high surface area and facile production have made them appealing materials for various biomedical applications. While nanofiber scaffolds have been widely used for drug release through physical entrapment, control over the passive release and precise dosage regulation remains challenging. To overcome these limitations, in this study, maleimide-modified functional molecules were covalently conjugated to reduced graphene oxide-containing nanofiber scaffolds (average diameter 475 ± 94 nm) fabricated using furan-containing copolymers. The Diels-Alder cycloaddition at ambient temperature conjugates the molecules of interest, whereas the thermally promoted retro Diels-Alder cycloreversion reaction releases them. Photothermal heating using near-infrared light at 980 nm facilitated control over the drug release, and switching the irradiation on and off allows on-demand release. One can envision that these photothermally active nanofiber mats could enable on-demand drug delivery of a variety of active therapeutic agents for localized delivery.

Enhanced Photostability and Photoactivity of Ruthenium Polypyridyl-Based Photocatalysts by Covalently Anchoring Onto Reduced Graphene Oxide.

Recentstudies toward finding more efficient ruthenium metalloligands for photocatalysis applications have shown that the derivatives of the linear [Ru(dqp)2]2+ (dqp: 2,6-di(quinolin-8-yl)-pyridine) complexes hold significant promise due to their extended emission lifetime in the μs time scale while retaining comparable redox potential, extinction coefficients, and absorption profile in the visible region to [Ru(bpy)3]2+ (bpy: 2,2'-bipyridine) and [Ru(tpy)2]2+ (tpy: 2,2':6',2″-terpyridine) complexes. Nevertheless, its photostability in aqueous solution needs to be improved for its widespread use in photocatalysis. Carbon-based supports have arisen as potential solutions for improving photostability and photocatalytic activity, yet their effect greatly depends on the interaction of the metal complex with the support. Herein, we present a strategy for obtaining Ru-polypyridyl complexes covalently linked to aminated reduced graphene oxide (rGO) to generate novel materials with long-term photostability and increased photoactivity. Specifically, the hybrid Ru(dqp)@rGO system has shown excellent photostable behavior during 24 h of continual irradiation, with an enhancement of 10 and 15% of photocatalytic dye degradation in comparison with [Ru(dqp)2]2+ and Ru(tpy)@rGO, respectively, as well as remarkable recyclability. The presented strategy corroborates the potential of [Ru(dqp)2]2+ as an interesting photoactive molecule to produce more advantageous light-active materials by covalent attachment onto carbon-based supports.

Deep Learning for Gas Sensing via Infrared Spectroscopy.

Deep learning methods, a powerful form of artificial intelligence, have been applied in a number of spectroscopy and gas sensing applications. However, the speciation of multi-component gas mixtures from infrared (IR) absorption spectra using deep learning remains to be explored. Here, we propose a one-dimensional deep convolutional neural network gas classification model for the identification of small molecules of interest based on IR absorption spectra in flexible user-defined frequency ranges. The molecules considered include ten that are of interest in the atmosphere or in industrial and environmental processes: water vapor, carbon dioxide, ozone, nitrous oxide, carbon monoxide, methane, nitric oxide, sulfur dioxide, nitrogen dioxide, and ammonia. A simulated dataset of IR absorption spectra for mixtures of these molecules diluted in air was generated and used to train a deep learning model. The model was tested against simulated spectra containing noise and was found to provide speciation predictions with accuracy from 82 to 97%. The internal operation of the model was investigated using class activation maps that illustrate how the model prioritizes spectral information for classification. Finally, the model was demonstrated for the prediction of speciation for two synthetic experimental mixture spectra. The proposed model and the dataset generation strategies are generalized and can be implemented for other gases, different frequency ranges, and spectroscopy types. The multi-component speciation method developed herein is the first application of a convolutional neural network model, trained on HITRAN-based simulations, for spectral identification.

High-throughput microcontact printing of proteins in microwell cell culture plates

Microcontact printing (MCP) is used to pattern a surface with a specific compound, allowing the spatially restricted response of cells to be assayed as they encounter a molecule of interest. MCP is a relatively low-cost and accessible technique that uses commercially available reagents and common cell culture equipment. However, it can be technically challenging, slow, and incompatible with microwell cell culture plates that are widely used for screening and other applications. Here, we describe a novel protocol using medical biopsy punches to transfer patterns into standard 96-well plates via polydimethylsiloxane (PDMS) cutouts. We demonstrate that this method can be used to deposit patterns of poly-D-lysine (PDL) into the microwells of glass-bottom plates. As a proof-of-concept, we show that cultured rodent glial cells preferentially grow and extend processes on the pattern. This method will allow larger scale MCP experiments in which different patterns, proteins, or other factors can be assayed in parallel.•Biopsy punches enable both cutting out small circular stamps and plunging them into tissue culture microwells to transfer proteins.•Compared to standard MCP, this method offers a more rapid workflow to pattern proteins onto substrates, and allows use of microwell plates that permits larger-scale experiments.

Performance of EOM-CCSD(T)(a)*-Based Quartic Force Fields in Computing Fundamental, Anharmonic Vibrational Frequencies of Molecular Electronically Excited States with Application to the Ã1A″ State of :CCH2 (Vinylidene).

Highly accurate anharmonic vibrational frequencies of electronically excited states are not as easily computed as their ground electronic state counterparts, but recently developed approximate triple excited state methods may be changing that. One emerging excited state method is equation of motion coupled cluster theory at the singles and doubles level with perturbative triples computed via the (a)* formalism, EOMEE-CCSD(T)(a)*. One of the most employed means for the ready computation of vibrational anharmonic frequencies for ground electronic states is second-order vibrational perturbation theory (VPT2), a theory based on quartic force fields (QFFs),fourth-order Taylor series expansions of the potential portion of the internuclear Watson Hamiltonian. The combination of these two is herein benchmarked for its performance for use as a means of computing rovibrational spectra of electronically excited states. Specifically, the EOMEE-CCSD(T)(a)* approach employing a complete basis set extrapolation along with core electron inclusion and relativity (the so-called "CcCR" approach) defining the QFF produces anharmonic fundamental vibrational frequencies within 2.83%, on the average, of reported gas-phase experimentally assigned values for the test set including the states of HCF, HCCl, HSiF, HNO, and HPO. However, some states have exceptional accuracy in the fundamentals, most notably for ν2 of HCCl in which the CcCR QFF value is within 1.8 cm-1 at 927.9 cm-1 (or 0.2%) of the experiment. Additionally, this approach produces rotational constants to, on the absolute average, within 0.41% of available experimental data, showcasing notable accuracy in the computation of rovibronic spectral data. Furthermore, utilizing a hybrid approach composed of harmonic CcCR force constants along with a set of simple EOMEE-CCSD(T)(a)*/aug-cc-pVQZ QFF cubic and quartic force constants is faster than using pure CcCR and better represents those modes that suffer from numerical instability in the anharmonic portion of the QFF, implying that this so-called "CcCR + QZ" QFF approach may be the best for future applications. Finally, complete, rovibrational spectral data are provided for :CCH2, a molecule of potential astrochemical interest, in order to aid in its potential future experimental rovibronic characterization.

SimpleNMR: An interactive graph network approach to aid constitutional isomer verification using standard 1D and 2D NMR experiments.

Despite progress in computer automated solutions, constitutional isomer verification by NMR using one- and two-dimensional data sets is still, in the main, a manual, user-intensive activity that is challenging for a number of reasons. These include the problem of simultaneously keeping track of the information from a number of separate NMR experiments and the difficulty of another researcher subsequently verifying the assignments made without having to independently repeat the whole analysis. This paper describes a graphical interactive approach that overcomes some of these problems. By using concepts used to visualise graph networks, we have been able to represent the NMR data in a manner that highlights directly the link between the different NMR experiments and the molecule of interest. Furthermore, by making the graph networks interactive, a user can easily validate and correct the assignment and understand the decisions made in arriving at the solution. We have developed a usable proof-of-concept computer program, 'simpleNMR', written in Python to illustrate the ideas and approach.

In silico Molecular Docking Analysis of Three Molecules Isolated from Litsea guatemalensis Mez on Anti-inflammatory Receptors.

The Litsea genus has four native species from Mesoamerica. Litsea guatemalensis Mez. is a native tree, traditionally used as a condiment and herbal medicine in the region. It has demonstrated antimicrobial, aromatic, anti-inflammatory and antioxidant activity. Bioactive fractionation attributed the anti-inflammatory and anti-hyperalgesic activities to pinocembrin, scopoletin, and 5,7,3´4´-tetrahydroxy-isoflavone. In silico analysis, these molecules were analyzed on receptors involved in the anti-inflammatory process to determine which pathways they interact. To analyze and evaluate 5,7,3',4'-tetrahydroxyisoflavone, pinocembrin, and scopoletin using the in silico analysis against selected receptors involved in the inflammatory pathway. Known receptors involved in the anti-inflammatory process found as protein-ligand complex in the Protein Data Bank (PDB) were used as references for each receptor and compared with the molecules of interest. The GOLD-ChemScore function, provided by the software, was used to rank the complexes and visually inspect the overlap between the reference ligand and the poses of the studied metabolites. 53 proteins were evaluated, each one in five conformations minimized by molecular dynamics. The scores obtained for dihydroorotate dehydrogenase were greater than 80 for the three molecules of interest, scores for cyclooxygenase 1 and glucocorticoid receptor were greater than 50, and identified residues with interaction in binding sites overlap with the reference ligands in these receptors. The three molecules involved in the anti-inflammatory process of L. guatemalensis show in silico high affinity to the enzyme dihydroorotate dehydrogenase, glucocorticoid receptors and cyclooxygenase-1.

Electrochemical Gas Separations for Green Energy Integration

Separation and purification of molecules and compounds is one of the fundamental processes of chemistry and a hugely important factor in industrialization, accounting for as much as 15% of world’s energy consumption. As the world tries to limit and reduce the effects of climate change, simultaneous development of a green chemical economy and carbon sequestration strategies are needed. Both these goals need to effectively and efficiently separate gas phase molecules to make the implementation of these technologies feasible, requiring an even higher demand for economical and green gas phase separation. The current methods of gas phase separation used in industry rely predominantly on inefficient processes, such as cryogenic distillation or temperature or pressure swing absorption. Gas phase separation by electrochemical means can offer theoretically high energy efficiency separation, as the energy supplied can operate exclusively on the molecule of interest, if proper material and design criteria are met, while traditional methods act upon the entire gas mixture. Additionally, electrochemical separations can reduce the number of steps needed as they can simultaneously separate and compress the purified gas, easing the demand for high energy processing required when using mechanical pumps. However, the effectiveness of these technologies depends largely on the operating conditions and materials that make up the electrochemical cell. Thus, a key factor driving improvement in this field relies heavily on material development, such as improved membranes/separators, catalysts, and other cell materials which can in turn give rise to novel techniques and high performance of the electrochemically driven devices. Electrochemical gas phase separations integrated with green energy are critical to reaching climate change targets, but they in turn rely on the development of novel materials at enlarged scales and implementation of these technologies at reduced costs. In this article, we discuss the principles and applications of three electrochemical gas separations: hydrogen (H2) pump, ammonia (NH3)compression, and carbon dioxide (CO2) separation.

Near- to mid-IR spectral purity transfer with a tunable frequency comb: Methanol frequency metrology over a 1.4 GHz span

We report the upgrade and operation of a frequency-comb-assisted high-resolution mid-infrared molecular spectrometer, allowing us to combine high spectral purity, International System of Units (SI)-traceability, wide tunability, and high sensitivity. An optical frequency comb is used to transfer the spectral purity of a SI-traceable 1.54 μm metrology-grade frequency reference to a 10.3 μm quantum cascade laser (QCL). The near-infrared reference is operated at the French time/frequency metrology institute, calibrated there to primary frequency standards, and transferred to Laboratoire de Physique des Lasers via the REFIMEVE fiber network. The QCL exhibits a linewidth of δν ∼ 0.1 Hz and a sub-10−15 relative frequency stability from 0.1 to 10 s, and its frequency is traceable to the SI with a total relative uncertainty better than 4 × 10−14 after 1 s averaging time. We have developed the instrumentation allowing comb modes to be continuously tuned over 9 GHz, resulting in a QCL of record spectral purity uninterruptedly tunable at the precision of the reference over an unprecedented span of Δν = 1.4 GHz. We have used our apparatus to conduct sub-Doppler spectroscopy of methanol in a multi-pass cell, demonstrating state-of-the-art frequency uncertainties down to the few kilohertz level (∼10−10 in relative value). We have observed weak intensity resonances unreported so far, resolved subtle doublets never seen before, and brought to light discrepancies with HITRAN. This demonstrates the potential of our apparatus for probing subtle internal molecular processes, building accurate spectroscopic models of polyatomic molecules of atmospheric or astrophysical interest, and carrying out precise spectroscopic tests of fundamental physics.

Enzymatic Synthesis of Hydroxycinnamic Acid Amides in Water Using the Promiscuous Hydrolase/Acyltransferase PestE from Pyrobaculum calidifontis VA1

AbstractHydroxycinnamic acid amides are believed to have antioxidant, antidiabetic, cytotoxic, anticancer, neuroprotective, and antiinflammatory properties, making them interesting target molecules for potential applications in the food, cosmetics, and pharmaceutical industries. Here, we describe the synthesis of hydroxycinnamic acid amides starting from hydroxycinnamic acid esters and the corresponding amines by using variants of the promiscuous hydrolase/acyltransferase from Pyrobaculum calidifontis VA1 (PestE) in water as a solvent. Up to 97% conversion within two hours at 60 °C was achieved with methyl ferulate and tyramine as substrates. This is a promising, environmentally friendly alternative strategy to established chemical synthesis routes or enzymatic methods using lipases in nonaqueous organic solvents.

The Reaction of Aryl Thiols or Thioureas with o‐Diiodoarenes/NaH to Access o‐Iodoaryl Thioethers

AbstractHerein we report a method for the synthesis of thioethers by forging C(aryl)‐S bond via an aryne mechanism. The active aryne species can be generated from o‐diiodoarenes and NaH in THF at room temperature, then lead to the arylations of a wide range of aryl thiols and thioureas. Different from transition metal‐catalyzed cross‐coupling reactions, no disubstituted byproduct is formed in our protocol. The o‐iodoaryl thioether products are intermediates that could be transformed into pharmaceutically interesting molecules.

Evolution of Impact Melt Pools on Titan

AbstractTitan is an ocean world with a dense atmosphere, where photochemistry produces complex organic molecules that fall to the surface. An important astrobiological question is whether this material can mix with water and form molecules of biological interest. Large impacts heat the moon's subsurface and create liquid water melt pools. A recent study investigated impacts into Titan's clathrate‐covered ice shell. Methane clathrates are stable at Titan's surface conditions and have low thermal conductivity, making them efficient insulators that can lead to steep thermal gradients and a thin stagnant lid. The authors showed that the clathrate layer thickness primarily influences the melt distribution, while its volume is governed by the impactor size. Here, we investigate the fate of melt formed during an impact into a clathrate‐covered ice shell. Our results show two different behaviors: in cases when less melt is produced, the subsurface melt pool remains close to the surface and freezes on timescales ≲25 kyr; in cases when larger volumes of melt are produced, a downward‐oriented transport of the molten material occurs. As it descends, part of the melt freezes but some may reach the ocean within a few kyr under certain conditions; vertical impacts, high surface porosity, low viscosity, and tidal heating all favor this surface‐to‐ocean exchange. While providing insights on parameters that allow a subsurface melt pool to remain liquid beneath a Selk‐sized crater for a few kyr, this study suggests that Dragonfly may be able to sample melt deposits where organics reacted with liquid water to produce biomolecules.

Metformin and pancreatic neuroendocrine tumors: A systematic review and meta-analysis.

Most patients with advanced pancreatic neuroendocrine tumors (pNETs) die due to tumor progression. Therefore, identifying new therapies with low toxicity and good tolerability to use concomitantly with the established pNET treatment is relevant. In this perspective, metformin is emerging as a molecule of interest. Retrospective studies have described metformin, a widely used agent for the treatment of patients with type 2 diabetes mellitus (T2DM), to be effective in modulating different tumor-related events, including cancer incidence, recurrence and survival by inhibiting mTOR phosphorylation. This systematic review evaluates the role of T2DM and metformin in the insurgence and post-treatment outcomes in patients with pNET. To systematically analyze and summarize evidence related to the diagnostic and prognostic value of T2DM and metformin for predicting the insurgence and post-treatment outcomes of pNET. A systematic review of the published literature was undertaken, focusing on the role of T2DM and metformin in insurgence and prognosis of pNET, measured through outcomes of tumor-free survival (TFS), overall survival and progression-free survival. A total of 13 studies (5674 patients) were included in this review. Analysis of 809 pNET cases from five retrospective studies (low study heterogeneity with I² = 0%) confirms the correlation between T2DM and insurgence of pNET (OR = 2.13, 95%CI = 1.56-4.55; P < 0.001). The pooled data from 1174 pNET patients showed the correlation between T2DM and post-treatment TFS in pNET patients (hazard ratio = 1.84, 95%CI = 0.78-2.90; P < 0.001). The study heterogeneity was intermediate, with I² = 51%. A few studies limited the possibility of performing pooled analysis in the setting of metformin; therefore, results were heterogeneous, with no statistical relevance to the use of this drug in the diagnosis and prognosis of pNET. T2DM represents a risk factor for the insurgence of pNET and is a significant predictor of poor post-treatment TFS of pNET patients. Unfortunately, a few studies with heterogeneous results limited the possibility of exploring the effect of metformin in the diagnosis and prognosis of pNET.