An overview of CCN4 (WISP1) role in human diseases.

CCN4 (cellular communication network factor 4), a highly conserved, secreted cysteine-rich matricellular protein is emerging as a key player in the development and progression of numerous disease pathologies, including cancer, fibrosis, metabolic and inflammatory disorders. Over the past two decades, extensive research on CCN4 and its family members uncovered their diverse cellular mechanisms and biological functions, including but not limited to cell proliferation, migration, invasion, angiogenesis, wound healing, repair, and apoptosis. Recent studies have demonstrated that aberrant CCN4 expression and/or associated downstream signaling is key to a vast array of pathophysiological etiology, suggesting that CCN4 could be utilized not only as a non-invasive diagnostic or prognostic marker, but also as a promising therapeutic target. The cognate receptor of CCN4 remains elusive till date, which limits understanding of the mechanistic insights on CCN4 driven disease pathologies. However, as therapeutic agents directed against CCN4 begin to make their way into the clinic, that may start to change. Also, the pathophysiological significance of CCN4 remains underexplored, hence further research is needed to shed more light on its disease and/or tissue specific functions to better understand its clinical translational benefit. This review highlights the compelling evidence of overlapping and/or diverse functional and mechanisms regulated by CCN4, in addition to addressing the challenges, study limitations and knowledge gaps on CCN4 biology and its therapeutic potential.

Alkaliphilic and thermostable lipase production by leaf litter fungus Leptosphaerulina trifolii A SMR-2011.

Fungi that inhabit fire-prone forests have to be adapted to harsh conditions and fungi affiliated to Ascomycota recovered from foliar litter samples were used for bioprospecting of molecules such as enzymes. Agni's fungi isolated from leaf litter, whose spores are capable of tolerating 110 oC were screened for thermostable lipases. One of the isolates, Leptosphaerulina trifolii A SMR-2011 exhibited high positive lipase activity than other isolates while screening through agar plate assay using Tween 20 in the medium. Maximum lipase activity (173.2 U/mg) of L. trifolii was observed at six days of inoculation and decreased thereafter. Among different oils used, the maximum lipase activity was attained by soybean oil (940.1 U/mg) followed by sunflower oil (917.1 U/mg), and then by mustard oil (884.8 U/mg), showing its specificity towards unsaturated fatty acids. Among the various organic nitrogen sources tested, soybean meal showed maximum lipase activity (985.4 U/mg). The partially purified enzyme was active over a wide range of pH from 8 to 12 with a pH optimum of 11.0 (728.1 U/mg) and a temperature range of 60-80 oC with an optimal temperature of 70 oC (779.1 U/mg). The results showed that lipase produced by L. trifolii is alkali stable and retained 85% of its activity at pH 11.0. This enzyme also showed high thermal stability retaining more than 50% of activity when incubated at 60 oC to 90 °C for 2 h. The ions Ca2+ and Mn2+ induced the lipase activity, while Cu2+ and Zn2+ ions lowered the activity compared to control. These results suggests that the leaf litter fungus L. trifolii serves as a potential source for the production of alkali-tolerant and thermostable lipase.

The Skeletal Muscle Relaxer Cyclobenzaprine Is a Potent Non-Competitive Antagonist of Histamine H1 Receptors.

Cyclobenzaprine is a tricyclic dimethylpropanamine skeletal muscle relaxant, which is used clinically to decrease muscle spasm and hypercontractility, as well as acute musculoskeletal pain. Although the absolute mechanism of action of cyclobenzaprine remains elusive, it is known to mediate its effects centrally via inhibition of tonic somatic motor function, likely through modulation of noradrenergic and serotonergic systems. While cyclobenzaprine is effective as a muscle relaxant, greater than 30% of patients experience drowsiness and sedative-hypnotic effects, yet the mechanisms that cause this adverse effect are also undescribed. Based on this common adverse effect profile and the structural similarity of cyclobenzaprine to tricyclic antidepressants, as well as ethanolamine first-generation antihistamines, we hypothesized that cyclobenzaprine facilitates sedative effects via off-target antagonism of central histamine H1 receptors (H1Rs). Here, for the first time, we present data that demonstrate that cyclobenzaprine exhibits low nanomolar affinity for the cloned human H1R, as well as that expressed in both rat and mouse brain. Using saturation radioligand binding, we also demonstrate that cyclobenzaprine binds to the H1R in a noncompetitive manner. Similarly, functional assays measuring both Ca+2 influx and novel TRUPATH G-protein subunit bioluminescence resonance energy transfer biosensors reveal that cyclobenzaprine also blocks histamine-mediated H1R functional activity in a noncompetitive manner, whereas the classical H1R antagonist diphenhydramine does so competitively. Given that cyclobenzaprine readily crosses the blood-brain barrier and its muscle relaxant effects occur centrally, our data suggest that off-target central antagonism of H1R by cyclobenzaprine facilitates the significant sedative effect of this agent seen in patients. SIGNIFICANCE STATEMENT: Cyclobenzaprine, a clinically used muscle relaxant that is strongly linked to sedation, demonstrates high-affinity noncompetitive antagonism at the histamine H1 receptor. This effect likely modulates the high degree of sedation that patients experience.

Dynamic Phosphorylation of miRNA Biogenesis Factor HYL1 by MPK3 Involving Nuclear-Cytoplasmic Shuttling and Protein Stability in Arabidopsis.

MicroRNAs (miRNAs) are one of the prime regulators of gene expression. The recruitment of hyponastic leaves 1 (HYL1), a double-stranded RNA binding protein also termed as DRB1, to the microprocessor complex is crucial for accurate primary-miRNA (pri-miRNA) processing and the accumulation of mature miRNA in Arabidopsis thaliana. In the present study, we investigated the role of the MAP kinase-mediated phosphorylation of AtHYL1 and its sub-cellular activity. AtMPK3 specifically phosphorylates AtHYL1 at the evolutionarily conserved serine-42 present at the N-terminal regions and plays an important role in its nuclear-cytosolic shuttling. Additionally, we identified that AtHYL1 is cleaved by trypsin-like proteases into an N-terminal fragment, which renders its subcellular activities. We, for the first time, report that the dimerization of AtHYL1 not only takes place in the nucleus, but also in the cytosol, and the C-terminal of AtHYL1 has a role in regulating its stability, as well as its subcellular localization. AtHYL1 is hyper-phosphorylated in mpk3 mutants, leading to higher stability and reduced degradation. Our data show that AtMPK3 is a negative regulator of AtHYL1 protein stability and that the AtMPK3-induced phosphorylation of AtHYL1 leads to its protein degradation.

Characterization of different parts of litchi fruit using UHPLC-QExactive Orbitrap.

Litchi fruit is consumed across the globe for its high nutritional value and taste. The qualitative profiling of litchi fruit has been carried out by using ultra-high-performance liquid chromatography with QExactive high-resolution accurate mass spectrometry. Acidified water: methanol: acetonitrile (1:1:1) extracts from individual parts (skin, pulp, and seed) of matured litchi, were subjected to LC-MS analysis with electrospray ionization in full MS-ddMS2 mode as a non-target approach. The data was processed through compound discoverer software by the use of mzCloud and ChemSpider databases, for compound identification. We identified 77 compounds with protonated or deprotonated forms based on the polarity and their characteristic fragments are within ± 4 ppm mass error and retention time ± 0.1 min for parent and fragments. Hypoglycin B is the first time reported in litchi fruit along with hypoglycin A. Further, we verified the distribution of the identified components and differentiation of three different parts of litchi through principal component analysis. Supplementary Information: The online version contains supplementary material available at 10.1007/s13197-022-05577-z.

Aggregation-Induced Enhanced Emission-Active Zinc(II) ß-Diketiminate Complexes Enabling High-Performance Solution-Processable OLEDs.

Earth-abundant and cheaper zinc-based organometallic molecules as luminophores are drawing significant research attention for solid-state lighting devices. In this paper, we report two air-stable zinc complexes, where the zinc is coordinated to two sterically encumbered ß-diketiminate ligands in a tetrahedral geometry. In such a geometry, eight phenyl/aryl rings from the ligand backbones are oriented in a propeller shape, augmenting the restricted rotation of the putative rings. Such an architecture harnesses aggregation-induced emission behavior with an excellent solid-state emission property. The rigidity of these molecules reduces the possibility of non-radiative transitions and makes them excellent fluorescence emitters. Both molecules exhibit electroluminescence (EL) in the yellowish-green region of the visible spectrum. We have utilized these molecules as emitters to fabricate multilayered organic light-emitting diode (OLED) devices. The emitter Zn-I in host m-MTDATA exhibits EL with a maximum external quantum efficiency of 4.4%. Among the handful of zinc-based OLEDs, the performance of this emitter is very commendable with power and current efficacies of 15.2 lm W-1 and 12.1 cd A-1, respectively, along with a brightness of 2426 cd m-2.

Iris clues in ACG.

Primary angle closure glaucoma is a major cause of visual morbidity in Asia, which hosts 80% of the worldwide cases. In India, primary angle closure glaucoma (PACG) comprises almost 50% of adult glaucomas in hospital setting with its asymptomatic presentation predominating at 80%. Early diagnosis is critical to prevent the blinding trajectory of this disease, which is purported to cause twice as much blindness compared to open angle glaucoma. Traditional screening methods to identify PACG range from van Herick and flashlight test (relatively poor predictors) to gonioscopy (gold standard). Altered iris morphology are intrinsic to PACG, resulting in specific iris patterns. Iris appraisal could emerge as a method to screen underlying PACG. This would not only be specific, objective, but also easily performed at the peripheral level by a trained personnel and used in the era of tele-medicine for mass screening by AI softwares. This article seeks to detail these iris changes.

Carboxy-Terminal Phosphoregulation of the Long Splice Isoform of Free-Fatty Acid Receptor-4 Mediates ß-Arrestin Recruitment and Signaling to ERK1/2.

Free-fatty acid receptor-4 (FFA4), previously termed GPR120, is a G protein-coupled receptor (GPCR) for medium and long-chained fatty acids, agonism of which can regulate a myriad of metabolic, sensory, inflammatory, and proliferatory signals. Two alternative splice isoforms of FFA4 exist that differ by the presence of an additional 16 amino acids in the longer (FFA4-L) transcript, which has been suggested to be an intrinsically ß-arrestin-biased GPCR. Although the shorter isoform (FFA4-S) has been studied more extensively, very little is known about mechanisms of regulation or signaling of the longer isoform. Because ß-arrestin recruitment is dependent on receptor phosphorylation, in the current study, we used the endogenous agonist docosahexaenoic acid (DHA) to examine the mechanisms of FFA4-L phosphorylation, as well as DHA-dependent ß-arrestin recruitment and DHA-dependent extracellular-signal regulated kinase-1/2 (ERK1/2) signaling in human embryonic kidney 293 cells. Our results reveal differences in basal phosphorylation of the two FFA4 isoforms, and we show that DHA-mediated phosphorylation of FFA4-L is primarily regulated by G protein-coupled receptor kinase 6, whereas protein kinase-C can also contribute to agonist-induced and heterologous phosphorylation. Moreover, our data demonstrate that FFA4-L phosphorylation occurs on the distal C terminus and is directly responsible for recruitment and interactions with ß-arrestin-2. Finally, using CRISPR/Cas9 genome-edited cells, our data reveal that unlike FFA4-S, the longer isoform is unable to facilitate phosphorylation of ERK1/2 in cells that are devoid of ß-arrestin-1/2. Together, these results are the first to demonstrate phosphoregulation of FFA4-L as well as the effects of loss of phosphorylation sites on ß-arrestin recruitment and ERK1/2 activation. SIGNIFICANCE STATEMENT: Free-fatty acid receptor-4 (FFA4) is a cell-surface G protein-coupled receptor for medium and long-chained fatty acids that can be expressed as distinct short (FFA4-S) or long (FFA4-L) isoforms. Although much is known about FFA4-S, the longer isoform remains virtually unstudied. Here, we reveal the mechanisms of docosahexaenoic acid-induced phosphorylation of FFA4-L and subsequent ß-arrestin-2 recruitment and extracellular-signal regulated kinase-1/2 activity.

Alterations in contact lens fitting parameters following cross-linking in keratoconus patients of Indian ethnicity.

BACKGROUND: Most studies have either excluded patients using contact lens or not taken their effect while analyzing post-collagen cross-linkage (CXL) changes. This study aims to study impact of CXL on lens fit in both quantitative and qualitative manner. OBJECTIVE: To evaluate changes in CL fit post-CXL and to correlate these changes with alterations in corneal topographic parameters. STUDY DESIGN: Prospective intervention study on 20 keratoconic eyes of 14 patients (age > 18 years), with mean follow-up of 6 months. METHODS: Preoperative evaluation included UCVA, BCVA, corneal topography, AS-OCT and contact lens fit. Patients were evaluated at 2 weeks, 1, 3, 4 and 6 months post-CXL; contact lens trial with standard rigid gas permeable (RGP) lens performed at 3 and 6 months. MAIN OUTCOME MEASURE: Changes in objective and subjective parameters of lens fit. RESULTS: Over 6-month follow-up post-CXL, improvement in visual acuity by one Snellen line, both UCVA and BCVA, and decrease in flat/mean/apical K by 0.8 D, 0.8 D and 1.3 D, respectively, resulted in significant improvement in RGPCL fit. Almost 20% increase in near-ideal fit, 100% acceptable fit, 65% improved subjective comfort with 8 h/day increase in duration of comfortable CL wear were observed. CONCLUSION: Despite no statistically significant change in objective parameters of lens fit, a tendency for flatter lens fit along with contact lens induced further flattening of the ectatic cornea which resulted in marked improvement in both objective and subjective contact lens fit.

Diode laser cyclophotocoagulation in Indian eyes: efficacy and safety.

Diode laser cyclophotocoagulation (DLCP) has emerged as a time-tested procedure for end-stage glaucoma with fewer complications. By means of this study, we have evaluated its wide indications, its efficacy, and safety in darkly pigmented Asian Indian eyes. Ninety-one eyes with uncontrolled glaucoma presenting to glaucoma clinic of a tertiary care center over a period of 6 years were scheduled for DLCP. The semiconductor diode laser with a G probe was used with laser energy delivered about 1.5 mm behind the surgical limbus. The extent of clock hours of laser application was determined by pretreatment intraocular pressure (IOP) and superior area was spared in cases where future filtration surgery was contemplated. The DLCP was repeated earliest at 1 month in case of non-response and a maximum of three laser procedures were performed for any patient. Ninety-one eyes of 89 patients (40 males, 49 females) were included. Common indications included secondary glaucoma (37.3 %), failed trabeculectomies (27.4 %), angle closure glaucoma (17.5 %), etc. Laser power delivered ranged from 990 to 1800 mW, (mean 1396 + 182.14 mW) with an average of 17 spots. Patients improved from pretreatment IOP of 38.18 + 8.96 mmHg (range 20.6-64) to post treatment IOP of 17.86 + 7.75 mmHg (range 10-42). Qualified success was defined as final IOP of 20 mm Hg or less on topical medications that could be achieved in 70 % eyes with one or repeat treatment. Pre op visual acuity ranged from PL+ to 6/18 showing a slight improvement to PL+ to 6/12 post op. A 58.5 % reduction of IOP was noted. No incidence of serious complications was noted during follow-up ranging from 9 months to 3 years. DLCP is an effective and safe tool to be used in Indian population for control of IOP. It can be safely used as a primary modality to bring IOP to permissible levels before trabeculectomy.

Diode laser cyclophotocoagulation paves way to a safer trabeculectomy in eyes with medically uncontrollable intraocular pressure.

High intraocular pressure (IOP) not responding to systemic and topical anti-glaucoma medications renders the eye at risk for both intra- and post-operative complications of glaucoma filtration surgery. Laser cyclophotocoagulation is able to lower IOP in such refractory glaucoma eyes and may make the surgical event safer. This study assessed diode laser cyclophotocoagulation (DLCP) when used as a temporary measure for lowering IOP prior to performing trabeculectomy. This study is a  retrospective analysis of cases planned for trabeculectomy surgery, uncontrolled on maximally tolerable systemic anti-glaucoma medications. They were analysed for response to DLCP in terms of IOP control, vision-related complications, increased inflammation, post-trabeculectomy hypotony and chances of phthisis and ciliary shutdown. Twelve eyes of ten patients aged 35-65 years were identified and all followed up for at least 2 years. One week following DLCP, the IOP (mean ± SD) declined by 51 % from 46.8 ± 5.4 to 22.8 ± 3.3 mmHg. The IOP was further reduced to 15.4 ± 2.7 mmHg at 4 weeks after trabeculectomy; it remained in the mid-teens for a minimum of 2 years in all cases. The mean (±SD) visual acuity improved from 1.4 ± 0.4 to 0.8 ± 0.4 LogMAR equivalents following trabeculectomy. In four eyes, phacoemulsification was performed 5-7 months after trabeculectomy with improvement in best-corrected visual acuity. One patient developed transient hypotony, post-trabeculectomy, which resolved by 6 days. There were no other complications like increased inflammation, prolonged hypotony or suprachoroidal haemorrhage. DLCP is, thus, effective and safe for temporarily controlling IOP; thereby trabeculectomy can be performed in a quieter ocular milieu.

Reduced ocular blood flow in asymmetric glaucoma: cause or effect?

Carotid Doppler measures blood flow velocity and vascular resistance index in the central retinal arteries and short posterior ciliary arteries. The blood flow profile of the optic nerve in chronic angle-closure glaucoma (CACG), however, has not been well documented. We report a 48-year-old female patient who presented with grossly asymmetric CACG and was evaluated by carotid Doppler. The patient had coexistent reduced blood flow in the ophthalmic artery of the more afflicted eye. Color Doppler imaging clarifies hemodynamic alterations in the glaucomatous optic nerve and helps to identify vascular aspects of the disease and its treatment.

Purtscher's retinopathy in pre-eclampsia: a blinding combination.

Blindness in pregnancy can occur due to cortical infarcts, retinal vascular occlusions and retinal detachment. Purtscher's retinopathy is a rare entity causing visual loss during pregnancy and has so far been reported in association with complicated labor. We report here on a case of Purtscher's retinopathy leading to bilateral blindness in a pre-eclamptic multigravida after an uncomplicated spontaneous delivery. The patient had no visual recovery after 3 months postpartum. Poorly controlled pregnancy-induced hypertension coupled with the hypercoagulable state of pregnancy probably led to a compromised optic nerve microvasculature and loss of retinal autoregulation. Subsequently the acute event of parturition triggered a complement-mediated leucocyte embolization to this already compromised microvasculature resulting in Purtscher's retinopathy.

Phacoemulsification in angle-closure glaucoma: A 360° evaluation.

PURPOSE: To evaluate the effect of phacoemulsification on intraocular pressure (IOP) and anterior chamber angle (ACA) morphology in primary angle-closure glaucoma (PACG). SETTING AND DESIGN: A hospital-based, prospective pre- and post-interventional study was carried out in 40 PAC and PACG eyes post patent PI with visually significant cataracts. METHODS: All patients underwent phacoemulsification and were evaluated for IOP control, ACA widening, and disease progression for a minimum of 6 months. Failure was defined as an IOP of >21 mmHg necessitating another intervention, including trabeculectomy and/or an increase in the required number of antiglaucoma medications (AGMs) by >1. RESULTS: A highly statistically significant reduction of IOP (P < 0.0001) was seen with an overall reduction of 42.2% over 6 months and a mean reduction of 8.9 ± 3.59 mmHg, with the requirement of AGMs reducing from 39/40 patients preoperatively to 1/38 postoperatively. Success was seen in 95% of cases, with two patients not achieving target IOP and requiring trabeculectomy. Angle widening was documented in all cases by both gonioscopy and AS-OCT, and none of the patients showed any progression in disc damage and visual field changes. CONCLUSION: Early cataract surgery in ACG not only helps to control IOP and disease progression by widening angles and improving aqueous outflow but also improves visual acuity and reduces the economic burden of AGMs. It also helps in better evaluation of disease progression by both structural and functional analysis, as was documented by the improved and more reliable visual field indices.

Factors affecting adherence to glaucoma medication: Patient perspective from North India.

PURPOSE: Adherence to glaucoma medical therapy is a key factor in achieving target intraocular pressure to prevent glaucoma progression. To determine factors affecting medication adherence in glaucoma patients in an urban population belonging to poor socioeconomic status. METHODS: A cross-sectional study was conducted on 200 patients attending glaucoma services in a tertiary referral hospital of North India. Adherence to medication was determined subjectively by questionnaire and objectively by counting the number of used bottles at the end of a month or during refill, whichever was earlier. Patient-related parameters in adherence toward glaucoma medication were studied based on demography, knowledge, attitudes, and practices (KAP). The statistical techniques of bivariate and multivariate logistic regression were adopted to test the objective. RESULTS: The population was statistically homogeneous based on gender and income in both groups. A large proportion of patients had bilateral disease (87%) and were on two or more medications (62.5%). Adherence to glaucoma medical therapy was seen in 68% of patients, with knowledge about glaucoma present in 58% of patients. Deterrents to drug adherence were identified as forgetfulness (71%), unavailability of drugs (19%) or funds to purchase the same (26%), polypharmacy (21%), and side effects (5%). Dependence on an escort by 44% and dependence on hospital supply of medications by 60% emerged as the contextual factors requiring scrutiny while prescribing lifelong glaucoma medications. Disease misconceptions (53%) were prevalent and drug instillation practices were unsatisfactory (57%). CONCLUSION: The study offers insight into patients' perspectives regarding the lifetime use of antiglaucoma medications and focuses on key issues linked to drug nonadherence.