Photobiomodulation preconditioned diabetic adipose derived stem cells with additional photobiomodulation: an additive approach for enhanced wound healing in diabetic rats with a delayed healing wound.

In this preclinical investigation, we examined the effects of combining preconditioned diabetic adipose-derived mesenchymal stem cells (AD-MSCs) and photobiomodulation (PBM) on a model of infected ischemic delayed healing wound (injury), (IIDHWM) in rats with type I diabetes (TIDM). During the stages of wound healing, we examined multiple elements such as stereology, macrophage polarization, and the mRNA expression levels of stromal cell-derived factor (SDF)-1α, vascular endothelial growth factor (VEGF), hypoxia-induced factor 1α (HIF-1α), and basic fibroblast growth factor (bFGF) to evaluate proliferation and inflammation. The rats were grouped into: (1) control group; (2) diabetic-stem cells were transversed into the injury site; (3) diabetic-stem cells were transversed into the injury site then the injury site exposed to PBM; (4) diabetic stem cells were preconditioned with PBM and implanted into the wound; (5) diabetic stem cells were preconditioned with PBM and transferred into the injury site, then the injury site exposed additional PBM. While on both days 4, and 8, there were advanced histological consequences in groups 2-5 than in group 1, we found better results in groups 3-5 than in group 2 (p < 0.05). M1 macrophages in groups 2-5 were lower than in group 1, while groups 3-5 were reduced than in group 2 (p < 0.01). M2 macrophages in groups 2-5 were greater than in group 1, and groups 3-5 were greater than in group 2. (p ≤ 0.001). Groups 2-5 revealed greater expression levels of bFGF, VEGF, SDF- 1α, and HIF- 1α genes than in group 1 (p < 0.001). Overall group 5 had the best results for histology (p < 0.05), and macrophage polarization (p < 0.001). AD-MSC, PBM, and AD-MSC + PBM treatments all enhanced the proliferative stage of injury repairing in the IIDHWM in TIDM rats. While AD-MSC + PBM was well than the single use of AD-MSC or PBM, the best results were achieved with PBM preconditioned AD-MSC, plus additional PBM of the injury.

Photobiomodulation and mesenchymal stem cell-conditioned medium for the repair of experimental critical-size defects.

Orthopedic surgeons face a significant challenge in treating critical-size femoral defects (CSFD) caused by osteoporosis (OP), trauma, infection, or bone tumor resections. In this study for the first time, the application of photobiomodulation (PBM) and bone marrow mesenchymal stem cell-conditioned medium (BM-MSC-CM) to improve the osteogenic characteristics of mineralized bone scaffold (MBS) in ovariectomy-induced osteoporotic (OVX) rats with a CSFD was tested. Five groups of OVX rats with CSFD were created: (1) Control (C); (2) MBS; (3) MBS + CM; (4) MBS + PBM; (5) MBS + CM + PBM. Computed tomography scans (CT scans), compression indentation tests, and histological and stereological analyses were carried out after euthanasia at 12 weeks following implantation surgery. The CT scan results showed that CSFD in the MBS + CM, MBS + PBM, and MBS + CM + PBM groups was significantly smaller compared to the control group (p = 0.01, p = 0.04, and p = 0.000, respectively). Moreover, the CSFD size was substantially smaller in the MBS + CM + PBM treatment group than in the MBS, MBS + CM, and MBS + PBM treatment groups (p = 0.004, p = 0.04, and p = 0.01, respectively). The MBS + PBM and MBS + CM + PBM treatments had significantly increased maximum force relative to the control group (p = 0.01 and p = 0.03, respectively). Bending stiffness significantly increased in MBS (p = 0.006), MBS + CM, MBS + PBM, and MBS + CM + PBM treatments (all p = 0.004) relative to the control group. All treatment groups had considerably higher new trabecular bone volume (NTBV) than the control group (all, p = 0.004). Combined therapies with MBS + PBM and MBS + CM + PBM substantially increased the NTBV relative to the MBS group (all, p = 0.004). The MBS + CM + PBM treatment had a markedly higher NTBV than the MBS + PBM (p = 0.006) and MBS + CM (p = 0.004) treatments. MBS + CM + PBM, MBS + PBM, and MBS + CM treatments significantly accelerated bone regeneration of CSFD in OVX rats. PBM + CM enhanced the osteogenesis of the MBS compared to other treatment groups.

Photobiomodulation and conditioned medium of adipose-derived stem cells for enhancing wound healing in rats with diabetes: an investigation on the proliferation phase.

This investigation tried to evaluate the combined and solo effects of photobiomodulation (PBM) and conditioned medium derived from human adipose tissue-derived stem cells (h-ASC-CM) on the inflammatory and proliferative phases of an ischemic infected delayed healing wound model (IIDHWM) in rats with type I diabetes mellitus (TIDM). The present investigation consisted of four groups: group 1 served as the control, group 2 treated with h-ASC-CM, group 3 underwent PBM treatment, and group 4 received a combination of h-ASC-CM and PBM. Clinical and laboratory assessments were conducted on days 4 and 8. All treatment groups exhibited significantly higher wound strength than the group 1 (p = 0.000). Groups 4 and 3 demonstrated significantly greater wound strength than group 2 (p = 0.000). Additionally, all therapeutic groups showed reduced methicillin -resistant Staphylococcus aureus (MRSA) in comparison with group 1 (p = 0.000). While inflammatory reactions, including neutrophil and macrophage counts, were significantly lower in all therapeutic groups rather than group 1 on days 4 and 8 (p < 0.01), groups 4 and 3 exhibited superior results compared to group 2 (p < 0.01). Furthermore, proliferative activities, including fibroblast and new vessel counts, as well as the measurement of new epidermal and dermal layers, were significantly increased in all treatment groups on 4 and 8 days after the surgery (p < 0.001). At the same times, groups 4 and 3 displayed significantly higher proliferative activities compared to group 2 (p < 0.001). The treatment groups exhibited significantly higher mast cell counts and degranulation phenotypes in comparison with the group 1 on day 4 (p < 0.05). The treatment groups showed significantly lower mast cell counts and degranulation phenotypes than group 1 on day 8 (p < 0.05).The combined and individual application of h-ASC-CM and PBM remarkably could accelerate the proliferation phase of wound healing in the IIDHWM for TIDM in rats, as indicated by improved MRSA control, wound strength, and stereological evaluation. Furthermore, the combination of h-ASC-CM and PBM demonstrated better outcomes compared to the individual application of either h-ASC-CM or PBM alone.

Therapeutic evaluation of immunomodulators in reducing surgical wound infection.

Despite many advances in infection control practices, including prophylactic antibiotics, surgical site infections (SSIs) remain a significant cause of morbidity, prolonged hospitalization, and death worldwide. Our innate immune system possesses a multitude of powerful antimicrobial strategies which make it highly effective in combating bacterial, fungal, and viral infections. However, pathogens use various stealth mechanisms to avoid the innate immune system, which in turn buy them time to colonize wounds and damage tissues at surgical sites. We hypothesized that immunomodulators that can jumpstart and activate innate immune responses at surgical sites, would likely reduce infection at surgical sites. We used three immunomodulators; fMLP (formyl-Methionine-Lysine-Proline), CCL3 (MIP-1α), and LPS (Lipopolysaccharide), based on their documented ability to elicit strong inflammatory responses; in a surgical wound infection model with Pseudomonas aeruginosa to evaluate our hypothesis. Our data indicate that one-time topical treatment with these immunomodulators at low doses significantly increased proinflammatory responses in infected and uninfected surgical wounds and were as effective, (or even better), than a potent prophylactic antibiotic (Tobramycin) in reducing P. aeruginosa infection in wounds. Our data further show that immunomodulators did not have adverse effects on tissue repair and wound healing processes. Rather, they enhanced healing in both infected and uninfected wounds. Collectively, our data demonstrate that harnessing the power of the innate immune system by immunomodulators can significantly boost infection control and potentially stimulate healing. We propose that topical treatment with these immunomodulators at the time of surgery may have therapeutic potential in combating SSI, alone or in combination with prophylactic antibiotics.

Application of combined photobiomodulation and curcumin-loaded iron oxide nanoparticles considerably enhanced repair in an infected, delayed-repair wound model in diabetic rats compared to either treatment alone.

Herein, we attempted to evaluate the therapeutic potential of photobiomodulation (PBM) and curcumin-loaded iron nanoparticles (CUR), alone and in combination, on wound closure rate (WCR), microbial flora by measuring colony-forming units (CFUs), the stereological and biomechanical properties of repairing wounds in the maturation stage of the wound healing course in an ischemic infected delayed healing wound model (IIDHWM) of type I diabetic (TIDM) rats. There were four groups: group 1 was the control, group 2 received CUR, rats in group 3 were exposed to PBM (80 Hz, 890 nm, and 0.2 J/cm2), and rats in group 4 received both PBM and CUR (PBM + CUR). We found CFU was decreased in groups 2, 3, and 4 compared to group 1 (p = 0.000 for all). Groups 2, 3, and 4 showed a considerable escalation in WCR compared to group 1 (p = 0.000 for all). In terms of wound strength parameters, substantial increases in bending stiffness and high-stress load were observed in groups 2, 3, and 4 compared to group 1 (p = 0.000 for all). Stereological examinations revealed decreases in neutrophil and macrophage counts and increases in fibroblast counts in groups 2, 3, and 4compared  to group 1 (p = 0.000 for all). Blood vessel counts were more dominant in the PBM and PBM + CUR groups over group 1 (p = 0.000 for all). CFU and wound strength as well as macrophage, neutrophil, and fibroblast counts were found to be improved in the PBM + CUR and PBM groups compared to the CUR group (ranging from p = 0.000 to p < 0.05). Better results were achieved in the PBM + CUR  treatment  over the PBM therapy. We determined therapy with PBM + CUR, PBM alone, and CUR alone substantially accelerated diabetic wound healing in an IIDHWM of TIDM rats compared to control  group. Concomitantly, the PBM + CUR and PBM groups attained significantly enhanced results for WCR, stereological parameters, and wound strength than the CUR group, with the PBM + CUR results being superior to those of the PBM group.

Catalyst-free synthesis of acenaphthoindolopyrimidine derivatives.

A one pot three component reaction of acenaphthoquinone, barbituric acid/thiobarbituric acid/N,N-dimethyl barbituric acid and arylamines in ethanol for the synthesis of acenaphthoindolopyrimidine derivatives is reported. The reactions take place without a catalyst and gentle conditions. This method is facile and has some benefits such as, readily available starting materials, green solvent, catalyst-free, no column chromatographic purification and good to high yields.

Efficient regioselective five-component synthesis of novel thiazolo[3,2-a]pyridine carbohydrazides and oxazolo[3,2-a]pyridine carbohydrazides.

Two new categories of fused pyridines include 2H-thiazolo[3,2-a]pyridine-6-carbohydrazides and 2H-oxazolo[3,2-a]pyridine-6-carbohydrazides have been successfully synthesized via five-component cascade reactions using 9-fluorenone, cyanoacetohydrazide, 1,1-bis(methylthio)-2-nitroethene, aromatic aldehydes and cysteamine hydrochloride or ethanol amine as starting materials. This new approach involves a subsequence of key steps: N,S-acetal or N,O-acetal formation, Knoevenagel condensation, Michael addition, tautomerization and N-cyclization. It also has some advantages, such as convenience of operation, tolerance of a wide diversity of functional groups, use of green solvent and ease of purification by washing the crude products with ethanol.

1,3-Dipolar cycloaddition reactions of isatin-derived azomethine ylides for the synthesis of spirooxindole and indole-derived scaffolds: recent developments.

The unique therapeutic and biological characteristics of spirooxindole have led to the presentation of numerous reactions for the synthesis of spirooxindoles through 1,3-Dipolar cycloaddition of highly reactive isatin-derived azomethine ylides with activated olefins as the main tool for the formation of spirocyclic oxindoles during the last 4 years. Therefore, there is a need to highlight the recent developments in this area, along with the representative synthetic methods and relevant reaction mechanisms from 2018 to 2021. The representative synthetic methodologies were listed in four sections based on the procedure to form the azomethine ylide species including isatins and amino acids, isatin-derived α-(trifluoromethyl)imine, isatins and benzylamines, and from isatin-derived cyclic imine 1,3-dipoles.

Photobiomodulation, alone or combined with adipose-derived stem cells, reduces inflammation by modulation of microRNA-146a and interleukin-1ß in a delayed-healing infected wound in diabetic rats.

Diabetic wounds are categorized by chronic inflammation, leading to the development of diabetic foot ulcers, which cause amputation and death. Herewith, we examined the effect of photobiomodulation (PBM) plus allogeneic diabetic adipose tissue-derived stem cells (ad-ADS) on stereological parameters and expression levels of interleukin (IL)-1ß and microRNA (miRNA)-146a in the inflammatory (day 4) and proliferation (day 8) stages of wound healing in an ischemic infected (with 2×107 colony-forming units of methicillin-resistant Staphylococcus aureus) delayed healing wound model (IIDHWM) in type I diabetic (TIDM) rats. There were five groups of rats: group 1 control (C); group 2 (CELL) in which rat wounds received 1×106 ad-ADS; group 3 (CL) in which rat wounds received the ad-ADS and were subsequently exposed to PBM(890 nm, 80 Hz, 3.5 J/cm2, in vivo); group 4 (CP) in which the ad-ADS preconditioned by the PBM(630 nm + 810 nm, 0.05 W, 1.2 J/cm2, 3 times) were implanted into rat wounds; group 5 (CLP) in which the PBM preconditioned ad-ADS were implanted into rat wounds, which were then exposed to PBM. On both days, significantly better histological results were seen in all experimental groups except control. Significantly better histological results were observed in the ad-ADS plus PBM treatment correlated to the ad-ADS alone group (p<0.05). Overall, PBM preconditioned ad-ADS followed by PBM of the wound showed the most significant improvement in histological measures correlated to the other experimental groups (p<0.05). On days 4 and 8, IL-1 ß levels of all experimental groups were lower than the control group; however, on day 8, only the CLP group was different (p<0.01). On day 4, miR-146a expression levels were substantially greater in the CLP and CELL groups correlated to the other groups, on day 8 miR-146a in all treatment groups was upper than C (p<0.01). ad-ADS plus PBM, ad-ADS, and PBM all improved the inflammatory phase of wound healing in an IIDHWM in TIDM1 rats by reducing inflammatory cells (neutrophils, macrophages) and IL-1ß, and increasing miRNA-146a. The ad-ADS+PBM combination was better than either ad-ADS or PBM alone, because of the higher proliferative and anti-inflammatory effects of the PBM+ad-ADS regimen.

Potential of stem cells for treating infected Diabetic Foot Wounds and Ulcers: a systematic review.

Infected diabetic foot ulcers (iDFUs) cause great concern, as they generally heal poorly and are precursive of diabetic-related foot amputation and even death. Scientists have tested various techniques in attempts to ascertain the best treatment for iDFUs; however, the results have remained inconclusive. Stem cell therapy (SCT) appears to improve iDFU through its antimicrobial impacts, yet cogent information regarding the repair of iDFUs with SCT is lacking. Herein, published articles are evaluated to report coherent information about the antimicrobial effects of SCT on the repair of iDFUs in diabetic animals and humans. In this systematic review, we searched the Scopus, Medline, Google Scholar, and Web of Science databases for relevant full-text English language articles published from 2000 to 2022 that described stem cell antimicrobial treatments, infected diabetic wounds, or ulcers. Ultimately, six preclinical and five clinical studies pertaining to the effectiveness of SCT on healing infected diabetic wounds or ulcers were selected. Some of the human studies confirmed that SCT is a promising therapy for diabetic wounds and ulcers. Notably, more controlled studies performed on animal models revealed that stem cells combined with a biostimulator such as photobiomodulation decreased colony forming units and hastened healing in infected diabetic wounds. Moreover, stem cells alone had lower therapeutic impact than when combined with a biostimulant.

Design a protocol to investigate the effects of climate change in vivo.

Climate change has a variety of effects on communities and the environment, most of which have been directly addressed, such as floods, droughts, and fires. To date, the impacts of climate change on health in in vivo conditions have not been assessed, and no protocol has been developed in this regard. Therefore, the purpose of the current study is to develop a protocol as well as design and build a pilot to deal with climate change in vivo to show the direct effects of climate change on health. For this purpose, twenty specialists, comprising ten experts active in field climate and 10 experts in field medicine and anatomy, have been consulted to design the proposed exposure protocol using the Delphi method. According to the prepared protocol, an exposure pilot was then designed and built, which provides the climatic conditions for animal exposure with a fully automatic HMI-PLC system. The results showed the average 12:12-h day/night temperature, humidity, and circadian cycle for three consecutive ten-year periods selected for exposure of 1-month-old male rats. The duration of the exposure period is four months, which is equivalent to a ten-year climatic period. This study is a framework and a starting point for examining the effects of climate change on in vivo conditions that have not yet been considered.

A one-pot synthesis of piperidinium spirooxindoline-pyridineolates and indole-substituted pyridones in aqueous or ethanol medium.

Piperidinium spirooxindoline-pyridineolate has been prepared via one-pot multicomponent reaction of isatin, malononitrile, cyanoacetohydrazide, and piperidine in water or ethanol medium at room temperature. In addition, the synthesis of two indole-substituted 2-pyridones from indole-3-carbaldehyde, malononitrile, and cyanoacetohydrazide in the presence of piperidine is described.

Synthesis and in vitro evaluation of antitumor activity of spiro[indolo[2,1-b]quinazoline-pyrano[2,3-d]pyrimidine] and spiro[indolo[2,1-b]quinazoline-pyrido[2,3-d]pyrimidine] derivatives by using 2D and 3D cell culture models.

Cancer as one of the biggest human health problems remains unsolved. The identification of novel platforms with the highest efficacy and low toxicity is a big challenge among interested researchers. In this regard, we are interested to synthesis and evaluate antitumor activity of spiro[indolo[2,1-b]quinazoline-pyrano[2,3-d]pyrimidine] and spiro[indolo[2,1-b]quinazoline-pyrido[2,3-d]pyrimidine] derivatives. The spiro heterocycles were synthesized via four-component reaction of isatoic anhydride, isatins, malononitrile, and some CH-acids including barbituric acid/thiobarbituric acid and 4(6)-aminouracil in CH2Cl2 under reflux condition. The significant features of this process are short reaction time, easy purification without chromatographic process, and high yields which make it attractive. Next, we employed 2D and 3D cell culture models to evaluate biological activity of our compounds. Our results showed that among our seven products (4a-g), the compounds 4a and 4e are the best with 50% growth inhibitory concentration (IC50) value lower than etoposide. Our results support this idea that the compounds 4a and 4e may be potential for drug designing in cancer therapy. However, more experiments will be required to find possible side effects of related compounds in vivo.

Catalyst-free synthesis of highly functionalized triazole hexahydroquinoline carbohydrazide scaffolds via four-component cyclocondensation reaction.

A new class of multi-functional triazole hexahydroquinoline carbohydrazide named 2-amino-7,7-dimethyl-5-oxo-4-phenyl-1-(4H-1,2,4-triazol-3-yl)-1,4,5,6,7,8-hexahydroquinoline-3-carbohydrazide has been synthesized by a novel multi-component process involving the reaction of dimedone, 3-amino-1,2,4-triazole, various benzaldehyde with cyanoacetohydrazide under mild conditions in the stoichiometric melt and chloroform in sequence. The simple one-pot process, straight product isolation without applying tedious purification procedures, progression of the reaction without using any catalyst, the application of diverse aldehydes causing a high molecular diversity, the existence of several nitrogen atoms in the product structure, and the possibility of creating multiple hydrogen bonding in the final compound are attractive specifications of the present strategy.

Strategies for synthesis of 1,2,4-triazole-containing scaffolds using 3-amino-1,2,4-triazole.

1,2,4-Triazole-containing scaffolds are unique heterocyclic compounds present in an array of pharmaceuticals and biologically important compounds used in the drug-discovery studies against cancer cells, microbes, and various types of disease in the human body. This review article summarizes the pharmacological significance of the 1,2,4-triazole-containing scaffolds and highlights the latest strategies for the synthesis of these privileged scaffolds using 3-amino-1,2,4-triazole. This review stimulates further research to find new and efficient methodologies for accessing new 1,2,4-triazole-containing scaffolds which would be very useful for the discover of new drug candidates.

Recent developments in green approaches for sustainable synthesis of indole-derived scaffolds.

An important issue to discover biological structures is the design of sustainable, safe, clean, cost-effective, excellent efficient synthetic reactions, and minimal energy consumption to provide structural diversity compounds with interesting biological properties. Among five-membered nitrogen-containing heterocyclic compounds, indole-containing scaffolds are heterocyclic structures found in abundance in natural products and various synthetic compounds, which have received remarkable attention in recent years due to their therapeutic and pharmaceutical properties and valuable role in the process of drug discovery. Indoles can be synthesized by various procedures although most of these procedures have their own restrictions and drawbacks such as performing the reaction in a toxic solvent, need of transition-metal catalysts, and amount of waste solvents. Due to the medicinal importance of indole and the need for green methods of drug synthesis, this review highlights the latest green synthetic methods leading to the formation of indole-containing compounds focusing on the past 4 years with typical examples. This review is divided into two sections: green solvents and green techniques that lead to the synthesis of indole-derived scaffolds.

The effect of curcumin on NRF2/Keap1 signalling pathway in the epididymis of mouse experimental cryptorchidism.

Nrf2/Keap1 pathway, which prevents cellular damage against reactive oxygen species production, is disrupted in epididymis following cryptorchidism. In this study, we aimed to use curcumin (Cur) as an activator of Nrf2 to decrease the effects of disruption in this pathway caused by cryptorchidism. In this study, animals were randomly divided into following groups: control, sham-surgery, sham-vehicle, sham-Cur50, sham-Cur100 , cryptorchidism, cryptorchidism-vehicle, cryptorchidism-Cur50 and cryptorchidism-Cur100 . For cryptorchidism induction, the left testicle was removed from the scrotum and sutured to the abdominal wall. Two weeks after surgery, Cur was given orally to animals. After 1 month, sperm parameters and testis histopathology were analysed. The expression of Nrf2, NQO1, HO1, and Keap1 genes was evaluated by real-time polymerase chain reaction. Our data showed that Cur, especially at high doses, could improve sperm parameters and testis histopathology, which were damaged following cryptorchidism induction. The expression of HO1, NQO1, and Nrf2 genes, which had decreased in the cryptorchidism group, showed a significant increase after administration of Cur in a dose-dependent manner. Cur, by inducing the expression of genes involved in the Nrf2/Keap1 pathway, could reduce the adverse effects of cryptorchidism and might be used as adjuvant therapy for decreasing cryptorchidism complications before surgery.

Aerobic training mitigates the negative impact of diabetes on fertility.

Diabetes negatively affects the reproductive system. This present study investigated the effects of aerobic training on protamine 1 and 2 mRNA expression, sex hormones, antioxidant defence and sperm quality in diabetic rats. Thirty-six male Wistar rats were randomly allocated into three groups including diabetic training (DT) group, diabetic (D) group and control (C) group. Rats in DT were exercised 5 times per week for 8 weeks. Blood samples were collected for evaluation of sex hormones 48 h after the last training session. Also, the testes were removed and subjected to histological evaluation and semen analysis. Testicular mRNA expressions of protamines were determined by RT-qPCR. Protamines 1 and 2, and the ratio of protamine 1 to protamine 2 were significantly lower in DT and D groups compared with C group (p < 0.01). LH and testosterone levels were significantly lower in D group compared with DT and C group (p < 0.01). Malondialdehyde was significantly lower in DT and C groups compared with D group (p < 0.001). Sperm parameters were significantly lower in D group compared with C group (p < 0.01). Our findings suggest that aerobic training may mitigate the negative impact of diabetes on sex hormones, oxidative stress, protamine content and sperm parameters in male rats.

Impact of photobiomodulation on macrophages and their polarization during diabetic wound healing: a systematic review.

This review aims to providing essential information and the current knowledge about the potential role of macrophages, especially their M2 subtypes in different diabetic wounds both in clinical and pre-clinical models under the influence of photobiomodulation (PBM). The long-term goal is to advance the macrophage-based therapies to accelerate healing of diabetic foot ulcers. We reviewed all databases provided by PubMed, Google Scholar, Scopus, Web of Science, and Cochrane precisely from their dates of inception to 25/10/2021. The keywords of Diabetes mellitus diseases, wound healing, macrophage, and photobiomodulation or low-level laser therapy were used in this systematic review.A total of 438 articles were initially identified in pubmed.ncbi.nlm.nih.gov (15 articles), Google scholar (398 articles), Scopus (18 articles), and Web of Science (7 articles). Four hundred sixteen articles that remained after duplicate studies (22 articles) were excluded. After screening abstracts and full texts, 14 articles were included in our analysis. Among them, 4 articles were about the effect of PBM on macrophages in type 2 diabetes and also found 10 articles about the impact of PBM on macrophages in type 1 diabetes. The obtained data from most of the reviewed studies affirmed that the PBM alone or combined with other agents (e.g., stem cells) could moderate the inflammatory response and accelerate the wound healing process in pre-clinical diabetic wound models. However, only very few studies conducted the detailed functions of polarized macrophages and M2 subtypes in wound healing of diabetic models under the influence of PBM. Further pre-clinical and clinical investigations are still needed to investigate the role of M2 macrophages, especially its M2c subtype, in the healing processes of diabetic foot ulcers in clinical and preclinical settings.

Effectiveness of preconditioned adipose-derived mesenchymal stem cells with photobiomodulation for the treatment of diabetic foot ulcers: a systematic review.

The primary goal of this systematic review article was to provide an outline of the use of diabetic autologous adipose-derived mesenchymal stem cells (DAAD-MSCs) in the treatment of wounds and ulcers in animal models and patients with diabetes mellitus (DM). The secondary goal was to present the outcomes of pretreatment of diabetic adipose-derived mesenchymal stem cells (DAD-MSCs) with probable different agents in the treatment of diabetic foot ulcers (DFUs) and wounds. In view of possible clinical applications of AD-MSC-mediated cell therapy for DFUs, it is essential to evaluate the influence of DM on AD-MSC functions. Nevertheless, there are conflicting results about the effects of DAAD-MSCs on accelerating wound healing in animals and DM patients. Multistep research of the MEDLINE, PubMed, Embase, Clinicaltrials.gov, Scopus database, and Cochrane databases was conducted for abstracts and full-text scientific papers published between 2000 and 2020. Finally, 5 articles confirmed that the usage of allogeneic or autologous AD-MSCs had encouraging outcomes on diabetic wound healing. One study reported that DM changes AD-MSC function and therapeutic potential, and one article recommended that the pretreatment of diabetic allogeneic adipose-derived mesenchymal stem cells (DAlD-MSCs) was more effective in accelerating diabetic wound healing. Recently, much work has concentrated on evolving innovative healing tactics for hastening the repair of DFUs. While DM alters the intrinsic properties of AD-MSCs and impairs their function, one animal study showed that the pretreatment of DAlD-MSCs in vitro significantly increased the function of DAlD-MSCs compared with DAlD-MSCs without any treatment. Preconditioning diabetic AD-MSCs with pretreatment agents like photobiomodulation (PBM) significantly hastened healing in delayed-healing wounds. It is suggested that further animal and human studies be conducted in order to provide more documentation. Hopefully, these outcomes will help the use of DAAD-MSCs plus PBM as a routine treatment protocol for healing severe DFUs in DM patients.