type-I Mechanism Research Articles

A design strategy of pure Type-I thiadiazolo[3,4-g]quinoxaline-based photosensitizers for photodynamic therapy

Most photosensitizers (PSs) for photodynamic therapy (PDT) can generate singlet oxygen through transferring energy with oxygen, called Type-II PSs. However, the microenvironment of solid tumor is usually anoxic. Type-I PSs can generate reactive oxygen species (ROS) through transferring electron to substrate, showing more efficient in PDT. But pure Type-I PSs are very rare. The relationship between PSs’ chemical structure and Type-I mechanism has not been explicitly stated. In this study, two thiadiazolo [3,4-g]quinoxaline (TQ) PSs (PsCBz-1 and PsCBz-2) are synthesized through introducing carbazole groups to the 4,9-position of TQ backbone. Comparing with their prototype PS, 4,9-dibrominated TQ (TQs-4), the introduction of carbazole groups reverses the reaction mechanism of PSs from pure Type-II to pure Type-I. Excitingly, the water-dispersible nanoparticles (NPs) of PsCBz-1 can achieve strong phototoxicity in vitro under both normoxia and hypoxia through Type-I mechanism. In addition, PsCBz-1 NPs also exhibits remarkable PDT antitumor effect in vivo. This study provides a feasible design strategy for pure Type-I PSs.

2D/2D Mn0.5Cd0.5In2S4/g-C3N4 heterojunctions with controllable charge transfer pathways for effective photocatalytic H2 production and antibiotics removal

The separation efficiency of photoinduced electron-hole pairs has an important function in photocatalytic reactions. In this work, the MnxCd1−xIn2S4 solid solutions with tunable band edge positions were fabricated by a facile hydrothermal route. Benefit from the regulation of band edge positions, the charge migration is regulated from type-I mechanism (MnIn2S4/g-C3N4 and CdIn2S4/g-C3N4) to type-II mechanism (Mn0.5Cd0.5In2S4/g-C3N4), which boosts the separation efficiency of charge carriers for photocatalytic reactions. The fabricated Mn0.5Cd0.5In2S4/g-C3N4 nanocomposites exhibit superior photocatalytic hydrogen production and tetracycline hydrochloride (TCH) photodegradation as compared to the g-C3N4 nanosheets, MnIn2S4, CdIn2S4, as well as the Mn0.5Cd0.5In2S4 solid solution. Based on the XPS test and the determination of band edge position, the type-II heterojunction photocatalytic mechanism is proposed to illustrate the transfer path of the charge carriers. This work offers a newfangled perspective for exploring an effective photocatalytic system.

Gauged Le − Lμ − Lτ symmetry, fourth generation, neutrino mass and dark matter

We present two models where the familiar leptonic symmetry Le−Lμ−Lτ is a gauge symmetry. We show how anomaly cancellation constrains the allowed theories, with one of them requiring a fourth sequential chiral standard model fermion generation and a second one with three generations, requiring gauging of (Le−Lμ−Lτ)−(B1−B2−B3) with Ba representing the baryon number of the ath generation quarks. Unlike global Le−Lμ−Lτ models which always leads to inverted mass hierarchy for neutrinos, the gauged version can lead to normal hierarchy. We show how to construct realistic models in both the cases and discuss the dark matter candidate in both. In our model, the breaking of U(1)Le−Lμ−Lτ is responsible for neutrino mass via type-I mechanism whereas the real part of U(1)Le−Lμ−Lτ breaking scalar field (called ϕ here) plays the role of freeze-in dark matter candidate. Since ϕ is unstable, for it to qualify as dark matter, its lifetime must be larger than the age of the Universe, implying that the relic of ϕ is generated through freeze-in mechanism and its mass must be less than an MeV. We also discuss the possibility of explaining both muon and electron g−2 while being consistent with the DM relic density and lifetime constraints.

Monojet search for heavy neutrinos at future Z-factories

The existence of heavy neutrinos is the most prominent feature of type-I seesaw-like mechanisms, which naturally explain tiny masses of observed neutrinos. Various experiments have been conducted to search for heavy neutrinos, with meson decays sensitive to heavy neutrinos lighter than B mesons and high energy collider experiments sensitive to the ones with masses larger than {mathcal {O}}(0.1) TeV. In between, there is a mass gap uncovered by these two kinds of experiments, and by this work, we investigate the 3–15 GeV neutrino searches at future Z-factories via the process e^{-}e^{+}rightarrow Z rightarrow nu N rightarrow nu ell {bar{q}}q' with ell =e,mu . Based on the simulation of signal and background events, we find that the signals appear as monojet events owning to the large Lorentz boost of the heavy neutrinos. Furthermore, the substructures of such monojet are essential to reconstruct the signal and suppress the background. The upper bounds on the cross section of the signal process and the mixing parameter {left| V_{ell N} right| }^2 are obtained. Compared with other experiments, the monojet method at future Z-factories will be able to fill the gap around this mass range.

Design of Photosensitizing Agents for Targeted Antimicrobial Photodynamic Therapy.

Photodynamic inactivation of microorganisms has gained substantial attention due to its unique mode of action, in which pathogens are unable to generate resistance, and due to the fact that it can be applied in a minimally invasive manner. In photodynamic therapy (PDT), a non-toxic photosensitizer (PS) is activated by a specific wavelength of light and generates highly cytotoxic reactive oxygen species (ROS) such as superoxide (O2−, type-I mechanism) or singlet oxygen (1O2*, type-II mechanism). Although it offers many advantages over conventional treatment methods, ROS-mediated microbial killing is often faced with the issues of accessibility, poor selectivity and off-target damage. Thus, several strategies have been employed to develop target-specific antimicrobial PDT (aPDT). This includes conjugation of known PS building-blocks to either non-specific cationic moieties or target-specific antibiotics and antimicrobial peptides, or combining them with targeting nanomaterials. In this review, we summarise these general strategies and related challenges, and highlight recent developments in targeted aPDT.

An Emerging Molecular Design Approach to Heavy-Atom-Free Photosensitizers for Enhanced Photodynamic Therapy under Hypoxia.

A novel strategy for designing highly efficient and activatable photosensitizers that can effectively generate reactive oxygen species (ROS) under both normoxia and hypoxia is proposed. Replacing both oxygen atoms in conventional naphthalimides (RNI-O) with sulfur atoms led to dramatic changes in the photophysical properties. The remarkable fluorescence quenching (ΦPL ≈ 0) of the resulting thionaphthalimides (RNI-S) suggested that the intersystem crossing from the singlet excited state to the reactive triplet state was enhanced by the sulfur substitution. Surprisingly, the singlet oxygen quantum yield of RNI-S gradually increased with increasing electron-donating ability of the 4-R substituents (MANI-S, ΦΔ ≈ 1.00, in air-saturated acetonitrile). Theoretical studies revealed that small singlet-triplet energy gaps and large spin-orbit coupling could be responsible for the efficient population of the triplet state of RNI-S. In particular, the ROS generation ability of MANI-S was suppressed under physiological conditions due to their self-assembly and was significantly recovered in cancer cells. More importantly, cellular experiments showed that MANI-S still produced a considerable amount of ROS even under severely hypoxic conditions (1% O2) through a type-I mechanism.

Isolation and identification of photoproducts from UVA-irradiated mixture of N-nitrosoproline with 2'-deoxyadenosine

N-Nitrosoproline (NPRO) is known to form endogenously from sodium nitrite and the amino acid proline, and is thought to be non-mutagenic and non-carcinogenic. However, earlier studies in our laboratory showed that irradiated NPRO can be converted directly to a mutagenic compound upon UVA irradiation. We previously investigated the mutagenic spectrum of NPRO on M13mp2 DNA with UVA irradiation, and found a hot spot comprising AT to GC, where there might be a particular photoreaction of adenine residues with NPRO. In the present study, we investigated the reaction of NPRO with 2'-deoxyadenosine (dA) under UVA irradiation, and identified the chemical structures of the photoproducts. Photoproducts from NPRO and dA were isolated and analyzed with HPLC, MS and NMR. (R)-, (S)-2-(2-pyrrolidyl)-2’-deoxyadenosine (P1, P2) and deoxyinosine (dI) were identified from the mixture of dA and NPRO irradiated with UVA. Results suggest that UVA-activated NPRO produces pyrrolidyl cations which react with dA to generate pyrrolidyl-dA adducts. Production of P1 and P2 from irradiated NPRO with dA increased under N2 saturation compared to those under air saturation, while production of P1 and P2 from irradiated solution under O2 saturation was lower compared to that under air. These results suggest that a Type-I mechanism is involved in the photoproduction of P1 and P2. Furthermore, reactive oxygen species generated during photo-reaction in the presence of O2 may act to destroy the activated form of irradiated NPRO to reduce the formation of P1 and P2. The formation of dI in the irradiated mixture of NPRO with dA might mediate NO release from irradiated NPRO.

Analytical Approach to Estimate Efficiency of Series Machines in Production Lines

Series machines, i.e., machines (which are usually unreliable) arranged in series with no buffering, are pervasive in production systems. In the analysis, design, and optimization of the series-machine system, the efficiency analysis is one of the most fundamental issues. There are not a lot of researches analyzing the efficiency of the series-machine system, and almost all of them assume that the system operates under type-I failure mechanisms (i.e., the breakdown of a machine could make all other series machines forced down) rather than under type-II mechanisms (i.e., the breakdown of a machine does not make any other series machines forced down). The reason that the type-I failure mechanisms are usually assumed in the literature is that the analysis of the series-machine system under type-II mechanisms is much more complex than under type-I mechanisms, although type-II mechanisms are more common in practice. To thoroughly and systematically estimate the efficiency of the series-machine system, in this paper, we propose a unified analytical approach to investigate the efficiency under both type-I and type-II failure mechanisms. Both cases of deterministic and random cycle times are considered. Different from under type-I failure mechanisms, analytical expressions of the efficiency of series-machine systems under type-II failure mechanisms are extremely hard to obtain, and thus, limit bounds of the efficiency are derived and algorithms are developed to calculate its exact value. Results show that the series-machine system under type-II failure mechanisms is more efficient than under type-I mechanisms, which, intuitively making sense, is the reason that type-II mechanisms are more common in the industry. Note to Practitioners —The series-machine system is pervasive in industry and it usually operates under type-II failure mechanisms (i.e., the breakdown of a machine does not make any other series machines forced down). Nevertheless, the existing research on type-II failure mechanisms is very limited. Thus, the efficiency and other performance measures of such systems are, in general, approximately evaluated based on type-I mechanisms (i.e., the breakdown of a machine could make all other series machines forced down). However, the error of this approximation may be large and unacceptable. In this paper, a unified approach is proposed to analyze the efficiency of the series-machine system. Due to the difficulties in deriving closed-form expressions under type-II failure mechanisms, algorithms are developed to calculate the efficiency of the series-machine system. Theoretical results ensure the effectiveness of the algorithms.

Photophysical and Photochemical Properties of 3-methylpterin as a New and More Stable Pterin-type Photosensitizer.

Pterin derivatives are heterocyclic compounds which are present in different biological systems. Neutral aqueous solutions of pterins present acid-base and keto-enol equilibria. These compounds, under UV-A radiation fluoresce, undergo photooxidation, generate reactive oxygen species and photoinduce the oxidation of biological substrates. As photosensitizers, they may act through different mechanisms, mainly through an electron transfer-initiated process (type-I mechanism), but they also produce singlet molecular oxygen (1 O2 ) upon irradiation (type-II mechanism). In general, upon UV-A excitation two triplet states, corresponding to the lactim and lactam tautomers, are formed, but only the last one is the responsible for the photosensitized reactions of biomolecules. We present a study of the photochemical properties of 3-methylpterin (3-Mep) which, in contrast to most pterin derivatives, exists only in the lactam form. Also an improvement in the synthesis of 3-Mep is reported. The spectroscopic properties 3-Mep in aqueous solution were similar to those of the unsubstituted pterin derivative (Ptr) in its acid form, such as absorption, fluorescent and phosphorescent emission spectra. Experiments using 2'-deoxyguanosine 5'-monophosphate (dGMP) as oxidizable target demonstrated that methylation at C-3 position of the pterin moiety does not affect significantly the efficiency of photosensitization, but results in a more photostable sensitizer.

Radiative seesaw model and DAMPE excess from leptophilic gauge symmetry

In the light of the e^{+}+e^{-} excess observed by DAMPE experiment, we propose an anomaly-free radiative seesaw model with an alternative leptophilic U(1)_X gauge symmetry. In the model, only right-handed leptons are charged under U(1)_X symmetry. The tiny Dirac neutrino masses are generated at one-loop level and charged leptons acquire masses though the type-I seesaw-like mechanism with heavy intermediate fermions. In order to cancel the anomaly, irrational U(1)_{X} charge numbers are assigned to some new particles. After the spontaneous breaking of U(1)_{X} symmetry, the dark Z_{2} symmetry could appear as a residual symmetry such that the stability of inert particles with irrational charge numbers are guaranteed, naturally leading to stable DM candidates. We show that the Dirac fermion DM contained in the model can explain the DAMPE excess. Meanwhile, experimental constraints from DM relic density, direct detection, LEP and anomalous magnetic moments are satisfied.

Bifunctional Tellurium Nanodots for Photo-Induced Synergistic Cancer Therapy.

Elemental tellurium (Te) nanoparticles are increasingly important in a variety of applications such as thermoelectricity, photoconductivity, and piezoelectricity. However, they have been explored with limited success in their biomedical use, and thus a tremendous challenge still exists in the exploration of Te nanoparticles that can treat tumors as an effective anticancer agent. Here, we introduce bifunctional Te nanodots with well-defined nanostructure as an effective anticancer agent for photo-induced synergistic cancer therapy with tumor ablation, which is accomplished using hollow albumin nanocages as a nanoreactor. Under near-infrared light irradiation, Te nanodots can produce effective photothermal conversion, as well as highly reactive oxygen species such as •O2- and dismutated •OH via a type-I mechanism through direct electron transfer, thereby triggering the potent in vivo hyperthermia and simultaneous intracellular reactive oxygen species at tumors. Moreover, Te nanodots possess perfect resistance to photobleaching, effective cytoplasmic translocation, preferable tumor accumulation, as well as in vivo renal elimination, promoting severe photo-induced cell damage and subsequent synergy between photothermal and photodynamic treatments for tumor ablation. These findings provide the insight of elemental Te nanodots for biomedical research.

Real-time imaging of photodynamic action in bacteria.

Fluorescence imaging studies of the processes leading to photodynamic inactivation of bacteria have been limited due to the small size of microorganisms as well as by the faint fluorescence of most photosensitizers. A versatile method based on highly-sensitive fluorescence microscopy is presented which allows to study, in real time, the incorporation of photosensitizers inside S. aureus upon photodynamic action. The method takes advantage of the fluorescence enhancement of phenothiazine and porphyrin photosensitizers upon entering the bacterial cytosol after the cell wall has been compromised. In combination with typical assays, such as the addition of specific enhancers of reactive oxygen species, it is possible to extract mechanistic information about the pathway of photodynamic damage at the single-cell level. Imaging experiments in deuterated buffer strongly support a Type-I mechanism for methylene blue and a very minor role of singlet oxygen.

Minimal 3-3-1 model with a spectator sextet

We consider the minimal 3-3-1 model with a heavy scalar sextet and realize, at the tree level, an effective dimension-five interaction that contributes to the mass of the charged leptons. In this case the charged leptons masses arise from a sort of type-II seesawlike mechanism while the neutrino masses are generated by a type-I mechanism. We also show that the parameters giving the correct lepton masses also accommodate the Pontecorvo-Maki-Nakawaga-Sakata matrix. We give the scalar mass spectra of the model and analyze under which conditions the fields in the scalar sextet are heavy even with small or zero vacuum expectation values. We also show the conditions under which it is possible to have a stable (bounded from below) potential and also a global minimum.

Testing νMSM with indirect searches

We consider neutrino Minimal extension of the Standard Model (νMSM), which by introducing only three sterile neutrinos in sub-electroweak region can explain active neutrino oscillations (via seesaw type-I mechanism), baryon asymmetry of the Universe (leptogenesis via oscillations) and dark matter phenomena (with keV-scale sterile neutrino forming dark matter). We estimate sterile neutrino virtual contributions to various lepton flavor and lepton number violating processes. The contributions are too small, giving no chance for indirect searches to compete with direct measurements in exploring νMSM.

Photooxidation of tetrahydrobiopterin under UV irradiation: possible pathways and mechanisms.

Tetrahydrobiopterin (H4 Bip) is a cofactor for several key enzymes, including NO synthases and aromatic amino acid hydroxylases (AAHs). Normal functioning of the H4 Bip regeneration cycle is extremely important for the work of AAHs. Oxidized pterins may accumulate if the H4 Bip regeneration cycle is disrupted or if H4 Bip autoxidation occurs. These oxidized pterins can photosensitize the production of singlet molecular oxygen (1)O2 and thus cause oxidative stress. In this context, we studied the photooxidation of H4 Bip in phosphate buffer at pH 7.2. We found that UV irradiation of H4 Bip affected its oxidation rate (quantum yield Φ300 = (2.7 ± 0.4) × 10(-3)). The effect of UV irradiation at λ = 350 nm on H4 Bip oxidation was stronger, especially in the presence of biopterin (Bip) (Φ350 = (9.7 ± 1.5) × 10(-3)). We showed that the rate of H4 Bip oxidation linearly depends on Bip concentration. Experiments with KI, a selective quencher of triplet pterins at micromolar concentrations, demonstrated that the oxidation is sensitized by the triplet state biopterin (3) Bip. Apparently, electron transfer sensitization (Type-I mechanism) is dominant. Energy transfer (Type-II mechanism) and singlet oxygen generation play only a secondary role. The mechanisms of H4 Bip photooxidation and their biological meaning are discussed.

Sterile neutrinos and their role in particle physics and cosmology

Introducing new fermions into particles physics that are singlet under the gauge group of the Standard Model allows using the seesaw type-I mechanism to obtain small neutrino masses and explaining the phenomenon of neutrino oscillations. The mass scale of these fermions (sterile neutrinos) is a free parameter with values ranging widely from a subelectronvolt to . The mass scale determines the direct search strategy for these particles, and depending on it, sterile neutrinos can influence the evolution of the Universe and can be responsible for the baryon asymmetry of the Universe and for the phenomenon of dark matter.

Synthesis and Characterization of Mono-, Di-, and Tri-Poly(ethylene glycol) Chlorin e6 Conjugates for the Photokilling of Human Ovarian Cancer Cells

PEGylated chlorin e(6) photosensitizers were synthesized with tri(ethylene glycol) attached at the ester bond(s) for a 1:1 conjugate at the 17(3)-position, a 2:1 conjugate at the 15(2)- and 17(3)-positions, and a 3:1 conjugate at the 13(1)-, 15(2)-, and 17(3)-positions. These chlorin sensitizers were studied for hydrolytic stability and solubility, as well as ovarian OVCAR-5 cancer cell uptake, localization, and phototoxicity. Increasing numbers of the PEG groups in the mono-, di-, and tri-PEG chlorin conjugates increased the water solubility and sensitivity to hydrolysis and uptake into the ovarian cancer cells. The PEG chlorin conjugates accumulated in the cytoplasm and mitrochondria, but not in lysosomes. Higher phototoxicity was roughly correlated with higher numbers of PEG groups, with the tri-PEG chlorin conjugate showing the best overall ovarian cancer cell photokilling of the series. Singlet oxygen lifetimes, solvent deuteration, and the effects of additives azide ion and d-mannitol were examined to help clarify the photokilling mechanisms. A Type-II (singlet oxygen) photosensitized mechanism is suggested for the di- and tri-PEG chlorin conjugates; however, a more complicated process based in part on a Type-I (radicals or radical ions) mechanism is suggested for the parent chlorin e(6) and the mono-PEG chlorin conjugate.

Advanced Glycation Endproducts Induce Photocrosslinking and Oxidation of Bovine Lens Proteins Through Type‐I Mechanism

Advanced glycation endproducts (AGEs) have been suggested as photosensitizers that are capable of mediating eye lens photo-damage during aging. In the present work, we investigate the photo-crosslinking and oxidation of bovine lens proteins sensitized by AGEs, with special regard to low oxygen conditions. A mechanistic study was conducted using different oxygen concentrations and specific additives with the aim either to scavenge or enhance Type-I or Type-II photoprocesses. Quantum yields for Trp decomposition were determined at 5%, 20% and 100% O(2), in the presence of ferricyanide and D(2)O to elucidate the mechanism of action of AGEs. Type-I mechanism proved to be the most efficient pathway for AGE-sensitized Trp decomposition at low oxygen concentration. Photocrosslinking of lens proteins and crystallin fractions due to Type-I interaction was observed. The influence of the oxygen concentration and additives was also studied. The results show that both Type-I mechanism and oxygen-mediated reactions contribute to protein crosslinking. Carbonyl group formation due to protein photo-oxidation was detected with Oxyblot technique. The generation of high levels of hydrogen peroxide during the irradiations was detected and attributed mainly to Type-I reactions. The results support that AGEs act preferentially as Type-I sensitizers at the low oxygen concentration found in the lens and are capable of inducing protein crosslinking, oxidation and peroxide formation.

Ground- and excited-state interactions of 2,7,12,17-tetraphenylporphycene with model target biomolecules for type-I photodynamic therapy

Biosubstrate-sensitizer binding is one of the factors that enhances the type-I mechanism over the type-II in the whole photodynamic process. 2,7,12,17-Tetraphenylporphycene (TPPo), a second-generation photosensitizer, is a hydrophobic compound with good photophysical properties for photodynamic therapy applications that has proved its ability for the photoinactivation of different cell lines. Nevertheless, little is known about its mechanism of action. This paper focuses on the study of the interaction/binding of TPPo with different model biomolecules that may favor the type-I mechanism in the overall photodynamic process, including nucleosides, proteins, and phospholipids. Compared with more hydrophilic photosensitizers, it is concluded that TPPo is more likely to undergo type-II (singlet oxygen) than type-I (electron transfer) photodynamic processes in biological environments.

Spectroscopic Studies and Photodynamic Actions of Hypocrellin B in Liposomes¶

Hypocrellin B (HB), a lipid-soluble natural pigment of perylenequinone derivative, is considered as potential photosensitizer for photodynamic therapy. Liposomes loaded with HB can constitute a simple model system, appropriate for better understanding the photodynamic action of HB in vivo. The steady-state absorption and emission spectra, quantum yield and lifetime of fluorescence of HB incorporated into egg l-a-phosphatidyl-choline (EPC) liposome were examined. The photochemical properties (Type I and/or Type II) of HB have also been studied in aqueous dispersions of small unilamellar liposomes of EPC using electron paramagnetic resonance and spectrophotometric methods, respectively. The quantum yield of 1O2 generated by HB is ca 0.76 in chloroform solution and it did not change upon the incorporation of HB into liposomes of EPC. The superoxide anion radical was generated by the electron transfer from the anion radical of HB (HB·−) to oxygen. The disproportionation of O2·− can generate H2O2 and ultimately the highly reactive ·OH via the Fenton reaction. It could be that the disproportionation proceeded too fast, so we could not detect O2·− directly in aqueous dispersions of liposome EPC. Moreover, the self-sensitized photooxygenation of HB embedded in liposomes was studied, and almost fully (87%) inhibiting this reaction of HB by p-benzoquinone (as the quencher of O2·−) in aqueous dispersion of liposome EPC indicated that the radical mechanism (Type I) might be mainly involved in this oxygenation. All these findings suggested that the photodynamic action of HB proceeded via both Type-I and -II mechanisms, but Type-I mechanism might play a more important role in the aqueous dispersion.